Cur rent Ap pli ca tions of Deep Brain Stim u la tion for Treat ment of Neu ro log i cal and Psy chi at ric Disorders

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1 Apþvalginiai moksliniai straipsniai Cur rent Ap pli ca tions of Deep Brain Stim u la tion for Treat ment of Neu ro log i cal and Psy chi at ric Disorders R. Juðkys* R. Mameniðkienë** *Faculty of Medicine, Vilnius University, Vilnius, Lithuania **De part ment of Neu rol ogy and Neu ro sur gery, Cen ter for Neurology, Vilnius University, Vilnius, Lith u a nia Summary. Deep Brain Stim u la tion (DBS) seems to be an ef fec tive and min i mally in va sive sur gi cal treat ment for a variety of neurological and psychiatric disorders. In comparison to early sur gi cal lesioning pro ce dures, DBS has a con sid er ably lower ad verse ef fect rate and is usu ally re vers ible, mak ing this pro ce dure very at trac tive. De spite the clin i cal suc cess of DBS, the ex act ther a peu tic mech a nism re mains un der ac tive de bate. Cur rent clin i cal tri als fo cus on iden ti fication of alternative targets, establishing new indications and capturing elec - tri cal biomarkers during DBS in order to improve individual stimulation parameters. In this ar ti cle we pro vide a comprehensive review of DBS focusing on movement, psychiatric and ictal dis or ders, including the historical evolution of the technique, applications and outcomes with an over view of the most per ti nent lit er a ture, cur rent views on mech a nisms of stim u la - tion and de scrip tion of hard ware and pro gram ming tech niques. Fi nally, we con clude with a dis cus sion of potential future applications of neurostimulation and currently active topics of research. Keywords: deep brain stim u la tion, Par kin son dis ease, tremor, dystonia, de pres sion, Tourette syn drome, obsessive-compulsive disorder, epilepsy, treatment. Neurologijos seminarai 2017; 21(74): IN TRO DUC TION Deep brain stim u la tion (DBS) is a sur gi cal pro ce dure that involves unilateral or bilateral implantation of electrodes in a spe cific area of the brain. Elec trodes are con nected to wires which de liver a very fine elec tri cal cur rent to those re gions in the brain from the gen er a tor placed in fe ri orly to the clav i cle, un der the skin. Af ter re cov ery of the pro ce - dure, generators are activated and electrical parameters in - clud ing pulse widths, cur rent am pli tudes and pat terns of stim u la tion are tuned in di vid u ally for each pa tient, hence de sired clin i cal ef fect can be achieved. DBS in fact is an evo lu tion of func tional stereotactic neu ro sur gery tech - niques, ini tially used to pro duce se lec tive le sions of spe - cific deep brain struc tures. For merly, intra-op er a tive elec - trical stimulation of these targets was systematically used for the ex plo ra tion and the lo cal iza tion of the deep ce re bral nu clei and for tar get con fir ma tion, but these ob ser va tions led to suggestion that electrical stimulation method could Ad dress: Raimondas Juðkys Fac ulty of Med i cine, Vilnius Uni ver sity M. K. Èiurlionio str. 21, LT Vilnius raimondas.juskys@gmail.com not only be used for di ag nos tic pur poses but also as a ther a - peu tic method it self [1]. DBS is ap plied to a wide range of neu ro log i cal and psy chi at ric dis or ders, in clud ing Par kin - son s dis ease, es sen tial tremor, dystonia, ob ses sive- com - pul sive dis or der, treat ment-re sis tant de pres sion, Tourette syn drome, and ep i lepsy [2, 3]. The ex act phys i o log i cal mech a nism of DBS re mains un known. Cur rent the o ries in - clude in hi bi tion, ex ci ta tion or dis rup tion the ory but to this day it is known that stim u la tion of cer tain groups of neu - rons in the brain stops patho log i cal pat tern of neuronal ac - tiv ity [4]. DBS is con tra in di cated for pa tients who have in - abil ity to op er ate the de vice or if test stim u la tion was un - suc cess ful. There is a po ten tial for neu ro psy chi at ric sideef fects in clud ing de pres sion, cog ni tive dys func tion, ap a - thy, hal lu ci na tions or eu pho ria, but usu ally it is a con se - quence of poorly cal i brated stim u la tion pat tern or wrong site of implantation [5]. Additional limitations of DBS ther apy that need to be con sid ered prior to the sur gery in - clude risk for intracranial hem or rhage (in ap prox i mately 3% of all cases), elec trode mis place ment (in up to 2%), elec trode mi gra tion (up to 1.7%) and elec trode lead in fec - tion (1 to 8%) [3]. None the less, prin ci pal fea ture of DBS at trac tive ness is that in case of un de sired side ef fects it can be re versed at any time dur ing the pe riod of ap pli ca tion, bring ing pa tient back to pre-op er a tional con di tion. 201

2 R. Juðkys, R. Mameniðkienë MECH A NISM OF DBS Al though an ef fec tive sur gi cal ther apy for neu ro log i cal and psy chi at ric dis or ders, the mech a nism of ac tion of DBS con tin ues to be de bated. The ear li est hy poth e ses on DBS mech a nisms pro posed that high-fre quency stim u la tion in - hib its neu rons and de creases out put from the stim u lated site. In hi bi tion of ac tiv ity was ini tially ob served in rat STN DBS and sim i lar find ings were rep li cated in hu mans and mon keys with ei ther STN or GPI stim u la tion [6, 7]. It was hy poth es ised that the un der ly ing in hib i tory mech a nism was an ac ti va tion of presynaptic in hib i tory afferents. Sim i - lar find ings were seen with in hib i tory efferents. GPI stim u - la tion in hib ited thalamic neu rons in nor mal mon keys and pa tients with dystonia, and ex ter nal glo bus pallidus stim u - la tion in hib ited STN neu rons [8, 9]. Hu man pos i tron emis - sion to mog ra phy stud ies showed an in crease in blood flow in the re gion of the GPI dur ing STN DBS and an in crease in cor ti cal blood flow dur ing thalamic DBS, both con sis tent with ac ti va tion of out put from the stim u lated site [10, 11]. Sim i larly, a func tional mag netic res o nance im ag ing study showed an in crease of blood ox y gen level de pend ent sig - nal in the GPI of pa tients un der go ing STN DBS [12]. Re - cent stud ies have shown that DBS-in duced reg u lar iza tion of basal gan glia in put into the thalamus re stores the re - spon sive ness of thalamocortical cells to the in com ing sensorimotor in for ma tion, re sult ing in im proved mo tor func tion. This sug gests that in for ma tion pro cess ing is en - hanced and DBS is as so ci ated with im proved in for ma tion con tent in the net work [13]. Also, stim u la tion of the STN can activate nigrostriatal (increasing release of dopamine), pallidothalamic, cerebellothalamic, and pallidonigral fi ber tracts, all of which could con trib ute to the ther a peu tic ef - fects of DBS [14]. So, DBS in creases out put from the stim - u lated nu cleus and ac ti vates sur round ing fi ber path ways re sult ing in a com plex pat tern of ex cit atory and in hib i tory ef fects that mod u late the en tire basal gan glia- thalamo - cortical net work. The stim u la tion-in duced reg u lar iza tion of neuronal pat terns pre vents trans mis sion of patho logic burst ing and os cil la tory ac tiv ity within the net work, re sult - ing in im proved pro cess ing of sensorimotor in for ma tion and re duc tion of dis ease symp toms. AP PLI CA TION OF DBS FOR PAR KIN SON S DIS EASE One of the pri mary clin i cal uses of DBS is for the treat ment of Par kin son s dis ease (PD). PD is a pro gres sive neurode - generative dis or der char ac ter ized by tremor at rest, ri gid - ity, bradykinesia, stooped pos ture, loss of pos tural re flexes and shuf fling gait. Pathophysiology of PD could be char - ac ter ised as prom i nent de gen er a tion of dopaminergic neu - rons in sub stan tia nigra pars compacta and the con se quent de fi ciency of do pa mine in brain ar eas that re ceive dopaminergic in puts from those neu rons, spe cif i cally the post- commissural putamen and caudate nu cleus. Loss of dopaminergic cells in sub stan tia nigra causes fail ure of basal gan glia s di rect path way to suc cess fully in hibit glo - bus pallidus internus and this leads to over in hi bi tion of thalamus and thalamocortical path way [15]. Con ven tional treat ment for Par kin son s Dis ease symp toms in clude Levodopa, COMT in hib i tors, do pa mine ag o nist and other med i ca tion, but long-term use of these pharmaceuticals leads to drug-in duced mo tor com pli ca tions. A pow er ful mo tor re sponse to Levodopa is gen er ally con sid ered as es - sen tial for suc cess ful DBS out come (ex cept for tremorpre dom i nant form), and stim u la tion may be con sid ered when pa tients de velop mo tor fluc tu a tions and dyskinesias. Stud ies of DBS for PD have re ported sig nif i cant im prove - ment in car di nal mo tor signs, in clud ing tremor, brady - kinesia, and ri gid ity, and vari able re sponse in med i ca tionre frac tory gait freez ing, pos tural in sta bil ity, and gait me - chan ics. Also, marked ben e fits in im prove ment of levodopa- re lated com pli ca tions such as drug-in duced dyskinesia, mo tor fluc tu a tions and off-pe riod dystonia have been dem on strated [16]. DBS for PD at this day is mainly ap plied to two parts of basal gan glia: subthalamic nu clei (STN) and glo bus pallidus internus (GPI). Elec trode place ment in the STN was ini tially fa voured be cause of re - ports that it yielded greater im prove ment in mo tor scores and a greater re duc tion in antiparkinsonian mediations com pared with place ment in the GPI [17]. Ad di tional stud - ies have shown that GPI DBS also sig nif i cantly im proved the car di nal mo tor symp toms, drug-in duced dyskinesia, and mo tor fluc tu a tions [18]. Al though STN re mains the pre ferred tar get, GPI can be con sid ered in pa tients who have speech, cog ni tive, and mood dis tur bances, as STN DBS can some times worsen these symp toms [19]. In study of 299 ran domly as signed pa tients (152 pallidal and 147 subthalamic), deep-brain stim u la tion im proved mo tor func tion in pa tients with Par kin son s dis ease who un der - went ei ther pallidal or subthalamic stim u la tion, with no significant difference between the two surgical targets during 24 months of fol low-up [20]. DBS treat ment both in long and short term is su pe rior to the con ven tional treat - ment op tions in pa tients with ad vanced PD [21]. AP PLI CA TION OF DBS FOR TREMOR DBS is an attractive alternative to conventional treatment for the man age ment of tremor. Es sen tial tremor is mainly treated with antiepileptic Primidone or beta blocker Propranolol. Both med i cines im prove con di tion in 50 70% of pa tients, but their use is lim ited be cause of ad - verse ef fects that in clude se da tion, diz zi ness, ataxia (for Primidone) and bradychardia, bronchospasms and hypo - tension (for Propranolol) [22]. In com par i son to phar ma - ceu ti cal ap proach, DBS shows better re sults but it is not so sig nif i cant to state that ei ther method is su pe rior to each other [23]. Sur gi cal ab la tion of the ven tral in ter me di ate nu - cleus of the thalamus (VIN) has been used as a ther apy for tremor since the 1950s [24]. Both bi lat eral and uni lat eral 202

3 Cur rent Ap pli ca tions of Deep Brain Stimulation for Treatment of Neurological and Psychiatric Disorders DBS of VIN in study of 34 in di vid u als showed a sig nif i - cant long term (up to 7 years) im prove ment of symp toms in >80% of pa tients [25]. Bi lat eral VIN stim u la tion shows slightly better out comes, es pe cially man ag ing head and voice tremor [3]. How ever, bi lat eral thalamotomy is not well tol er ated be cause of the risk of speech and swal low ing def i cits. Thalamic DBS has been shown to be ef fi ca cious in the treat ment of es sen tial and parkinsonian tremor, with an ex cel lent long-term out comes and an ac cept able ad - verse ef fect pro file. The main side ef fects of the stim u la - tion were paresthesias, head ache, dysarthria, pa re sis, gait dis tur bance, and ataxia but these ad verse re ac tions are usu - ally mild and ef fec tively man aged by stim u la tion pa ram e - ter ad just ment [26]. Deep brain stim u la tion and thalamo - tomy have also been used with less suc cess in the treat ment of ac tion tremor. This type of tremor typ i cally oc curs in pa - tients with mul ti ple scle ro sis, trauma, or stroke that leads to in ter rup tion of cer e bel lar out flow path ways and has a more com plex pathophysiology [27]. Clin i cal im prove - ment in these pa tients is of ten short lived and, in the case of mul ti ple scle ro sis, com pli cated by dis ease pro gres sion [28]. Al though treat ment for tremor tar gets the ven tral in - ter me di ate nu cleus, sev eral stud ies have sug gested that the pos te rior subthalamic area is a better lo ca tion and that pa - tients may be in ci den tally ben e fit ing from elec trode con - tacts lo cated out side of the thalamus [29]. Over all, DBS for es sen tial and parkinsonian tremor has been suc cess ful, while treat ment of other causes of tremor has been more limited. both re spond better to stim u la tion than sec ond ary dystonia [34]. Un like tremor and PD, there is typ i cally a grad u ally in creas ing clin i cal re sponse to stim u la tion over weeks to months of ther apy. Ef fi cacy of DBS in pri mary gen er al - ized and seg men tal dystonia has been well doc u mented [35]. Op ti mal site of im plan ta tion at this day is thought to be glo bus pallidus internus [32, 35]. Pallidal neurostimula - tion study of 22 adult pa tients showed sig nif i cant im prove - ment in pri mary dystonia in volv ing neck, trunk and limbs, but fa cial and speech as pects of dis ease were not af fected [32]. The same 22 sub jects were re-eval u ated af ter 3 years and re sults showed sus tained mo tor ben e fit of in ter ven tion [36]. Other study of 40 adult sub jects, who were split into 2 groups of 20 peo ple (one group re ceiv ing pallidal stim u - la tion and other sham stim u la tion) showed sig nif i cantly better out comes in pa tients re ceiv ing neurostimulation, nev er the less sham group af ter 3 months was as signed to neurostimulation and showed sim i lar pos i tive re sults in a 6 months fol low-up [35]. Also, a ben e fi cial ef fect of bi lat - eral stim u la tion of the GPI has been re ported in chil dren with pri mary gen er al ized dystonia, how ever, there has been no dif fer ence in out comes based on DYT1 gene sta tus but shorter dis ease du ra tion has been re lated to better re - sults [37, 38]. In ad di tion, in trac ta ble cer vi cal dystonia has also shown im prove ment in sev eral smaller case se ries [39]. On the other hand, sec ond ary dystonia is a set of heterogenous dis or ders and their re sponse to neurostimu - lation is more vari able. For ex am ple, tardive dyskinesias typ i cally re spond well whereas dystonias sec ond ary to en - ceph a li tis or birth in jury fare worse [40]. AP PLI CA TION OF DBS FOR DYSTONIA DBS has also shown suc cess in treat ment of dystonia. Dystonia is a group of neu ro log i cal dis or ders de scribed by sus tained or in ter mit tent mus cle con trac tions caus ing twist ing and re pet i tive move ments that re sult in ab nor mal, of ten pain ful pos tures. Dystonia can be clas si fied ac cord - ing to eti ol ogy (pri mary or sec ond ary), lo ca tion af fected (gen er al ised or seg men tal) and time of on set (early or late) [30]. Pa tients with dystonia are thought to have mal func - tion ing con nec tions be tween subcortical and cor ti cal path - ways re sult ing in a re duced ac tiv ity of the glo bus pallidus internus of basal gan glia with al ready ob serv able re duc tion in ac tiv ity dur ing rest ing state. When move ment is at - tempted, the ef fer ent in hib it ing neu rons of the GPI fur ther re duce their ac tiv ity, lead ing to a disinhibition of the thalamus thus caus ing dystonic move ments [31]. Phar ma - ceutical treatment of dystonia with injections of botulinum toxin or anticholinergics is not al ways work ing and if drug ther apy is un sat is fac tory, sur gi cal ap proach with fa vour - able risk-ben e fit ra tio is worth in ves ti ga tion [32]. Re - newed in ter est in pallidotomy for PD in the early 1990s and the ob ser va tion that it im proved dystonic symp toms in PD led to the pro posal of us ing pallidotomy for pa tients with pri mary gen er al ized dystonia [33]. DBS could be ap plied for pri mary gen er al ised and seg men tal dystonia, which AP PLI CA TION OF DBS FOR OB SES SIVE-COM PUL SIVE DIS OR DER (OCD) Ob ses sive-com pul sive dis or der is char ac ter ised by in tru - sive thoughts or im ages (ob ses sions), which in crease anx i - ety, and by re pet i tive or rit u al is tic ac tions (com pul sions), which de crease anx i ety. OCD is linked with neurochemi - cal and neu ro ana tomi cal ab nor mal i ties in the brain. Struc - tur ally, basal gan glia (with in crease of grey mat ter) and orbitofrontal/cingulate cor tex (with de crease of grey mat - ter) are thought to be de fec tive caus ing cortico-striatalthalamic-cor ti cal path way dys func tion [41]. Seratonin sys tem seems to be in volved as well since the se lec tive se - rotonin reuptake inhibitors (SSRi) are the effective treat - ment for OCD [42]. Un like move ment dis or ders, patho - physiology of psy cho log i cal dis or ders is more com plex thus there are more po ten tial tar gets for DBS. Tra di tional treat ment of OCD in volves com bi na tion of med i ca tion and psychotherapy but in severe, treatment-resistant cases, neurostimulation can pro vide de sir able ef fects for the pa - tients. Pop u lar choices of DBS in clude: an te rior limb of in - ter nal cap sule, ven tral cap sule and ven tral striatum, nu - cleus accumbens, STN and in fe rior thalamic peduncle with all of them show ing prom is ing re sults there fore it is hard to ex clude su pe rior tar get [43]. 203

4 R. Juðkys, R. Mameniðkienë AP PLI CA TION OF DBS FOR TREAT MENT- RE SIS TANT MA JOR DE PRES SION Com bi na tion of ge net ics and en vi ron men tal fac tors, such as child hood trauma or al co hol abuse, plays a crit i cal role in de vel op ment of de pres sion [44]. Ma jor de pres sive dis - or der (MMD) is a med i cal con di tion that in cludes ab nor - mal i ties of mood and mo ti va tion, neurovegetative func - tions, cog ni tion, and psychomotor ac tiv ity that last lon - ger than 2 weeks [45]. Func tional mag netic res o nance im ag ing (fmri) stud ies showed that there is ab nor mal ac - tiv ity in the cingulate cor tex, ven tral striatum and dorso - medial or bital cor tex in pa tients with MMD [46, 47].Tra - di tional treat ment for de pres sion in volves med i ca tion, psy cho ther apy and electroconvulsive ther apy, but ap - prox i mately 20% of de pres sion cases are treat ment-re sis - tant [48]. In such cases, DBS could be ap plied as a next line treat ment op tion. As in OCD, there are few po ten tial tar gets for neuro stimulation, in clud ing: subgenual cingulate (Brodmann area 25), nu cleus accumbens and ven tral cap sule/ven tral striatum with all re gions re spond - ing with 50 80% of suc cess, subgenual cingulate seem - ing to be su pe rior in com par i son with other tar gets [49 51]. AP PLI CA TION OF DBS FOR TOURETTE SYN DROME Tourette syn drome (TS) is char ac ter ised by quick, nonrhyth mic move ments or vo cal iza tions which pa tient has lit tle or no con trol over, called tics. Rather than a dis tinct con di tion, TS is de fined as a part of spec trum of tics dis or - ders, be ing most se vere of them. Eti ol ogy of TS is un - known, it seems that ge netic fac tors play a key role while caus ing the dis or der, al though the ex act type of in her i - tance and caus ative genes have not yet been iden ti fied. Ad di tion ally, both pre na tal and postnatal en vi ron men tal in flu ences, such as ma ter nal smok ing/stress or cer tain in - fec tions, are more re lated to se ver ity of TS rather than be - ing caus ative fac tor [52]. Still pathophysiology re mains un cer tain, with most re cent hy poth e ses in volv ing dys - func tion of basal gan glia- cer e bel lar-thalamo-cor ti cal cir - cuit and striatal GABAergic net works, even tu ally lead ing to ex cess dopaminergic in put to striatum that causes un - de sir able disinhibition of thalamo-cor ti cal path ways, pro duc ing tics [53, 54]. While most of cases can be con - trolled by med i ca tion and/or be hav ioral ther apy, sub sets of them are treat ment- re sis tant and DBS is show ing prom is ing re sults for such pa tients. Re cent meta-anal y sis in volv ing 57 stud ies re port ing to tal of 162 par tic i pants showed mean 52.5% im prove ment ac cord ing to Yale Global Tics Se ver ity Scale (YGTSS) with more than 80% par tic i pants show ing >25% re duc tion of YGTSS score. Sev eral po ten tial stim u la tion tar gets ex ist and it is hard to ex clude the ideal one. From sys tem atic re view data, both post ero ventro lateral and anteromedial parts of glo bus pallidus internus dem on strated best av er age (58% and 55%, re spec tively) de crease in YGTSS grade, while thalamic nu clei (48%) and an te rior limb of in ter nal cap - sule/nu cleus accumbens (44%) neuro stimulation in di - cated slightly worse re sults [55]. Nev er the less, the pa tient num bers are too small to draw any con clud ing an swer, yet re gard ing the di lemma of ideal tar get and op ti mal re sults may be achieved by care fully as sess ing each in di vid ual case. AP PLI CA TION OF DBS FOR EP I LEPSY Con ven tional ep i lepsy treat ment is of ten based on daily use of antiepileptic drugs of which there are wide va ri ety of op tions avail able that have dif fer ent tar gets in the brain and the choice is based on spe cific needs of the pa tients, such as age, life style, other health prob lems and a cat e gory of ep i - lepsy syn drome. De spite med i ca tion, ep i lepsy sur gery, vagus nerve stim u la tion and ketogenic diet are also con sid - ered as a po ten tial treat ment op tions, but about 30% of ep i - lepsy cases are treat ment-re sis tant [56]. In such re frac tory ep i lepsy cases, DBS could be con sid ered as a next step in - ter ven tion. There are sev eral po ten tial tar gets for neuro - stimulation application, but anterior nuclei of thalamus (ANT) are most well in ves ti gated and show prom is ing re - sults. One prom i nent multicenter study in volv ing 110 par - ticipants with medically refractory partial seizures, includ - ing secondarily generalized seizures showed an average 40.4% re duc tion of sei zures fre quency af ter 3 months ran - dom ized, dou ble-blinded phase in com par i son with 14.5% re duc tion for pa tients re ceiv ing sham stim u la tion. Af ter blinded phase, all par tic i pants re ceived the stim u la tion and af ter 2 years there was a mean 56% re duc tion in sei zure fre - quency with 14 pa tients be ing sei zure-free for at least 6 months [57]. An other study in volv ing 15 pa tients with poorly controlled seizures assessed effectiveness of ANT stim u la tion with eval u a tion of prog ress in long-term and com pared the out come with pre vi ously de scribed trial. Re - sults of this study in di cated an av er age 70.4% re duc tion in fre quency of the sei zures with a mean to tal amount of fol - low- ups be ing 39 months since the start of stim u la tion. This sug gests that a short-term out come of ANT DBS di - rectly re flects long-term ef fec tive ness of the treat ment [58]. An te rior nu clei of thalamus are lo cated in a key junc - tion of Papez cir cuit which is be lieved to be in volved in propogation of sei zures while on the same hand an a tom i cal po si tion is rel a tively easy to reach with min i mal risk of sur - gi cal com pli ca tions fol low ing elec trodes im plan ta tion, mak ing it very at trac tive for DBS. An other po ten tial tar - gets for DBS ap pli ca tion for ep i lepsy in clude cer e bel lum, hip po cam pus, subthalamic nu cleus, caudate nu cleus, cor - pus cal lo sum and lo cus coeruleus, all of which showed im - prove ment re gard ing ep i lep tic sei zures con trol but fur ther in ves ti ga tion is nec es sary since pop u la tion of stud ies was very small [59]. 204

5 Cur rent Ap pli ca tions of Deep Brain Stimulation for Treatment of Neurological and Psychiatric Disorders FU TURE AP PLI CA TIONS OF DBS The po ten tials of the DBS for ther a peu tic use are fas ci nat - ing, but there are still many un re solved tech ni cal and eth i - cal prob lems, con cern ing the iden ti fi ca tion of the tar gets for each con di tion, the pa tient se lec tion and the eval u a tion of the re sults. Even though DBS is be com ing more and more pop u lar in clin i cal set ting, poor un der stand ing of phys i o log i cal and ther a peu tic mech a nism fol low ing neurostimulation re mains the main lim i ta tion in fur ther de - vel op ment of this tech nique. For tu nately, prom is ing at - tempts to ex plain these com plex pro cesses are be ing made. One study showed that DBS in PD not only af fects lo cal cir cuit of basal gan glia but also has dif fuse modulatory ef - fect on cor ti cal ac tiv ity by in flu enc ing phase-am pli tude cou pling (PAC) which is thought to be a com mu ni ca tion link be tween dif fer ent brain re gions and is re spon si ble for the co or di nated neuronal ac tiv ity in dif fer ent brain net - works. Dur ing ac tive stim u la tion of STN, PAC seemed to be re duced, sim i larly re duc ing parkinsonian mo tor signs, pro pos ing that DBS of the basal gan glia im proves cor ti cal func tion by sup press ing ex ces sive beta phase lock ing of pri mary mo tor cor tex neu rons [60]. In ter est ingly, these ab - nor mally ac tive neu rons could be used as elec tri cal biomarkers of the dis ease and iden ti fi ca tion of such ab nor - mal neuronal ac tiv ity by lo cal po ten tial re cord ing lead has opened the pos si bil ity for DBS de vices to de liver re spon - sive stim u la tion, in which the pa ram e ters of neurostimu - lation self-ad just as nec es sary in real-time based on re - corded elec tri cal biomarkers ac tiv ity. This adap tive DBS is ca pa ble of de liv er ing treat ment that can be in di vid u al ized based on pa tient and pa thol ogy sta tus, thus pro vid ing more efficient therapeutic benefit with smaller amount of ad - verse effects and increased battery longevity. Similarly, stimulator firmware improvement may facilitate delivery of dif fer ent pulses in dif fer ent pulse shapes which could fur ther im prove adap tive DBS ap pli ca tion in pa tient-per - son al ized ap proach [61]. To con tinue, fu ture DBS ap pli ca - tion should aim at the man age ment of symp toms that are dis abling and yet not treated ef fec tively us ing cur rent med - i cal and sur gi cal meth ods. Levodopa-re sis tant signs and symp toms such as gait and pos tural in sta bil ity, dif fer ent types of apha sia, de creased level of con scious ness and cog ni tive or af fec tive dys func tion are of par tic u lar im por - tance and fur ther ad vances in DBS may elim i nate cur rent limitations in treatment of these debilitating conditions. Fur ther re search is needed to ex pand our un der stand ing of the phys i o log i cal changes in the brain re sult ing from the com bi na tion of dis ease and electrical stimulation. 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