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17 October 2014
, Pages 27-31
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Non-motor symptoms in patients with Parkinson's disease (PD) are often poorly recognized, significantly impair quality of life and cause severe disability. Currently, there is limited evidence to guide treatment of associated psychiatric and cognitive problems. Non-invasive brain stimulation techniques have emerged as non-pharmacological alternatives to target cognitive symptoms without worsening motor function. In this context, we conducted a multicenter, sham controlled, double-blinded study to assess the immediate and long-term effects of ten consecutive sessions of transcranial direct current stimulation (tDCS) over the anode on the right dorsolateral prefrontal cortex (DLPFC) (n=5), left DLPFC (n=6) or sham (n=7). We assessed cognitive functions, depressive symptoms and motor functions in 18 PD patients at baseline, at the end of the 2-week stimulation sessions and at 1-month follow-up. Our results showed that active stimulation of both left and right DLPFC resulted in prolonged improvements in Trail Making Test B, an established test to measure executive function, compared to sham tDCS at the 1-month follow-up. These results suggest the existence of a beneficial long-term effect on executive functions in PD patients following active tDCS over the DLPFC. Thus, our findings encourage further investigation exploring tDCS as an adjuvant therapy for cognitive and behavioral treatment in PD.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by gradual impairment of affective, cognitive and motor function . Although motor symptoms such as resting tremor, bradykinesia, rigidity and postural instability are the hallmark of this disorder, cognitive and psychiatric non-motor symptoms (NMS) are equally disabling and directly impact the quality of life (QOL) of patients with PD . In fact, recent reports show that even after controlling for duration and severity of motor symptoms, cognitive abilities, such as executive and visuospatial functions, remain positively associated with QOL . Furthermore, psychiatric comorbidities, namely depression, consistently emerge amongst the strongest determinant of health related QOL in this patient cohort . For these reasons, there is growing interest in treating and managing neuropsychiatric symptoms in patients with PD .
Cognitive functions are predominantly executed by the cortex, where dopamine is known to play a key role . It has been suggested that impairment of cognitive function is related to a disruption of the dopaminergic system , which is also severely affected in PD. In fact, cognitive deficits in Parkinson's disease are similar to a dysexecutive syndrome. Depression, a common co-morbidity in PD, is also suggested to be caused by changes in dopaminergic transmission and alterations in excitability and imbalance between the 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) have shown to be safe and effective methods for improving cognitive and affective functions . TDCS applied with the anode over the L-DLPFC and the cathode over the right supraorbital region, can improve working memory in healthy subjects , as well as improve mood in patients with major depression , . In this context, several studies have documented the beneficial effects of TMS and tDCS on behavioral and cognitive symptoms in PD , , ,  without worsening motor symptoms .
These results support the idea that active stimulation of the DLPFC with tDCS could have beneficial, lasting effects on both affective and cognitive domains in patients with PD. Therefore, we conducted a two-site, double-blind, sham-controlled, 10-session tDCS study in patients with PD. We hypothesized that tDCS applied over the L-DLPFC would improve cognitive function and affective symptoms without altering motor function when compared to sham stimulation.
Eighteen patients (6 women and 12 men) aged between 40 and 71 years (mean age 61±8 years) with idiopathic PD were enrolled in the study. Inclusion criteria included a clinical diagnosis of PD defined by the presence of at least two out of three cardinal motor features of PD (resting tremor, rigidity, and bradykinesia, plus a sustained and significant response to dopaminergic treatment), age of 40 and over, and stable maintenance of their medication at least 30 days prior to enrollment and
Eighteen patients were included in the study: six patients were randomly assigned to the L-DLPFC group, five patients to the R-DLPFC group, and seven patients to the sham tDCS group. The mean baseline MMSE score for all groups was 29.2±0.3 (mean±SEM). There was no significant difference between groups in demographics or in any of the cognitive, affective, or behavioral measures at baseline (all p>0.05). The most common side effects reported were tingling (50%), sleepiness (55%) and mild
In this study we assessed the effects of tDCS with the anode over the L-DLPFC or R-DLPFC on a wide range of cognitive, affective and motor functions in patients with PD. We found that anodal tDCS over both L-DLPFC and R-DLPFC showed a significantly lasting improvement specifically in TMT-B performance when compared to sham.
Beneficial effects of tDCS on cognitive function have been shown in healthy subjects and in other neuropsychiatric conditions , , , . However, only a few
Results of this exploratory study suggest that anodal tDCS over the prefrontal cortex might enhance certain executive functions in PD without worsening of motor or mood symptoms. Further studies are needed to determine if there is a topographic specificity to the effects of tDCS on the various symptoms in PD, and whether these effects can be sustained when used as a co-adjuvant to pharmacological treatment.
Conflict of interest
Source of funding
This study is sponsored by the RJG Foundation.
We would like to acknowledge Huashun Cui, Jean-François Lepage, and Pakorn Wivatvongvana for their technical assistance in this protocol.
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Is quality of life in non-demented Parkinson's disease patients related to cognitive performance? A clinic-based cross-sectional study
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The cortical dopamine system: role in memory and cognition
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Cognition and freezing of gait in Parkinson's disease: A systematic review and meta-analysis
2023, Neuroscience and Biobehavioral Reviews
Freezing of gait (FOG) is a common and disabling symptom in people with Parkinson's Disease (PwPD). Although cognition is thought to be worse in PwPD who freeze, a comprehensive analysis of this relationship will inform future research and clinical care. This systematic review and meta-analysis compared cognition between PwPD who do and do not exhibit FOG across a range of cognitive domains and assessed the impact of disease severity and medication status on this relationship. 145 papers (n=9010 participants) were included in the analysis, with 144 and 138 articles meeting the criteria to assess moderating effects of disease severity and medication status, respectively. PwPD who freeze exhibited worse cognition than PwPD without FOG across global cognition, executive function/attention, language, memory, and visuospatial domains. Greater disease severity and "ON" levodopa medication status moderated the FOG status-cognition relationship in global cognitive performance but not in other cognitive domains. This meta-analysis confirmed that cognition is worse in PwPD with FOG and highlights the importance of disease severity and medication status in this relationship.
Cerebral metabolic rate of oxygen (CMRO<inf>2</inf>) changes measured with simultaneous tDCS-MRI in healthy adults
2022, Brain Research
Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive technique used for cortical excitability modulation. tDCS has been extensively investigated for its clinical applications; however further understanding of its underlying in-vivo physiological mechanisms remains a fundamental focus of current research.
We investigated the simultaneous effects of tDCS on cerebral blood flow (CBF), venous blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO2) using simultaneous MRI in healthy adults to provide a reference frame for its neurobiological mechanisms.
Twenty-three healthy participants (age=35.6±15.0years old, 10 males) completed a simultaneous tDCS-MRI session in a 3T scanner fitted with a 64-channels head coil. A MR-compatible tDCS device was used to acquire CBF, Yv and CMRO2 at three time points: pre-, during- and post- 15minutes of 2.0mA tDCS on left anodal dorsolateral prefrontal cortex.
During tDCS, CBF significantly increased (57.10±8.33mL/100g/min) from baseline (53.67±7.75mL/100g/min; p<0.0001) and remained elevated in post-tDCS (56.79±8.70mL/100g/min). Venous blood oxygenation levels measured in pre-tDCS (60.71±4.12%) did not significantly change across the three timepoints. The resulting CMRO2 significantly increased by 5.9% during-tDCS (175.68±30.78µmol/100g/min) compared to pre-tDCS (165.84±25.32µmol/100g/min; p=0.0015), maintaining increased levels in post-tDCS (176.86±28.58µmol/100g/min).
tDCS has immediate effects on neuronal excitability, as measured by increased cerebral blood supply and oxygen consumption supporting increased neuronal firing. These findings provide a standard range of CBF and CMRO2 changes due to tDCS in healthy adults that may be incorporated in clinical studies to evaluate its therapeutic potential.
Things you wanted to know (but might have been afraid to ask) about how and why to explore and modulate brain plasticity with non-invasive neurostimulation technologies
2022, Revue Neurologique
Brain plasticity can be defined as the ability of local and extended neural systems to organize either the structure and/or the function of their connectivity patterns to better adapt to changes of our inner/outer environment and optimally respond to new challenging behavioral demands. Plasticity has been traditionally conceived as a spontaneous phenomenon naturally occurring during pre and postnatal development, tied to learning and memory processes, or enabled following neural damage and their rehabilitation. Such effects can be easily observed and measured but remain hard to harness or to tame ‘at will’. Non-invasive brain stimulation (NIBS) technologies offer the possibility to engage plastic phenomena, and use this ability to characterize the relationship between brain regions, networks and their functional connectivity patterns with cognitive process or disease symptoms, to estimate cortical malleability, and ultimately contribute to neuropsychiatric therapy and rehabilitation. NIBS technologies are unique tools in the field of fundamental and clinical research in humans. Nonetheless, their abilities (and also limitations) remain rather unknown and in the hands of a small community of experts, compared to widely established methods such as functional neuroimaging (fMRI) or electrophysiology (EEG, MEG). In the current review, we first introduce the features, mechanisms of action and operational principles of the two most widely used NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Current Stimulation (tCS), for exploratory or therapeutic purposes, emphasizing their bearings on neural plasticity mechanisms. In a second step, we walk the reader through two examples of recent domains explored by our team to further emphasize the potential and limitations of NIBS to either explore or improve brain function in healthy individuals and neuropsychiatric populations. A final outlook will identify a series of future topics of interest that can foster progress in the field and achieve more effective manipulation of brain plasticity and interventions to explore and improve cognition and treat the symptoms of neuropsychiatric diseases.
Neuromodulation of cognition in Parkinson's disease
2022, Progress in Brain Research
Neuromodulation is a widely used treatment for motor symptoms of Parkinson's disease (PD). It can be a highly effective treatment as a result of knowledge of circuit dysfunction associated with motor symptoms in PD. However, the mechanisms underlying cognitive symptoms of PD are less well-known, and the effects of neuromodulation on these symptoms are less consistent. Nonetheless, neuromodulation provides a unique opportunity to modulate motor and cognitive circuits while minimizing off-target side effects. We review the modalities of neuromodulation used in PD and the potential implications for cognitive symptoms. There have been some encouraging findings with both invasive and noninvasive modalities of neuromodulation, and there are promising advances being made in the field of therapeutic neuromodulation. Substantial work is needed to determine which modulation targets are most effective for the different types of cognitive deficits of PD.
Parkinson's disease: Alterations of motor plasticity and motor learning
2022, Handbook of Clinical Neurology
This chapter reviews the alterations in motor learning and motor cortical plasticity in Parkinson's disease (PD), the most common movement disorder. Impairments in motor learning, which is a hallmark of basal ganglia disorders, influence the performance of motor learning-related behavioral tasks and have clinical implications for the management of disturbance in gait and posture, and for rehabilitative management of PD. Although plasticity is classically induced and assessed in sliced preparation in animal models, in this review we have concentrated on the results from non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS), transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) in patients with PD, in addition to a few animal electrophysiologic studies. The chapter summarizes the results from different cortical and subcortical plasticity investigations. Plasticity induction protocols reveal deficient plasticity in PD and these plasticity measures are modulated by medications and deep brain stimulation. There is considerable variability in these measures that are related to inter-individual variations, different disease characteristics and methodological considerations. Nevertheless, these pathophysiologic studies expand our knowledge of cortical excitability, plasticity and the effects of different treatments in PD. These tools of modulating plasticity and motor learning improve our understanding of PD pathophysiology and help to develop new treatments for this disabling condition.
Noninvasive neuromodulation in Parkinson's disease: Neuroplasticity implication and therapeutic perspectives
2022, Handbook of Clinical Neurology
Noninvasive brain stimulation techniques can be used to study in vivo the changes of cortical activity and plasticity in subjects with Parkinson's disease (PD). Also, an increasing number of studies have suggested a potential therapeutic effect of these techniques. High-frequency repetitive transcranial magnetic stimulation (rTMS) and anodal transcranial direct current stimulation (tDCS) represent the most used stimulation paradigms to treat motor and nonmotor symptoms of PD. Both techniques can enhance cortical activity, compensating for its reduction related to subcortical dysfunction in PD. However, the use of suboptimal stimulation parameters can lead to therapeutic failure. Clinical studies are warranted to clarify in PD the additional effects of these stimulation techniques on pharmacologic and neurorehabilitation treatments.
Estradiol alleviates the ischemic brain injury-induced decrease of neuronal calcium sensor protein hippocalcin
Neuroscience Letters, Volume 582, 2014, pp. 32-37
Estradiol has protective and reparative effects in neurodegenerative diseases. Hippocalcin is a neuronal calcium-sensor protein that acts as a calcium buffer to regulate the intracellular concentration of Ca2+. This study was investigated to elucidate whether estradiol regulates hippocalcin expression in a focal cerebral ischemia model and glutamate-treated neuronal cells. An ovariectomy was performed in adult female rats, and vehicle or estradiol was administered before middle cerebral artery occlusion (MCAO). Cerebral cortex tissues were collected at 24h after MCAO. A proteomic approach revealed that hippocalcin expression decreased in vehicle-treated animals with combined MCAO, while estradiol treatment attenuated this decrease. Reverse transcription-PCR and Western blot analyses also showed that estradiol administration prevented the MCAO injury-induced decrease in hippocalcin expression. In cultured hippocampal cells, glutamate exposure increased the intracellular Ca2+ concentration, which was rescued by the presence of estradiol. Moreover, glutamate toxicity decreased hippocalcin expression, whereas estradiol attenuated this decrease. Together, these findings suggest that estradiol has a neuroprotective function by regulating hippocalcin expression and intracellular Ca2+ levels in ischemic brain injury.
Polarity Independent Effects of Cerebellar tDCS on Short Term Ankle Visuomotor Learning
Brain Stimulation, Volume 6, Issue 6, 2013, pp. 966-968
Transcranial direct current stimulation (tDCS), an emerging technique of noninvasive brain stimulation, has shown to produce beneficial neural effects in consequence with improvements in motor behavior. There are not many studies examining the use of tDCS for lower limb motor control and learning. Most studies using tDCS for facilitating lower limb motor coordination have applied tDCS to the lower limb motor cortex (M1). As the cerebellum is also critically involved in movement control, it is important to dissociate the effect of tDCS on the cerebellum and M1 with respect to lower limb motor control before we begin the application of tDCS as a neuromodulatory tool.
The purpose of this study was to determine the effects of cerebellar vs. motor cortical tDCS on short term ankle visuomotor learning in healthy individuals.
Eight healthy individuals practiced a skilled ankle motor tracking task while receiving either facilitatory anodal tDCS to cerebellum, inhibitory cathodal tDCS to cerebellum, facilitatory anodal tDCS to M1, inhibitory cathodal tDCS to M1 or sham stimulation. Pre- and post-measures of changes in cortical excitability of the tibialis anterior muscle and measures of tracking accuracy were assessed.
Anodal cerebellar, cathodal cerebellar, and anodal M1 stimulation improved target-tracking accuracy of the ankle. This was not dependent on the observed changes in motor cortical excitability of the tibialis anterior muscle.
Polarity independent effects of tDCS on cerebellum were observed. The present study shows that modulation effects of tDCS can occur because of changes in the cerebellum, a structure implicated in several forms of motor learning, providing an additional way in which tDCS can be used to improve motor coordination.
Quantitative Review Finds No Evidence of Cognitive Effects in Healthy Populations From Single-session Transcranial Direct Current Stimulation (tDCS)
Brain Stimulation, Volume 8, Issue 3, 2015, pp. 535-550
Over the last 15-years, transcranial direct current stimulation (tDCS), a relatively novel form of neuromodulation, has seen a surge of popularity in both clinical and academic settings. Despite numerous claims suggesting that a single session of tDCS can modulate cognition in healthy adult populations (especially working memory and language production), the paradigms utilized and results reported in the literature are extremely variable. To address this, we conduct the largest quantitative review of the cognitive data to date.
Single-session tDCS data in healthy adults (18–50) from every cognitive outcome measure reported by at least two different research groups in the literature was collected. Outcome measures were divided into 4 broad categories: executive function, language, memory, and miscellaneous. To account for the paradigmatic variability in the literature, we undertook a three-tier analysis system; each with less-stringent inclusion criteria than the prior. Standard mean difference values with 95% CIs were generated for included studies and pooled for each analysis.
Of the 59 analyses conducted, tDCS was found to not have a significant effect on any – regardless of inclusion laxity. This includes no effect on any working memory outcome or language production task.
Our quantitative review does not support the idea that tDCS generates a reliable effect on cognition in healthy adults. Reasons for and limitations of this finding are discussed. This work raises important questions regarding the efficacy of tDCS, state-dependency effects, and future directions for this tool in cognitive research.
The Uncertain Outcome of Prefrontal tDCS
Brain Stimulation, Volume 7, Issue 6, 2014, pp. 773-783
Transcranial direct current stimulation (tDCS) is increasingly used in research and clinical settings, and the dorsolateral prefrontal cortex (DLPFC) is often chosen as a target for stimulation. While numerous studies report modulation of cognitive abilities following DLPFC stimulation, the wide array of cognitive functions that can be modulated makes it difficult to predict its precise outcome.
The present review aims at identifying and characterizing the various cognitive domains affected by tDCS over DLPFC.
Articles using tDCS over DLPFC indexed in PubMed and published between January 2000 and January 2014 were included in the present review.
tDCS over DLPFC affects a wide array of cognitive functions, with sometimes apparent conflicting results.
Prefrontal tDCS has the potential to modulate numerous cognitive functions simultaneously, but to properly interpret the results, a clear a priori hypothesis is necessary, careful technical consideration are mandatory, further insights into the neurobiological impact of tDCS are needed, and consideration should be given to the possibility that some behavioral effects may be partly explained by parallel modulation of related functions.
Effects of a Non-focal Plasticity Protocol on Apathy in Moderate Alzheimer's Disease: A Randomized, Double-blind, Sham-controlled Trial
Brain Stimulation, Volume 7, Issue 2, 2014, pp. 308-313
Apathy is the most common neuropsychiatric symptom in Alzheimer's disease (AD) and it is associated with changes in prefrontal neural circuits involved with generation of voluntary actions. To date no effective treatment for apathy has been demonstrated.
We aimed to investigate the effects and safety of repetitive transcranial direct current stimulation (tDCS) on apathy in moderate AD patients.
Forty patients were randomized to receive either active or sham-tDCS over the left dorsolateral prefrontal cortex (DLPFC). Patients received six sessions of intervention during 2 weeks and were evaluated at baseline, at week 1 and 2, and after 1 week without intervention. Clinical raters, patients, and caregivers were blinded. The primary outcome was apathy. Global cognition and neuropsychiatric symptoms were examined as secondary outcomes.
The mean MMSE score at baseline was 15.2±2.9 and the mean Apathy Scale score was 27.7±6.7. Changes on apathy scores over time were not different between active and sham tDCS (P=0.552 for repeated measures). Further analyses confirm that changes from baseline did not differ between groups after the sixth session (active tDCS−1.95 (95%CI−3.49,−0.41); sham-tDCS−2.05 (95%CI−3.68,−0.42); P=0.989]. Similarly, tDCS had no effect on secondary outcomes (P>0.40). tDCS was well tolerated and not associated with significant adverse effects.
In this adequately powered study for minimal clinically significant difference, our findings show that using the parameters we chose for this study, repeated anodal tDCS over the left DLPFC had no effect on apathy in elderly patients with moderate AD.
Testing the limits: Investigating the effect of tDCS dose on working memory enhancement in healthy controls
Neuropsychologia, Volume 51, Issue 9, 2013, pp. 1777-1784
Transcranial Direct Current Stimulation (tDCS) is a non-invasive form of brain stimulation which has been shown to induce changes in brain activity and subsequent functioning. In particular, there is a rapidly growing evidence base showing that anodal tDCS applied to the left prefrontal cortex (PFC) is able to enhance aspects of cognitive functioning, in particular working memory (WM). This has led to both excitement and concerns regarding the possibility of ‘electrodoping’ in order to greatly improve one's cognitive performance. We investigated the behavioural and neurophysiological effects of increasing the current (or ‘dose’) of tDCS on the degree of WM improvement in healthy controls. Single sessions of 1mA, 2mA and sham anodal tDCS to the left PFC were undertaken over a period of three weeks. Participants underwent a WM task at three time points post-stimulation (0, 20 and 40min) with concurrent electrophysiological (EEG) recordings. Our results showed that while active tDCS can enhance behavioural performance, with neurophysiological findings indicating improve efficiency of cognitive processing; we showed that 1mA produced the most significant effects. These findings are somewhat unexpected as tDCS dose effects in cognitive enhancement have been shown previously in patient populations. Our results provide valuable information regarding the potential limits of tDCS induced cognitive enhancement in healthy controls, as well as providing additional insights into the possible mechanisms of action of tDCS.
Equally contributing authors.
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