Transcranial direct current stimulation for progressive supranuclear palsy

Transcranial direct current stimulation for progressive supranuclear palsy

Case series

Alexoudi et al. conducted a pilot study in order to evaluate the effect of transcranial direct current stimulation over the motor cortex and premotor cortex in patients with progressive supranuclear palsy, with a particular emphasis on cognitive dysfunction. Eight patients affected by PSP were included (4 males and 4 females with mean age 67.4±7.4 years, range: 55-80 years and mean disease duration: 4.6±3.3 years, range: 1-11 years). The mean Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) was 49±16.1 and the mean Hoehn & Yahr (H&Y) scale was 3.9±1 at baseline. All pharmacological treatments (L-dopa, pramipexole, rotigotine, rasagiline, amantadine) were maintained stable during the study. They aimed at evaluating along with the motor outcome (as it is reflected on a disease-specific rating scale), the post-tDCS cognitive status after the completion of the intervention. The clinical evaluation involved the PSP-Rating Scale, the UPDRS III, and the Timed Up and Go test. The neuropsychological assessment focused on auditory-verbal memory and learning, episodic memory, visuomotor coordination and speed of information processing, executive functions and verbal fluency (phonemic and semantic). Anodal tDCS was applied over primary motor and pre-motor cortices in 10 daily sessions. During the tDCS stimulation, a constant current of 2 mA was delivered for 30 minutes. Clinical evaluations were performed at baseline, day 11, day 30 and at day 90. The PSP-Rating score (total and sections I & III) improved significantly on day 11 compared to baseline and similarly on day 30. A positive effect was also seen in action tremor. In addition to the global mental status improvement, patients showed increases in neuropsychological performance in the domains of visuomotor coordination and processing speed, auditory-verbal learning, episodic memory, phonological and semantic fluency (access and retrieval from lexical memory, selective inhibition, and lexical access speed). The results suggest that tDCS has a beneficial effect on Progressive Supranuclear Palsy patients’ bulbar and motor symptoms, cognitive dysfunction, as well as daily activities, which lasts beyond the duration of the treatment 1).

sham-controlled double-blind crossover design to assess the efficiency of tDCS over the DLPFC in a cohort of 12 patients with PSP. In 3 separate sessions, we evaluated the ability to boost the left DLPFC via left-anodal (excitatory) and right-cathodal (inhibitory) tDCS, while comparing them to sham tDCS. Tasks assessing lexical access (letter fluency task) and semantic access (category judgment task) were applied immediately before and after the tDCS sessions to provide a marker of potential language modulation.

The comparison with healthy controls showed that patients with PSP were impaired on both tasks at baseline. Contrasting poststimulation vs prestimulation performance across tDCS conditions revealed language improvement in the category judgment task following right-cathodal tDCS, and in the letter fluency task following left-anodal tDCS. A computational finite element model of current distribution corroborated the intended effect of left-anodal and right-cathodal tDCS on the targeted DLPFC.

The results demonstrate tDCS-driven language improvement in PSP. They provide proof-of-concept for the use of tDCS in PSP and set the stage for future multiday stimulation regimens, which might lead to longer-lasting therapeutic effects promoted by neuroplasticity.

This study provides Class III evidence that for patients with PSP, tDCS over the DLPFC improves performance in some language tasks 2).

Case reports

Madden et al. report the case of KN, who presented with reduced verbal fluency and connected speech production in the context of PSP. KN completed a set of language tasks, followed by an alternate version of the tasks in conjunction with either sham or active tDCS over the left dorsolateral prefrontal cortex (DLPFC) across four sessions. Results showed improved performance with active stimulation compared to sham stimulation for phonemic fluency and action naming, as well as mixed results suggesting possible benefits for connected speech production. There were no benefits of active stimulation for control tasks, indicating that tDCS can produce specific benefits for phonemic fluency, action naming, and connected speech production in PSP. These promising, preliminary findings warrant further investigation into whether these benefits of tDCS can be a useful therapeutic tool for PSP patients to maintain language 3).



Alexoudi A, Patrikelis P, Deftereos S, Fasilis T, Karakalos D, Verentzioti A, Korfias S, Sakas D, Gatzonis S. Effects of anodal transcranial direct current stimulation on cognitive dysfunction in patients with progressive supranuclear palsy. Psychiatriki. 2019 Oct-Dec;30(4):320-328. doi: 10.22365/jpsych.2019.304.320. PubMed PMID: 32283535.

Valero-Cabré A, Sanches C, Godard J, Fracchia O, Dubois B, Levy R, Truong DQ, Bikson M, Teichmann M. Language boosting by transcranial stimulation in progressive supranuclear palsy. Neurology. 2019 Aug 6;93(6):e537-e547. doi: 10.1212/WNL.0000000000007893. Epub 2019 Jul 3. PubMed PMID: 31270217; PubMed Central PMCID: PMC6709997.

Madden DL, Sale MV, O’Sullivan J, Robinson GA. Improved language production with transcranial direct current stimulation in progressive supranuclear palsy. Neuropsychologia. 2019 Apr;127:148-157. doi: 10.1016/j.neuropsychologia.2019.02.022. Epub 2019 Mar 2. PubMed PMID: 30836131.

Zona incerta stimulation

Zona incerta stimulation

Surgical targets for Tourette’s syndrome have included the frontal lobes, the cingulate gyrus, the anterior limb of the internal capsule (ALIC), the limbic system, and the subthalamic zona incerta1) Current targets of interest for DBS include: GPiSTN, ALIC, and thalamus. Early results have been promising. 2).

Posterior subthalamic deep brain stimulation (DBS) targeting the zona incerta (ZI) is an emerging treatment for tremor syndromes, including Parkinson’s disease (PD) and essential tremor (ET).

Evidence from animal studies has indicated that the ZI may play a role in saccadic eye movements via pathways between the ZI and superior colliculus (incerto collicular pathways).

Optics can be used for guidance in deep brain stimulation (DBS) surgery. The aim of Zsigmond and Wårdell was to use laser Doppler flowmetry (LDF) to investigate the intraoperative optical trajectory along the ventral intermediate nucleus (VIM) and zona incerta (Zi) regions in patients with essential tremor during asleep DBS surgery, and whether the Zi region could be identified.

A forward-looking LDF guide was used for the creation of the trajectory for the DBS lead, and the microcirculation and tissue greyness, i.e., total light intensity (TLI) was measured along 13 trajectories. TLI trajectories and the number of high-perfusion spots were investigated at 0.5-mm resolution in the last 25 mm from the targets.

All implantations were done without complications and with significant improvement of tremor (p < 0.01). Out of 798 measurements, 12 tissue spots showed high blood flow. The blood flow was significantly higher in VIM than in Zi (p < 0.001). The normalized mean TLI curve showed a significant (p < 0.001) lower TLI in the VIM region than in the Zi region.

Zi DBS performed asleep appears to be safe and effective. LDF monitoring provides direct in vivo measurement of the microvascular blood flow in front of the probe, which can help reduce the risk of hemorrhage. LDF can differentiate between the grey matter in the thalamus and the transmission border entering the posterior subthalamic area where the tissue consists of more white matter tract3).

Sixteen patients (12 with PD and 4 with ET) underwent DBS using the MRI-directed implantable guide tube technique. Active electrode positions were confirmed at the caudal ZI. Eye movements were tested using direct current electrooculography (EOG) in the medicated state pre- and postoperatively on a horizontal predictive task subtending 30°. Postoperative assessments consisted of stimulation-off, constituting a microlesion (ML) condition, and high-frequency stimulation (HFS; frequency = 130 Hz) up to 3 V.

With PSA HFS, the first saccade amplitude was significantly reduced by 10.4% (95% CI 8.68%-12.2%) and 12.6% (95% CI 10.0%-15.9%) in the PD and ET groups, respectively. With HFS, peak velocity was reduced by 14.7% (95% CI 11.7%-17.6%) in the PD group and 27.7% (95% CI 23.7%-31.7%) in the ET group. HFS led to PD patients performing 21% (95% CI 16%-26%) and ET patients 31% (95% CI 19%-38%) more saccadic steps to reach the target.

PSA DBS in patients with PD and ET leads to hypometric, slowed saccades with an increase in the number of steps taken to reach the target. These effects contrast with the saccadometric findings observed with subthalamic nucleus DBS. Given the location of the active contacts, incerto-collicular pathways are likely responsible. Whether the acute finding of saccadic impairment persists with chronic PSA stimulation is unknown 4).



Temel Y, Visser-Vandewalle V. Surgery in Tourette syndrome. Mov Disord. 2004; 19:3–14

Martinez-Fernandez R, Zrinzo L, Aviles-Olmos I, et al. Deep brain stimulation for Gilles de la Tourette syndrome: a case series targeting subre- gions of the globus pallidus internus. Mov Disord. 2011; 26:1922–1930

Zsigmond P, Wårdell K. Optical Measurements during Asleep Deep Brain Stimulation Surgery along Vim-Zi Trajectories. Stereotact Funct Neurosurg. 2020 Feb 20:1-7. doi: 10.1159/000505708. [Epub ahead of print] PubMed PMID: 32079023.

Bangash OK, Dissanayake AS, Knight S, Murray J, Thorburn M, Thani N, Bala A, Stell R, Lind CRP. Modulation of saccades in humans by electrical stimulation of the posterior subthalamic area. J Neurosurg. 2019 Mar 15:1-9. doi: 10.3171/2018.12.JNS18502. [Epub ahead of print] PubMed PMID: 30875687.

Subthalamic deep brain stimulation for Parkinson’s disease outcome

Subthalamic deep brain stimulation for Parkinson’s disease outcome

The surgical and clinical outcomes of asleep DBS for Parkinson’s disease are comparable to those of awake DBS 1).

Suboptimal targeting within the STN can give rise to intolerable sensorimotor side effects, such as dysarthria, contractions and paresthesias 2) 3) 4). eye movement perturbations, and psychiatric symptoms 5) 6) 7), limiting the management of motor symptoms. The small size of the STN motor territory and the consequences of spreading current to immediately adjacent structures obligate precise targeting. Neurosurgeons therefore rely on a combination of imaging, electrophysiology, kinesthetic responses, and stimulation testing to accurately place the DBS lead into the sensorimotor domain of STN 8) 9) 10).

Deep Brain Stimulation has been associated with post-operative neuropsychology changes, especially in verbal memory.

Deep brain stimulation (DBS) of subthalamic nucleus (STN) is widely accepted to treat advanced Parkinson disease (PD). However, published studies were mainly conducted in Western centers 11).

High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson’s disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony.

Low-frequency stimulation of the subthalamic nucleus via the optimal contacts is effective in improving overall motor function of patients with Parkinson Disease 12). In Parkinson’s disease significantly improved important aspects of QoL as measured by PDQ-39. The improvements were maintained at 2 years follow-up except for social support and communication. Sobstyl et al., demonstrated a positive correlation between changes in the off condition of motor UPDRS scores and Unified Dyskinesia Rating Scale in several PDQ-39 dimensions, whereas fluctuation UPDRS scores were negatively correlated with PDQ-39 mobility scores 13).

The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement.

A study reports on the evaluation of intraoperative MRI (iMRI) for adjusting deviated electrodes to the accurate anatomical position during DBS surgery and acute intracranial changes 14).



Wang J, Ponce FA, Tao J, Yu HM, Liu JY, Wang YJ, Luan GM, Ou SW. Comparison of Awake and Asleep Deep Brain Stimulation for Parkinson’s Disease: A Detailed Analysis Through Literature Review. Neuromodulation. 2019 Dec 12. doi: 10.1111/ner.13061. [Epub ahead of print] Review. PubMed PMID: 31830772.
2) , 9)

Benabid AL, Chabardes S, Mitrofanis J, Pollak P: Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 8:67–81, 2009
3) , 10)

Groiss SJ, Wojtecki L, Südmeyer M, Schnitzler A: Deep brain stimulation in Parkinson’s disease. Ther Adv Neurol Disorder 2:20–28, 2009

Zhang S, Zhou P, Jiang S, Wang W, Li P: Interleaving subthalamic nucleus deep brain stimulation to avoid side effects while achieving satisfactory motor benefits in Parkinson disease: a report of 12 cases. Medicine (Baltimore) 95:e5575, 2016

Kulisevsky J, Berthier ML, Gironell A, Pascual-Sedano B, Molet J, Parés P: Mania following deep brain stimulation for Parkinson’s disease. Neurology 59:1421–1424, 2002

Mallet L, Schüpbach M, N’Diaye K, Remy P, Bardinet E, Czernecki V, et al: Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc Natl Acad Sci U S A 104:10661–10666, 2007

Raucher-Chéné D, Charrel CL, de Maindreville AD, Limosin F: Manic episode with psychotic symptoms in a patient with Parkinson’s disease treated by subthalamic nucleus stimulation: improvement on switching the target. J Neurol Sci 273:116–117, 2008

Abosch A, Timmermann L, Bartley S, Rietkerk HG, Whiting D, Connolly PJ, et al: An international survey of deep brain stimulation procedural steps. Stereotact Funct Neurosurg 91:1–11, 2013

Chiou SM, Lin YC, Huang HM. One-year Outcome of Bilateral Subthalamic Stimulation in Parkinson Disease: An Eastern Experience. World Neurosurg. 2015 Jun 10. pii: S1878-8750(15)00709-3. doi: 0.1016/j.wneu.2015.06.002. [Epub ahead of print] PubMed PMID: 26072454.

Khoo HM, Kishima H, Hosomi K, Maruo T, Tani N, Oshino S, Shimokawa T, Yokoe M, Mochizuki H, Saitoh Y, Yoshimine T. Low-frequency subthalamic nucleus stimulation in Parkinson’s disease: A randomized clinical trial. Mov Disord. 2014 Jan 21. doi: 10.1002/mds.25810. [Epub ahead of print] PubMed PMID: 24449169.

Sobstyl M, Ząbek M, Górecki W, Mossakowski Z. Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study. Clin Neurol Neurosurg. 2014 Sep;124:161-5. doi: 10.1016/j.clineuro.2014.06.019. Epub 2014 Jun 23. PubMed PMID: 25051167.

Cui Z, Pan L, Song H, Xu X, Xu B, Yu X, Ling Z. Intraoperative MRI for optimizing electrode placement for deep brain stimulation of the subthalamic nucleus in Parkinson disease. J Neurosurg. 2016 Jan;124(1):62-9. doi: 10.3171/2015.1.JNS141534. Epub 2015 Aug 14. PubMed PMID: 26274983.
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