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Tdcs Effects On Executive Function In Parkinson'S Disease

Article written by: ANDREI BOGDAN, MD, Orthopedics-traumatology doctor

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Transcranial electrical stimulation is gaining more and more ground nowadays, being a therapy with very good results in many neurological diseases, but also for improving sports performance, or for increasing intellectual capacity. 

It can be used in neurological disorders as first-line therapy or in combination with drug treatments and remains an alternative if patients acquire drug resistance (drug resistance) or have not obtained favorable results after existing classic treatments. 

Neuromotor symptoms in patients with Parkinson's disease (PD) are often difficult to recognize, significantly affect the quality of life, and cause severe disability.  

Currently, there is limited evidence to guide the treatment of associated psychiatric and cognitive problems. Non-invasive brain stimulation techniques have emerged as non-pharmacological alternatives to detecting cognitive symptoms without worsening motor function. In this context, we present a multicenter, randomized, double-blind study to evaluate the immediate and long-term effects of the ten consecutive sessions of transcranial direct current stimulation (tDCS) on the right dorsolateral prefrontal cortex anode (DLPFC). (n = 5), on the left side of DLPFC (n = 6) or false (placebo) (n = 7).  

Cognitive function, depressive symptoms, and motor function were assessed in 18 patients with PD at baseline, at the end of 2-week stimulation sessions, and one-month follow-up. The results of the study showed that active stimulation resulted in prolonged improvements in the process of performing the B test, an established test for measuring executive function, compared to the false evaluation of DCDC at one month of monitoring. These results suggest a long-term beneficial effect on executive function in patients with PD following a tDCS asset within the DSLFC. Thus, our results encourage further investigations exploring the substance TDCS as a therapeutic adjuvant for cognitive and behavioral treatment in PD. 

Introduction 

Parkinson's disease (PD) is a neurodegenerative disorder characterized by gradual impairment of emotional, cognitive, and motor function. Although motor symptoms such as resting tremor, bradykinesia, stiffness, and postural instability are hallmarks of this disorder, nonmotor cognitive and psychiatric symptoms (NMS) are both disabling and have a direct impact on patients' quality of life (QOL). with PD. Recent reports show that even after controlling for the duration and severity of motor symptoms, cognitive abilities, such as executive and visual functions, remain positively associated with QOL. In addition, psychiatric comorbidities, namely depression, are constantly among the strongest determinants of QOL. For these reasons, 

Cognitive functions are performed primarily by the cortex, where dopamine is known to play a key role. It has been suggested that impaired cognitive function is linked to a disruption of the dopaminergic system, which is also severely affected by PD. Cognitive deficits in Parkinson's disease are similar to a dysexecutive syndrome. Depression, a common comorbidity in PD, is also suggested to be caused by changes in dopaminergic transmission and changes in arousal and imbalance between left DLPFC (L-DLPFC) and right DLPFC (R-DLPFC).

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), are safe and effective methods of improving cognitive and affective functions. TDCS applied with the anode over the LPFC and the cathode over the right supra-orbital region can improve the working memory of healthy subjects, and can improve the mood of patients with major depression. In this context, several studies have documented the beneficial effects of TMS and TDCS on cognitive and behavioral symptoms in PD, without aggravating motor symptoms. 

These results support the idea that active stimulation of DSLFC with TDCS could have long-term beneficial effects on both affective and cognitive domains in patients with PD. Therefore, we conducted a double-blind, double-blind tDCS study in patients with PD. We hypothesized that the application of tDCS by L-DLPFC would improve cognitive function and affective symptoms without altering motor function with false stimulation. 

Methods 

Subjects 
The study enrolled 18 patients (6 women and 12 men) aged between 40 and 71 years (mean age 61 8 years) with idiopathic PD. Inclusion criteria included a clinical diagnosis of PD defined by the presence of at least two of the three characteristics of the cardinal PD motor (tremor, stiffness, and bradykinesia, plus a sustained and significant response to dopaminergic treatment), age 40 and older. and maintaining their medication stable for at least 30 days before enrollment and throughout the study. Exclusion criteria included any contraindications to tDCS: history of seizures, substance abuse, dementia, major head trauma, or psychotic symptoms. The study was conducted in two centers: Berenson-Allen Center for Noninvasive Brain Stimulation at Beth Israel Deaconess Medical Center and Neuromodulation Center at Apolare Rehabilitation Hospital in Boston. A multicenter protocol was implemented in both locations. The study was reviewed and approved by the institutional evaluation boards of both centers, and all participants obtained written informed consent. 
Protocol. Experimental protocol 
Subjects were randomly assigned to one of three groups in a 1: 1: 1 ratio using permuted blocked randomization. Group 1 received tDCS with the anode over the L-DLFC and the cathode over the right supraorbital region; Group 2 received tDCS with the anode over the R-DLPFC and the cathode over the left supraorbital region, and Group 3 received the false (placebo) tDCS with two electrodes randomly placed on the l-DLPFC or R-DLPFC and the corresponding area, the contralateral supraorbital area. Each group received a total of 10 stimulation sessions over 2 weeks (Monday - Friday) with a 2-day break on the weekend. Cognitive, affective, and motor assessments were completed at baseline (visit 1), at the end of stimulation sessions (visit 11), and at a one-month follow-up visit (visit 12). 
Stimulation of transcranial direct current 
Direct current was delivered through a 1 1 tDCS low-intensity stimulator (Soferix Medical Inc., New York, NY) and Chattanooga Ionto (IontoTM iontophrin system, Chattanoogga Medical Supply Inc., Chattanooga, TN) via -a pair of electrodes soaked in saline (35 cm2). For CMFI stimulation The anode was placed above F3 or F4 according to the international system 10–20 for EEG placement of 1-DLPFC or R-DLPFC stimulation, respectively with the mounting described above. During the active tDCS, a constant current of 2 mA was delivered for 20 minutes so the false stimulus current was applied only for the initial ramp of 30 s upwards and 30 s downwards. After each session, a questionnaire was administered to monitor for possible side effects. 
Cognitive assessments 
To assess cognitive function, we used several neuropsychological tests targeting different cognitive areas with known difficulties for patients with PD. To test executive function, we used A&B route tests (TMT A & B), Wisconsin Card Sorting Test (WCST), Probabilistic Classification Learning (PCL), Executive Memory Test (WM), and Stroop Test. For visual-spatial ability, we used the Hooper Visual Organization (HPVOT) test and, for abstract reasoning, colored progressive matrices (CPM). Working memory was assessed using digital advance and regression tests as well as 3-back tests. These tests were previously used to evaluate the effects of rTMS on patients with PD. Furthermore.

Behavioral assessments 

Mood / emotional assessment included the Beck Depression Inventory (BDI), a 21-question self-report and multiple-choice questionnaire; The Hamilton Depression Assessment Scale (HRSD), a scale for several options scored with 21 questions; And the Hamilton Anxiety Scale (HAS), a 14-question scale for assessing the severity of anxiety symptoms. These scales have been used previously in evaluating the effects of rTMS on impairment in patients with PD.

Mood / emotional assessment included the Beck Depression Inventory (BDI), a 21-question self-report and multiple-choice questionnaire; The Hamilton Depression Assessment Scale (HRSD), a scale for several options scored with 21 questions; And the Hamilton Anxiety Scale (HAS), a 14-question scale for assessing the severity of anxiety symptoms. These scales have been used previously in evaluating the effects of rTMS on impairment in patients with PD.

Evaluation of engines 

To assess motor function, the following tests were administered: Unified Parkinson's Disease Assessment Scale Part-III (UPDRS-III), Reaction Time Test (SRT) (right and left), Optional Reaction Time Test (4-CRT) ) (right and left), Peglar PPPT test (right and left), Finger Touch (FT) (right and left), walking time (WT), and Pronation and Supination Test (PPT). 

Statistical analysis 

Statistical analyzes were performed using STATA / IC 12 (Stata-Corp LP, TX, USA). We used the analysis of the intention to treat with the last observation, made as a method of imputation. Between-group differences in demographics and benchmarks were compared using a single ANOVA for continuous variables and Fisher's exact test for variables that could be classified. Because we anticipated a differentiated effect during stimulation versus monitoring, we divided these two periods as tDCS treatment and monitoring. Thus, the analyzes took into account this differentiated effect. We ran models using a two-part linear spline function, which allowed us to analyze the slope at these two different time points. For group comparisons, we performed ANCOVA models that compare the differences between groups and we checked the basic values. The correlations between cognitive, affective, and motor functions were evaluated by correlation tests in pairs.

Result 

Eighteen patients were included in the study: Six patients were randomly assigned to the LPFC group, five patients from the R-DLPFC group, and seven patients from the Asham DCS group. The mean baseline MMSE reference score for all groups was 29.2 0.3 (mean SEM). There were no significant differences between demographic groups or in any of the cognitive, affective, or behavioral measures at the baseline level (all p> 0.05). The most common side effects reported were: tremor (50%), drowsiness (55%), and mild headache (22%). Other effects included sore throat (11%), redness of the skin (22%), and concentration disturbance (22%). None of the patients reported any unexpected serious side effects.

Cognitive effects

Route B Test (TMT-B)
This analysis shows that, although all groups showed an improvement in TMT-B performance immediately after 10 days of TDCS, only active TDCS groups showed an improvement in performance maintained at one-month monitoring as further detailed. In our analysis, we evaluated the basic effects of two different periods: TDCS treatment and monitoring. Initially, we made a model using a spleen transformation taking the end of the last stimulation session as a node for this model. The results showed:
  • DCDC treatment: There was a significant effect over time for the first period (from baseline to the end of the stimulation session - tDCS treatment period) (beta coefficient of -38.54 s, p = 0.006). To analyze the group effect we made an ANCOVA model adjusted for the reference values. In this model, no group differences were found for the tDCS treatment period (p = 0.49, effect size for the group; Eta2 = 0.02, percentage change eta2 = 7.75, eta2 = 0.03), indicating that improved TT-B performance was similar between groups. 
  • Follow-up period: No main effect of time was found for this period (beta coefficient of 43.76 and had only a significant trend, p = 0.064), there was no improvement in performance during the follow-up period. However, the group effect analysis with ANCOVA showed a significant group effect. (p = 0.02, effect size for group; eta2 = 0.15, percentage change eta2 = 22.19, eta2 = 0.32). The comparison of the group of fakes with both active groups of tDCS showed a significant difference (p <0.001) (fictitious group: 25.3 s 19.5; active group: -8.7 s 6.2), indicating that the groups had differentiated retention effects. Although both active groups maintained improved TMT-B performance, the performance of the MartDCS group returned to reference levels.
  • Reference scenario vs. Monitoring: Finally, to evaluate the general improvement of the groups, we developed an ANCOVA model comparing the reference scenario with the monitoring period and we also found significant effects (p = 0.03; the average difference between the subsequent actions and the reference scenario; L-DLFC = 45.25 s 59.83; R-DLPFC = 46.41 s 39.34 and false group = 15.45 s 57.97, the effect size for the group; Eta2 = 0.25, percentage variation eta2 = 64.68, eta2 = 0.29), which shows that, over time what active groups maintained the positive effects, the false tDCS product group lost most of this effect at one month of follow-up and returned to baseline levels.
Other cognitive tasks, including WSCT, PCL, WM, CPM, HVOT, STROOP, and figure measurement, did not indicate significant post-tDCS effects compared to monitoring effects when compared between stimulation groups. 
Effects on mood
ANCOVA models showed no significant effect on spleen functions. However, given previous findings on BDI changes following active tDCS, we performed individual exploration tests within each group, comparing the percentage change from baseline to group level. We found that the LPR-FC group had a higher reduction in BDI scores (mean reduction in SEM%: -49.8% 13.82) than in placebo (-1.28% 11.34) and the R-DLPFC group (-22.1% 29.82) at the end If a toxicity test is used to verify that the substance is less than 0.027%, the toxicity test may be applied to verify that the substance is less significant. 

Motor effects

Analyzes of tests related to motor functions (supination-pronation, buttoning, finger touch, walking time, grip plate, reaction time, and motor part of UPDRS) failed to show significant effects of stimulation (all p> 0.05). This suggests that motor function did not improve or decrease during the study.

Correlations

Correlation tests in parallel with the Bonferroni correction for the two significant results (BDI and TMT-B) did not show any significant association between any of the paired analyzes.

Discussion

In this study, we evaluated the effects of tDCS with the anode over L-DLPFC or R-DLPFC on a wide range of cognitive, affective, and motor functions in patients with PD. We found that anodal tDCS on both L-DLPFC and R-DLPFC showed a significant improvement in duration, especially in TMT-B performance, compared to fictitious.
The beneficial effects of tDCS on cognitive function have been shown in healthy subjects in other neuropsychiatric disorders. However, only a few studies have investigated the effects of cognitive symptoms of tDCS in patients with PD. The study is the first to show the long-term effects of tDCS on cognitive function in PD as measured by TMT-B. This test provides a measure of executive functions, such as mental flexibility, graphics engine speed, sequence line, and distributive attention.
It is important to discuss the results of this study in terms of main and simple effects. We showed a significant time effect for the TDCS treatment period without any group effect. This indicates that all groups had a similar improvement in TMT-B, which can be attributed to a learning outcome. Although these results contradict the findings of Boggio et al., Who showed that anodal tDCS over L-DLPFC was associated with a significant improvement in working memory immediately after stimulation, we should note the methodological differences between the study projects. Boggio et al. administered their cognitive tests during the stimulation session, while in the study, the tests were administered after stimulation. It is known that the mechanisms by which tDCS shows its effect are different for online and offline stimulation periods. The online effects of TDCS are related to changes in the polarization of neural membranes, while offline effects involve more complex processes, such as long-term potentiation (LTP) and long-term depression (LTD) that lead to the induction of long-term synaptic plasticity. The results from the follow-up period were consistent with the offline effects of tDCS.
There are several limitations to our study. The use of traditional neurophysiological measures to assess the effects of treatment may not be sensitive and insufficient to provide information about functional improvement. However, TMT-B has previously been used in clinical trials to measure the effects of treatment and has been used to predict clinical outcomes, such as the conversion from mild cognitive impairment to Alzheimer's disease. Therefore, future studies in PD should explore the use of other instruments to measure the effects of tDCS on cognition.
An important aspect to consider is the high placebo response rate observed in patients with PD. It was shown that the placebo response in tDCS studies could be higher than the placebo response in pharmacological studies.

Conclusions

The results of this study suggest that anodal tDCS over the prefrontal cortex could improve certain executive functions in PD without worsening motor or mood symptoms. Further studies are needed to determine whether there is a topographic specificity of the effects of tDCS on the various symptoms of PD and whether these effects can be sustained when used as a co-adjuvant for drug treatment.

At Centrokinetic you will find Dr. Edis Mustafa , a specialist in medical recovery, who specializes in tES therapy, treating over 200 patients, and none of them had any side effects. Dr. Mustafa did his doctorate in tES therapy, being the most experienced doctor in Romania.

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Our specialist,  Dr. Edis Mustafa, confidently recommends this new therapeutic approach, with exceptional personal results similar to those in various international studies published with patients treated so far. 

Here you can find a detailed list of prices for transcranial electrical stimulation (tES) services.

Prices

You can find here a detailed list of the prices of individual services. But any correct recovery process is based on a mixed plan of therapies and procedures, customized according to the condition, stage of the condition, patient profile, and other objective medical factors. As a result, in order to configure a treatment plan, with the therapies involved and the prices related to the plan, please make an appointment here for an initial consultation.

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