Research progress on the long-term effects of subthalamic nucleus deep brain stimulation on non-motor symptoms in Parkinson's disease

doi:10.3969/j.issn.1006-7795.2025.04.023

Abstract

Abstract: Deep brain stimulation (DBS) has witnessed rapid advancement as a neurosurgical intervention over the past four decades, addressing movement disorders and a spectrum of neuropsychiatric conditions. Notably, subthalamic nucleus deep brain stimulation (STN-DBS) is widely implemented in the management of Parkinson's disease（PD）patients experiencing refractory motor fluctuations and complications, and has shown promise in ameliorating non-motor symptoms (NMS). However, the long-term efficacy of STN-DBS on NMS remains a subject of scholarly discourse. This review endeavors to synthesize current knowledge regarding the long-term impacts, underlying mechanisms, and future research directions of STN-DBS in the context of NMS in Parkinson's disease.

Key words: Parkinson's disease, subthalamic nucleus, deep brain stimulation, cognitive function, affective disorders, autonomic dysfunction

CLC Number:

R742.5

Jiang Chenguan, Liu Yan, Yang Zhou, Li Bingxin, Zhang Jianguo, Shi Lin. Research progress on the long-term effects of subthalamic nucleus deep brain stimulation on non-motor symptoms in Parkinson's disease[J]. Journal of Capital Medical University, 2025, 46(4): 733-741.

References

［1］Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinsons disease-an evidence-based medicine review［J］. Mov Disord, 2019, 34(2): 180－198.
［2］Alexander G E, DeLong M R, Strick P L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex［J］. Annu Rev Neurosci, 1986, 9: 357－381.
［3］Benabid A L, Pollak P, Gross C, et al. Acute and long-term effects of subthalamic nucleus stimulation in Parkinson's disease［J］. Stereotact Funct Neurosurg, 1994, 62(1/4): 76－84.
［4］Chiken S, Nambu A. Disrupting neuronal transmission: mechanism of DBS?［J］. Front Syst Neurosci, 2014, 8: 33.
［5］Miocinovic S, Somayajula S, Chitnis S, et al. History, applications, and mechanisms of deep brain stimulation［J］. JAMA Neurol, 2013, 70(2): 163－171.
［6］Chen Y C, Zhu G Y, Liu D F, et al. Subthalamic nucleus deep brain stimulation suppresses neuroinflammation by fractalkine pathway in Parkinson's disease rat model［J］. Brain Behav Immun, 2020, 90: 16－25.
［7］Fauser M, Ricken M, Markert F, et al. Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model［J］. Neurobiol Dis, 2021, 156: 105404.
［8］Petersson P, Halje P, Cenci M A. Significance and translational value of high-frequency cortico-basal ganglia oscillations in Parkinson's disease［J］. J Parkinsons Dis, 2019, 9(1): 183－196.
［9］Mandat V H, Zdunek P R, Krolicki B, et al. Alterations of non-motor symptoms in Parkinson's disease, after of subthalamic deep brain stimulation［J］. World Neurosurg X, 2024, 23: 100375.
［10］Hely M A, Reid W G J, Adena M A, et al. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years［J］. Mov Disord, 2008, 23(6): 837－844.
［11］Rodriguez-Oroz M C, Obeso J A, Lang A E, et al. Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up［J］. Brain, 2005, 128(Pt 10): 2240－2249.
［12］Fasano A, Romito L M, Daniele A, et al. Motor and cognitive outcome in patients with Parkinson's disease 8 years after subthalamic implants［J］. Brain, 2010, 133(9): 2664－2676.
［13］Castrioto A, Lozano A M, Poon Y Y, et al. Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation［J］. Arch Neurol, 2011, 68(12): 1550－1556.
［14］Kudlicka A, Clare L, Hindle J V. Executive functions in Parkinson's disease: systematic review and meta-analysis［J］. Mov Disord, 2011, 26(13): 2305－2315.
［15］Rizzone M G, Fasano A, Daniele A, et al. Long-term outcome of subthalamic nucleus DBS in Parkinson's disease: from the advanced phase towards the late stage of the disease?［J］. Parkinsonism Relat Disord, 2014, 20(4): 376－381.
［16］Bucur M, Papagno C. Deep brain stimulation in Parkinson disease: a meta-analysis of the long-term neuropsychological outcomes［J］. Neuropsychol Rev, 2023, 33(2): 307－346.
［17］Kurtis M M, Rajah T, Delgado L F, et al. The effect of deep brain stimulation on the non-motor symptoms of Parkinson's disease: a critical review of the current evidence［J］. NPJ Parkinsons Dis, 2017, 3: 16024.
［18］Jahanshahi M, Leimbach F, Rawji V. Short and long-term cognitive effects of subthalamic deep brain stimulation in Parkinson's disease and identification of relevant factors［J］. J Parkinsons Dis, 2022, 12(7): 2191－2209.
［19］Witt K, Granert O, Daniels C, et al. Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinson's disease: results from a randomized trial［J］. Brain, 2013, 136(Pt 7): 2109－2119.
［20］Isler C, Albi A, Schaper F L, et al. Neuropsychological outcome in subthalamic nucleus stimulation surgeries with electrodes passing through the caudate nucleus［J］. Stereotact Funct Neurosurg, 2016, 94(6): 413－420.
［21］Yamanaka T, Ishii F, Umemura A, et al. Temporary deterioration of executive function after subthalamic deep brain stimulation in Parkinson's disease［J］. Clin Neurol Neurosurg, 2012, 114(4): 347－351.
［22］Mosley P E, Akram H. Neuropsychiatric effects of subthalamic deep brain stimulation［J］. Handb Clin Neurol, 2021, 180: 417－431.
［23］Salehi N, Nahrgang S, Petershagen W, et al. Theta frequency deep brain stimulation in the subthalamic nucleus improves working memory in Parkinson's disease［J］. Brain, 2024, 147(4): 1190－1196.
［24］Mainardi M, Ciprietti D, Pilleri M, et al. Deep brain stimulation of globus pallidus internus and subthalamic nucleus in Parkinson's disease: a multicenter, retrospective study of efficacy and safety［J］. Neurol Sci, 2024, 45(1): 177－185.
［25］Prange S, Klinger H, Laurencin C, et al. Depression in patients with Parkinson's disease: current understanding of its neurobiology and implications for treatment［J］. Drugs Aging, 2022, 39(6): 417－439.
［26］Irmen F, Horn A, Mosley P, et al. Left prefrontal connectivity links subthalamic stimulation with depressive symptoms［J］. Ann Neurol, 2020, 87(6): 962－975.
［27］Cartmill T, Skvarc D, Bittar R, et al. Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: a meta-analysis of mood effects［J］. Neuropsychol Rev, 2021, 31(3): 385－401.
［28］Tanvir A ,Jo J ,Park M S .Targeting Glucose Metabolism: A Novel Therapeutic Approach for Parkinson’s Disease［J］.Cells,2024,13(22):1876-1876.
［29］Bejjani B P, Damier P, Arnulf I, et al. Transient acute depression induced by high-frequency deep-brain stimulation［J］. N Engl J Med, 1999, 340(19): 1476－1480.
［30］Doshi P K, Chhaya N, Bhatt M H. Depression leading to attempted suicide after bilateral subthalamic nucleus stimulation for Parkinson's disease［J］. Mov Disord, 2002, 17(5): 1084－1085.
［31］Zoon T J C, Van Rooijen G, Balm G M F C, et al. Apathy induced by subthalamic nucleus deep brain stimulation in Parkinson's disease: a meta-analysis［J］. Mov Disord, 2021, 36(2): 317－326.
［32］Debove I, Paschen S, Amstutz D, et al. Management of impulse control and related disorders in Parkinson's disease: an expert consensus［J］. Mov Disord, 2024, 39(2): 235－248.
［33］Thobois S, Ardouin C, Lhommée E, et al. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation［J］. Brain, 2010, 133(Pt 4): 1111－1127.
［34］张文颖, 牛焕江, 朱先理, 等. 双侧丘脑底核脑深部电刺激术对帕金森病患者睡眠及其他非运动症状的治疗效果分析［J］. 中华神经医学杂志, 2020, 19(9): 952－957.
［35］Zhang X, Xie A M. Improvement of subthalamic nucleus deep brain stimulation in sleeping symptoms in Parkinson's disease: a meta-analysis［J］. Parkinsons Dis, 2019, 2019: 6280896.
［36］Bellini G, Best L A, Brechany U, et al. Clinical impact of deep brain stimulation on the autonomic system in patients with Parkinson's disease［J］. Mov Disord Clin Pract, 2020, 7(4): 373－382.
［37］Rukmini Mridula K, Borgohain R, Jabeen S A, et al. Comparison of frequencies of non motor symptoms in Indian Parkinson's disease patients on medical management versus deep brain stimulation: a case-control study［J］. Iran J Neurol, 2015, 14(2): 86－93.
［38］Wang Y, Gao P, Zhang X, et al. Bilateral subthalamic nucleus deep brain stimulation improves gastric emptying time in Parkinson disease［J］. World Neurosurg, 2021, 154: e683-e688.
［39］Onder H, Comoglu S. Investigation of the nonmotor symptoms in patients with STN-DBS therapy in comparison with those without STN-DBS［J］. J Neural Transm, 2024, 131(8): 931－940.
［40］Jost S T, Sauerbier A, Visser-Vandewalle V, et al. A prospective, controlled study of non-motor effects of subthalamic stimulation in Parkinson's disease: results at the 36-month follow-up［J］. J Neurol Neurosurg Psychiatry, 2020, 91(7): 687－694.
［41］Gorecka‐Mazur A, Krygowska-Wajs A, Furgala A, et al. Associations between gut microbiota characteristics and non-motor symptoms following pharmacological and surgical treatments in Parkinson's disease patients［J］. Neurogastroenterol Motil, 2024, 36(8): e14846.
［42］Sakakibara R, Panicker J, Finazzi-Agro E, et al. A guideline for the management of bladder dysfunction in Parkinson's disease and other gait disorders［J］. Neurourol Urodyn, 2016, 35(5): 551－563.
［43］周永, 陈锐, 支中文, 等. 丘脑底核-脑深部刺激术治疗帕金森病相关疼痛的疗效分析［J］. 临床神经外科杂志, 2020, 17(5): 538－542.
［44］Cury R G, Galhardoni R, Fonoff E T, et al. Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease［J］. Neurology, 2014, 83(16): 1403－1409.
［45］Diao Y, Bai Y T, Hu T Q, et al. A meta-analysis of the effect of subthalamic nucleus-deep brain stimulation in Parkinson's disease-related pain［J］. Front Hum Neurosci, 2021, 15: 688818.
［46］Pont-Sunyer C, Hotter A, Gaig C, et al. The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study)［J］. Mov Disord, 2015, 30(2): 229－237.
［47］Friedman J H, Brown R G, Comella C, et al. Fatigue in Parkinson's disease: a review［J］. Mov Disord, 2007, 22(3): 297－308.
［48］Alves G, Wentzel-Larsen T, Larsen J P. Is fatigue an Independent and persistent symptom in patients with Parkinson disease?［J］. Neurology, 2004, 63(10): 1908－1911.
［49］Pavlovsky P, Sayfulina K, Gamaleya A, et al. Clinical asymmetry in Parkinson's disease is characterized by prevalence of subthalamic pause-burst neurons and alpha-beta oscillations［J］. Clin Neurophysiol, 2024, 165: 36－43.
［50］Chen Y C, Zhu G Y, Liu D F, et al. Seed-Based connectivity prediction of initial outcome of subthalamic nuclei deep brain stimulation［J］. Neurotherapeutics, 2022, 19(2): 608－615.
［51］Jorge A, Lipski W J, Wang D Y, et al. Hyperdirect connectivity of opercular speech network to the subthalamic nucleus［J］. Cell Rep, 2022, 38(10): 110477.
［52］Peeters J, Boogers A, Van Bogaert T, et al. Electrophysiologic evidence that directional deep brain stimulation activates distinct neural circuits in patients with Parkinson disease［J］. Neuromodulation, 2023, 26(2): 403－413.
［53］Fleming J E, Dunn E, Lowery M M. Simulation of closed-loop deep brain stimulation control schemes for suppression of pathological beta oscillations in Parkinson's disease［J］. Front Neurosci, 2020, 14: 166.
［54］Prasad A A, Wallén-Mackenzie Å. Architecture of the subthalamic nucleus［J］. Commun Biol, 2024, 7(1): 78.
［55］Ilango A, Kesner A J, Keller K L, et al. Similar roles of substantia nigra and ventral tegmental dopamine neurons in reward and aversion［J］. J Neurosci, 2014, 34(3): 817－822.
［56］Ztaou S, Amalric M. Contribution of cholinergic interneurons to striatal pathophysiology in Parkinson's disease［J］. Neurochem Int, 2019, 126: 1－10.
［57］Alosaimi F, Boonstra J T, Tan S, et al. The role of neurotransmitter systems in mediating deep brain stimulation effects in Parkinson's disease［J］. Front Neurosci, 2022, 16: 998932.
［58］Fauser M, Ricken M, Markert F, et al. Subthalamic nucleus deep brain stimulation induces sustained neurorestoration in the mesolimbic dopaminergic system in a Parkinson's disease model［J］. Neurobiol Dis, 2021, 156: 105404.
［59］Cury R G, Carvalho M J, Lasteros F J L, et al. Effects of subthalamic stimulation on olfactory function in Parkinson disease［J］. World Neurosurg, 2018, 114: e559-e564.
［60］Chang B W, Mei J M, Ni C, et al. Functional connectivity and anxiety improvement after subthalamic nucleus deep brain stimulation in Parkinson's disease［J］. Clin Interv Aging, 2023, 18: 1437－1445.
［61］Jung Y J, Kim H J, Paek S H, et al. Effects of deep brain stimulation on sleep-wake disturbances in patients with Parkinson's disease: a narrative review［J］. Curr Neuropharmacol, 2021, 19(10): 1716－1727.
［62］Zhang X, Xie A M. Improvement of subthalamic nucleus deep brain stimulation in sleeping symptoms in Parkinson's disease: a meta-analysis［J］. Parkinsons Dis, 2019, 2019: 6280896.
［63］Chang C W, Li N, Wu Y Y, et al. Associations between bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and anxiety in Parkinson's disease patients: a controlled study［J］. J Neuropsychiatry Clin Neurosci, 2012, 24(3): 316－325.
［64］Pham T A, Dao P D, Nguyen L T, et al. Accuracy of subthalamic nucleus electrode implantation in deep brain stimulation surgery for Parkinson's disease treatment and affecting factors: outcomes at two centers in Vietnam［J］. World Neurosurg, 2023, 179: e32-e38.
［65］史若琳, 高秀洁, 崔家宁, 等. 5-羟色胺与帕金森病非运动症状研究进展［J］. 中国现代神经疾病杂志, 2024, 24(6): 497－501.
［66］安宁, 白妍, 李元, 等. 帕金森病伴神经精神障碍的发病机制及中医治疗研究进展［J］. 中医药学报, 2024, 52(5): 98－104.
［67］王珏, 邱娴, 高颖, 等. 帕金森病患者双侧丘脑底核脑深部电刺激术后2年非运动症状的研究［J］. 立体定向和功能性神经外科杂志, 2023, 36(4): 193－199.
［68］牛朝诗, 常博文. 机器学习:辅助脑深部电刺激应用的新方向［J］. 中华医学杂志, 2023, 103(47): 3797－3801.
［69］张建国. 脑深部电刺激的技术创新与未来［J］. 中华神经外科杂志, 2024, 40(1): 2－5.

[1]	Luo Binbin, Hu Yasong, Yue Feng, Chen Biao. Long lasting changes of motor function in MPTP-induced unilateral cynomolgus monkeys model [J]. Journal of Capital Medical University, 2018, 39(2): 217-222.
[2]	Liu Junhua, Wang Yong, Wang Yanyan, Wang Xiaomin. Safety evaluation during deep-brain magnetic stimulation (DMS)treating motor symptoms in Parkinsonian rats [J]. Journal of Capital Medical University, 2017, 38(2): 260-267.
[3]	Gao Ge, Wang Zhipeng, Duan Chunli, Lu Lingling, Yang Hui. Topographic images analysis of mitochondria from α-synuclein transgenic mice utilizing atomic force microscopy [J]. Journal of Capital Medical University, 2016, 37(6): 806-811.
[4]	Bai Lijuan, Ren Yan, Luo Xiaoguang, Jiang Xin, Chen Xiaohong. Morphological and inflammatory factor changes of substantia nigra dopaminergic neurons and microglial cells after intraperitoneal injection of lipopolysaccharide in rat [J]. Journal of Capital Medical University, 2015, 36(6): 887-894.
[5]	Bai Lijuan, Jiang Xin, Chen Xiaohong, Ren Yan, Luo Xiaoguang. Effect of intraperitoneal injection of lipopolysaccharides on the substantia nigra NADPH oxidase in rats [J]. Journal of Capital Medical University, 2015, 36(6): 882-886.
[6]	CHEN Yudong, YIN Na, LI Xin, YANG Weiwei, LI Xuran, YU Shun. Changes of α-synuclein and its oligomeric formation in plasmas of patients with stroke [J]. Journal of Capital Medical University, 2013, 34(6): 826-829.
[7]	YANG Weiwei, YANG Hui, YU Shun. Activation of protein phosphatase 2A alleviates α-synuclein-induced apoptosis of SK-N-SH cells [J]. Journal of Capital Medical University, 2013, 34(6): 835-839.
[8]	Xuan Qi;Xu Shengli;Zhou Ming;Cui Yeqing;Chen Biao. Stereological Analysis of Age Associated Neuronal Changes in Human Substantia Nigra [J]. Journal of Capital Medical University, 2008, 29(3): 270-273.
[9]	Liu Hongjun;Zhao Lijie;Ding Hui;Chen Biao. The Study on Incidence of Depression and Correlated Factors in Patients with Parkinson's Disease [J]. Journal of Capital Medical University, 2007, 28(3): 370-372.
[10]	Wang Xuemei;Chen Biao. Histone Deacetylase Maybe Involved in the Mechanism of Inhibition of Tyrosine Hydroxylase Expression in α-Synuclein-Transfected Dopaminergic Neuronal Cells [J]. Journal of Capital Medical University, 2006, 27(4): 476-479.
[11]	Guan Xiaoting;Wang Chunxue;Long Jie;Zi Shen. Level Changes of Cytokines TNF-α and IL-6 in Periphery Blood with Parkinson Disease [J]. Journal of Capital Medical University, 2004, 25(2): 233-235.
[12]	Ma Kai;Li Yongjie Department of Functional Neurosurgery;Xuanwu . Diagnosis of Parkinson Disease [J]. Journal of Capital Medical University, 2004, 25(1): 103-105.
[13]	Zou Chunlin;Sun Yilin;Qu Baoqing;Sheng Shuli;Zhao Zhiwei;Duan Chunli. On NACP and the preclinic animal model of Parkinson's Disease [J]. Journal of Capital Medical University, 2003, 24(3): 262-267.
[14]	Ma Kai;Li Yongjie. Clinical Characters of Young-Onset Parkinson's Disease [J]. Journal of Capital Medical University, 2003, 24(2): 190-192.
[15]	Ma Kai;Li Yongjie . Curative Analysis of Surgical Treatment for Young-onset Parkinson Disease [J]. Journal of Capital Medical University, 2002, 23(2): 122-124.