Literture Review of the effects of deep brain stimulation in parkinsons disease on cognition.Abstract The aim of this paper is to examine the literture of the effects of deep brain stimulation in Parkinsons disease on cognition. Findings : There is a slight impairment in congition following deep brain stimulation of patients with parkinsons disease. Verbal fluency and phonemic fluency appear to be most affected. Introduction with Aim(s) & Objectives Parkinsons disease (PD) is a long-term neurodegenerative disease which mainly affects the motor system. It is a slowly progressing disease characterised by motor impairment including difficulty with walking, slowness of movement, rigidity and postural instability (1). Behaviour and cognitive problems may occur also, with dementia common in advanced stages. It is a common diease worldwide, especially among the elderly population.(2)The cause is idiopathic, but genes and the enviroment are thought to play a part. Those who have a family member with PD are more likely to develop the disease themselves (Ref). Also, those that are exposed to pesticides and those who have suffered previous head injuries, have an increased risk of PD.The mechanism of the pathology of the disease is the degeneration of the dopaminergic neurons located in the substantia nigra of the basal ganglia. An accumulation of mainly alpha synuclein proteins occurs in the pars compacta of the substantia nigra causing a loss of dopaminergic terminals and a subsquent fall in the dopamine transporter density.(3) Interestingly, there is a reduced risk for those who drink coffee and appears to be a reduced risk for those who smoke (Ref).Deep brain stimulation (DBS) has been used as a treatment for PD for over 30 years.(4) It involves the implantation of an extrancranial pulse generator and stimulating electrodes which target the subthalamic nucleus (STN) or the globus pallidus interna (Gpi) of the basal ganglia (5). It is commonly used as a form of treatment when drug therapy is no longer effective, for the motor symptoms of PD. Randomised trials have found that the stimulation of the Gpi and the STN, both are equally effective at improving motor symptoms. Several studies have shown a significant improvement of the motor symptoms in STN DBS of PD patients, with a reduction in dopaminergic treatment dose and in the severity and timing of dyskinesia (6). There is still an improvement of motor function after a 5 year period post-op (7).With regards psychiatric complications of STN DBS, symptoms reported include mild servere depression, apathy, aggression and hypomania (8, 9). Mood improvement was observed after STN DBS in a review of 23 studies, with the majority of patients reporting improvement or unchanged mood after surgery (9). It was suggested that those who experienced psychiatric complications post surgery also had the issues pre-surgery, thus not resulting from the surgery itself (10).Although PD is traditionally considered a motor disorder, several studies have reported cognition changes, including impairments in language, vision, memory, psychomotor speed and exexcutive function (1, 11). fMRI studies have indicated that changes in the recruitment of frontal striatal thalamic circuitary may explain the cognitve changes (11). Therefore, there is a growing interest in the cognitive effects of DBS on PD.The aim of this paper is to review deep brain stimulation (DBS) effect on cognition as a form of treatment in Parkinsons Disease. h) Methods A search of the literture was completed using pubMed and the UCC library search engine.Using pubMed, 40052 search results were given for using the title Parkinsons Disease, 197 Parkinsons Disease cognition , 9 papers were found using the titleDeep Brain Stimulation Parkinsons Disease Cognition. 1 paper DBS Parkinsons Disease Cognition.Using UCC library search engine, 27 results were given for the title search Deep Brain stimulation parkinsons disease. This was narrowed down to 20 when only peer reviewed publications were allowed. This was subsequntely reduced to 9 allowing for removal of repeated papers and those already recorded from pubMed search. 1 paper was removed as the study was conducted on animals, while for 2 of the papers listed, the papers could not be found in either search engine.Results Table 1. Authors YearTitleParticipantsMain FindingsHagelweide, K.Schonberger, A. R.Kracht, L. W.Grundler, T. O. J.Fink, G. R.Schubotz, R. I.2018Motor cognition in patients treated with subthalamic nucleus deep brain stimulation: Limits of compensatory overactivity in Parkinsons disease8Cognition did not differ in the On/OFF position for DBS Xie, Y.Du, X. B.Liang, J. Y.Xiao, J. S.Zhang, J. J.2017Influence of subthalamic nucleus deep brain stimulation on cognition and acetylcholine in a rat model of Parkinsons disease30Excluded Non-Human Saad, A; Harty, S; Richardson, R; Myal, S; Pardini, J; Henry, L2017Emotion and Cognition in Movement Disorders: Comparing Pre-operative Deep Brain Stimulation Patients with Parkinsons Disease and Essential Tremor122Anxiety within PD patients presenting for DBS may negatively influence neuropsychological performance. Gruber, D; Lisa, C; Kuehn, A; Kopp, U; Schneider, GH; Kupsch, A2016Long term outcome of cognition following subthalamic deep brainstimulation in Parkinsons disease37Long term cognitive decline was recorded in patients who received DBS. No control group to compare against. Noboa, MBJ; Vasquez, RS; Achi, J; Navarrete, M; Mawyin, C2016The effects of deep brain stimulation for Parkinsons disease on cognition and perceived quality of life: Preliminary results from an Ecuadorian sample10Participants revaled significant worsening of some aspects of memory function, mainly immediate and short term free recall. Relative preservation of rest of cognitve functions. Combs, H. L.Folley, B. S.Berry, D. T.Segerstrom, S. C.Han, D. Y.Anderson-Mooney, A. J.Walls, B. D.van Horne, C.2015Cognition and Depression Following Deep Brain Stimulation of the Subthalamic Nucleus and Globus Pallidus Pars Internus in Parkinsons Disease: A Meta-Analysis1622DBS of Gpi resulted in fewer neurocognitive declines than STN. DBS of STN resulted in small declines in attention and small to moderate declines in verbal fluency. Massano, João2015New insights on cognition after deep brain stimulationin Parkinson disease STN DBS does not associate with substantial cognitive saftey issues in comparison to Gpi DBS. Goubareva, N.Fedorova, N.V.Bril, E.V.Tomskiy, A.A.Gamaleya, A.A.Shabalov, V.A.Bondarenko, A.A.Buklina, S.B2015Efficiency of deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinsons disease on mood and cognition22Insignificant deterioration after 3 years. Depressive symptoms and anxiety improved while an significant decrease in verbal activity was noted. Zangaglia, R.Pasotti, C.Mancini, F.Servello, D.Sinforiani, E.Pacchetti, C.2012Deep brain stimulation and cognition in Parkinsons disease: an eight-year follow-up study32Compared to the PD patients who did not have DBS performed, patients who underwent DBS had a decline in phonemic fluency. Cyron, D.Funk, M.Deletter, M. A.Scheufler, K.2010Preserved cognition after deep brain stimulation (DBS) in the subthalamic area for Parkinsons disease: a case report1Avoiding the STN may be advantageous in progressive Parkinsons disease to avoid non-motor complications. Okun, M. S.Fernandez, H. H.Wu, S. S.Kirsch-Darrow, L.Bowers, D.Bova, F.Suelter, M.Jacobson, C. E. thWang, X.Gordon, C. W., Jr.Zeilman, P.Romrell, J.Martin, P.Ward, H.Rodriguez, R. L.Foote, K. D.2009Cognition and mood in Parkinsons disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial45There was no significant differences in the co-primary outcome measures (mood and cognition) between the two groups. Halpern, C. H.Rick, J. H.Danish, S. F.Grossman, M.Baltuch, G. H.2009Cognition following bilateral deep brain stimulation surgery of the subthalamic nucleus for Parkinsons disease Cognitive decline has been observed in some domains. Heo, Jae-Hyeok|Kim, Min Ky|Ahn, Jin Young|Park, Tai Hwan|Lee, Kyoung-Min|Paek, Sun Ha|Jeon, Beom S2008The effects of bilateral subthalamic nucleus deep brainstimulation on cognition in Parkinsons disease46Verbal memory, the stroop test and the fluency test showed statistically significant changes. Aybek, S.Vingerhoets, F. J.2007Does deep brain stimulation of the subthalamic nucleus in Parkinsons disease affect cognition and behavior?99DBS of the STN in PD patients had a negative effect on executive functioning and was associated with psychiatric compliactions. However, overall quality of life improved. Castelli, L.Perozzo, P.Zibetti, M.Crivelli, B.Morabito, U.Lanotte, M.Cossa, F.Bergamasco, B.Lopiano, L.2006Chronic deep brain stimulation of the subthalamic nucleus for Parkinsons disease: effects on cognition, mood, anxiety and personality traits72Phonemic and semantic verbal fluency tasks worsened following implant of DBS. Pedersen, PM; Jorgensen, K; Lokkegaard, A; Regeur, L; Karlsborg, M; Werdelin, L2004Cognition and mood with subthalamic nucleus deep brainstimulation in Parkinsons disease Paper not available online Perrin, A; Ghika, J; Clarke, S; Berney, A; Villemure, JG; Bogousslavsky, J; Vingerhoets, FJG2002Effects on cognition of subthalamic nucleus deep brainstimulation for Parkinsons disease: A consecutive series of 36 patients Paper not available online Castelli et al. (12) in their study, compared 65 PD patients before and after surgery who had a bilateral DBS of the STN. The criteria for inclusion in the DBS surgery was the diagnosis of idiopathic PD, the presence of severe motor fluctuations, drug related dyskinesia, absence of marked atrophy, dementia and motor decline. Their neuropsychological assessment involved evaluating memory, reasoning, frontal executive functions and mood.They found that 15 months post surgery, only semantic and phonemic verbal flunency tasks worsened. They concluded that STN DBS did not lead to cognitive decline or behavioural disturbances in most cases. Executive function improved along with a slight improvement in mood on average. The analysis of individual outcomes (+/-1 SD criterion) that 3 patients showed postoperative decline, 1 patient exhibited pyschosis, 2 experienced clinically worsening symptoms of depression, 7 patients showed an increase in anxiety and 3 patients showed an increase in both anxiety and depessive symptoms. On the contrary, 12 patients showed relevant improvement in mood and 14 showed a reduction in anxiety after surgery.Okun et al.(13) compared the effects of DBS of the STN vs GPi with regards mood and cognition. They recruited 52 patients for the study and they were randomised to unilateral GPi or STN DBS. 3 patients (approx. 5%) could not complete the study because of hemorrhage or death which is a greater percentage than reported than in other studies. After 7 months post surgery, no difference was noted in mood or cognition between the two methods. The subjects in both targets were less happy and less energetic and more confused when stimulated ventrally. A worsening of letter verbal fluency was seen in STN however, but the persistence of deterioration in verbal fluency in the off position of the DBS device suggests that this may be a result of the surgery. They noted that similar motor improvements was seen in both target areas. Their results also suggested that patients tended to be less dense, happier but also more angry/irritable and confused following DBS. The increased anger and aggressiveness was also reported in further studies (14, 15).In contrast to Okun et al. , Massano (16) found that STN should remain the target of choice for DBS.The author reported that STN offered higher efficency regarding motor symptoms and disability, lower battery depletion, and a larger dopaminergic drug reduction. He did note that DBS GPi did have better results in some tests such as, the Stroop word reading test, colour naming tests and Trail Making Test but overall, felt the STN should be the preferred site.Halpern et al. (1) in their literture review of DBS of the subthamlamic nucleus effect on cognition noted mild post-operative impairments in executive function and verbal learning who underwent DBS surgery. However, when comparing the on vs off stimulation, working memory and psychomotor speed improved in the on position.Zangaglia et al. (17) did an 8 year follow up of the effects of DBS and cogntion in 32 PD compared to 33 PD who did not undergo the procedure, the control group. Similar results were found as previous studies, worsening of verbal fluency and phonemic fluency. Both groups had significant worsening Mini Mental State Examination (MMSE) results, interestingly, a significant decline in the nonverbal test (Ravens Progressive Matrices) was only found in the control group.Heo et al.(18) estimated cognition and mood effects of bilateral STN DBS in 46 PD patitents at 6 months and 1 year postoperatively. Again, similar to other studies, verbal memory test, stroop tets and fluency test showed statistically significant changes. There was no significant change in other cognitive functions and the patients depression score did not alter from pre surgery result. Their results suggest memory and frontal lobe function have been impacted by the surgery.Jurado et al. (19), in their study of the effects of DBS on cognition in 10 idioapthic PD patients revealed significant worsening some memory function, mainly short term and immediate free recall. Other cognitive domains they studied including verbal fluency, were relatively preservated.It is important to consider whether the length of time a patient has been diagnosed with PD and their could be responsible for any of the changes noted after DBS. Also it is valuable to see if dopaminergic medication could have any effect. From Combe et al. meta regression analysis, of the literiture, they suggest that the small declines seen after DBS cannot be explained by an individuals age, initial medication, baseline UPDRS off phase scores nor the length of time since the patient has been diagnosised with PD (5).It is worth noting that anxiety and depression is common within PD (20). It may therefore impact negatively neurophychologial performance.Discussion Review of the current literture demonstrates that there are sutule declines in overall cognition with both techniques of DBS in PD. DBS targeted at GPi does seem to offer better cognivie results than DBS of the STN. However, STN seems to be the site most used by neuosurgeons. The reasons for this may include the greater reduction in medication for patients who undergo DBS of the STN. There is fewer studies with regards GPi DBS, and as results with a positive result are more likely to be published, this may result in an overinflated effect in the literture search (5).It is worth noting the case (21) reported a case where stimulation of the subthalamic white matter tracts (pallidothalamic and cerebellothalamic), avoiding the STN, showed a marked improvement of social skills and cognition after DBS. They found 3 months post operation, the patients anxiety and depressive symptoms had disappeared while his irritabilty had reduced greatly. His quality of life, mobility, communicaiton, emotional wellbeing and physical wellbeing had all greatly improved. His ability to learn verbal information became normal. It was noted that the patients executive function remained stable which is vunerable to impairment in STN stimulation. The authors stated that by avoiding direct stimluation of the STN, a pallidotomy like effect allowed dopaminergic medication to be maintained at a high level which was of an advantage to the patient.It is worth noting that anxiety and depression is common within PD (20). It may therefore impact negatively neurophychologial performance.Conclusion From the current literture, the evidence suggests that DBS target choice should be tailored towards individual patient needs. If behaviour or cognitive issues are of a concern, DBS should target the GPi. If the goal is medication reduction, than bilateral STN DBS may be the better choice. The Gpi (approx 478mm^3 ) is a larger nucleus than the STN (approx. 158mm^3) (22). The STN contains multiple fiber pathways within a compact area, motor, associative and limbic circuits. It resulted in more cognitve declines than Gpi DBS. Both Gpi DBS and STN DBS resulted in fewer depressive symptoms.The verbal fluency findings from the studies is likely from structural damage from the insertion of the DBS. Any cognitive declines after DBS in the STN area is also likely due to damage from insertion of DBS during surgery (13). Small declines were found in attention, memory, executive function and overall cogniton while both semantic and phonemic fluency had moderate declines. However, DBS seems to be well tolerated, safe and an effective treatment for the motor symptoms of PD.References Halpern CH, Rick JH, Danish SF, Grossman M, Baltuch GH. Cognition following bilateral deep brain stimulation surgery of the subthalamic nucleus for Parkinsons disease. Int J Geriatr Psychiatry. 2009;24(5):443-51.Machado FA, Reppold CT. The effect of deep brain stimulation on motor and cognitive symptoms of Parkinsons disease: A literature review. 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