Parkinson Disease: Fregni F

Williams JA, Imamura M, Fregni F. · Department of Neurology, Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA. · J Rehabil Med. · Pubmed #19363560 No free full text.

Abstract: Brain stimulation for the treatment of neuropsychiatric diseases has been used for more than 50 years. Although its development has been slow, current advances in the techniques of brain stimulation have improved its clinical efficacy. The use of non-invasive brain stimulation has significant advantages, such as not involving surgical procedures and having relatively mild adverse effects. In this paper we briefly review the use of 2 non-invasive brain stimulation techniques, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as therapeutic approaches in physical and rehabilitation medicine. We also compare the effects of non-invasive central nervous system stimulation with techniques of non-invasive peri notpheral electrical stimulation, in order to provide new insights for future developments. Although the outcomes of these initial trials include some conflicting results, the evidence supports that rTMS and tDCS might have a therapeutic value in different neurological conditions. Studies published within the last year have examined new approaches of stimulation, such as longer intensities of stimulation, new electrode sizes for tDCS, novel coils for stimulation of deeper areas, and new frequencies of stimulation for rTMS. These new approaches need to be tested in larger clinical trials in order to determine whether they offer significant clinical effects.

Wu AD, Fregni F, Simon DK, Deblieck C, Pascual-Leone A. · Department of Neurology, University of California, Los Angeles, California 90095, USA. · Neurotherapeutics. · Pubmed #18394576 No free full text.

Abstract: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are promising noninvasive cortical stimulation methods for adjunctive treatment of movement disorders. They avoid surgical risks and provide theoretical advantages of specific neural circuit neuromodulation. Neuromodulatory effects depend on extrinsic stimulation factors (cortical target, frequency, intensity, duration, number of sessions), intrinsic patient factors (disease process, individual variability and symptoms, state of medication treatment), and outcome measures. Most studies to date have shown beneficial effects of rTMS or tDCS on clinical symptoms in Parkinson's disease (PD) and support the notion of spatial specificity to the effects on motor and nonmotor symptoms. Stimulation parameters have varied widely, however, and some studies are poorly controlled. Studies of rTMS or tDCS in dystonia have provided abundant data on physiology, but few on clinical effects. Multiple mechanisms likely contribute to the clinical effects of rTMS and tDCS in movement disorders, including normalization of cortical excitability, rebalancing of distributed neural network activity, and induction of dopamine release. It remains unclear how to individually adjust rTMS or tDCS factors for the most beneficial effects on symptoms of PD or dystonia. Nonetheless, the noninvasive nature, minimal side effects, positive effects in preliminary clinical studies, and increasing evidence for rational mechanisms make rTMS and tDCS attractive for ongoing investigation.

Fregni F, Pascual-Leone A. · Harvard Medical School and the Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · Nat Clin Pract Neurol. · Pubmed #17611487 No free full text.

Abstract: In neurology, as in all branches of medicine, symptoms of disease and the resulting burden of illness and disability are not simply the consequence of the injury, inflammation or dysfunction of a given organ; they also reflect the consequences of the nervous system's attempt to adapt to the insult. This plastic response includes compensatory changes that prove adaptive for the individual, as well as changes that contribute to functional disability and are, therefore, maladaptive. In this context, brain stimulation techniques tailored to modulate individual plastic changes associated with neurological diseases might enhance clinical benefits and minimize adverse effects. In this Review, we discuss the use of two noninvasive brain stimulation techniques--repetitive transcranial magnetic stimulation and transcranial direct current stimulation--to modulate activity in the targeted cortex or in a dysfunctional network, to restore an adaptive equilibrium in a disrupted network for best behavioral outcome, and to suppress plastic changes for functional advantage. We review randomized controlled studies, in focal epilepsy, Parkinson's disease, recovery from stroke, and chronic pain, to illustrate these principles, and we present evidence for the clinical effects of these two techniques.

Fregni F, Simon DK, Wu A, Pascual-Leone A. · Harvard Center for Noninvasive Brain Stimulation, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #16291882 links to  free full text

Abstract: A systematic review and meta-analysis were conducted to quantify the efficacy of transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) for the treatment of motor dysfunction in patients with Parkinson's disease (PD). Prospective studies which evaluated the effects of either TMS (12 studies) or ECT (five studies) on motor function in PD using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) for TMS studies and any continuous measures of motor function in PD for ECT studies were included. The pooled effect size (standardised mean difference between pre-treatment versus post-treatment means) from a random effects model was 0.62 (95% confidence interval: 0.38, 0.85) for TMS treatment and 1.68 (0.79, 2.56) for ECT treatment, and from a fixed effects model was 0.59 (0.39, 0.78) for TMS treatment and 1.55 (1.07, 2.03) for ECT treatment. TMS, across applied stimulation sites and parameters, can exert a significant, albeit modest, positive effect on the motor function of patients with PD. ECT also may exert a significant effect on motor function in PD patients.

Fregni F, Boggio PS, Bermpohl F, Maia F, Rigonatti SP, Barbosa ER, Pascual-Leone A. · Harvard Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass, USA. · Eur Neurol. · Pubmed #17057382 No free full text.

Abstract: BACKGROUND: A recent well-conducted meta-analysis showed that placebo effect is associated with a possible small benefit for subjective outcomes, but has no significant effects on objective outcomes. Objective: Herein, we aimed to investigate the immediate effects of two different types of placebo [placebo pill and sham transcranial magnetic stimulation (TMS)] in Parkinson's disease (PD) patients and compared them to the standard treatment (levodopa) in a proper randomized, double-blind, crossover clinical trial. METHODS: PD patients received three different interventions on different days: levodopa, placebo pill, and sham TMS. The motor function was assessed using simple and choice reaction time, Unified Parkinson's Disease Rating Scale (UPDRS), finger tapping, Purdue Pegboard test, time to button up, walking time and supination-pronation. The subjective motor function was measured by a visual analogue scale (VAS). RESULTS: The results showed that there was a significant motor function in the motor function only after the treatment with levodopa, but not after treatment with placebo pills or sham TMS. However, patients reported a similar subjective improvement in motor function indexed by VAS following these three treatments. CONCLUSION: These results suggest that placebo interventions in PD may have an immediate subjective sensation of improvement but result in no significant objective motor changes compared with levodopa treatment. Although physiological changes are possible after a placebo intervention, our findings suggest that the acute placebo effect in PD may be the result of the subjective change in the motor rating only.

Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, Valente KD, Pascual-Leone A, Marcolin MA. · Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #15258224 links to  free full text

Abstract: OBJECTIVE: To study the efficacy of 15 Hz repetitive transcranial magnetic stimulation (rTMS) in treating depression in patients with Parkinson's disease. METHODS: 42 patients were enrolled into two groups: group 1, active rTMS (15 Hz rTMS for 10 days) and placebo drug treatment; group 2, sham rTMS and fluoxetine 20 mg/day. A specially designed sham coil was used for sham stimulation. The unified Parkinson's disease rating scale (UPDRS), activities of daily living (ADL), Hamilton rating scale for depression (HRSD), Beck depression inventory (BDI), and mini-mental state examination (MMSE) were assessed by a rater blinded to treatment arm. RESULTS: HRSD and BDI were improved to the same extent in both groups after two weeks of treatment (38% and 32% for group 1, 41% and 33% for group 2, respectively). At week 8 there was a tendency for worse motor UPDRS scores in group 2 (NS). ADL showed improvement at week 8 only in group 1. MMSE improved in both groups after treatment, but faster in group 1 than in group 2. There were fewer adverse effects in group 1 than in group 2. CONCLUSIONS: rTMS has the same antidepressant efficacy as fluoxetine and may have the additional advantage of some motor improvement and earlier cognitive improvement, with fewer adverse effects.

Cardoso EF, Maia FM, Fregni F, Myczkowski ML, Melo LM, Sato JR, Marcolin MA, Rigonatti SP, Cruz AC, Barbosa ER, Amaro E. · NIF, LIM-44, Department of Radiology, University of São Paulo, São Paulo, Brazil. · Neuroimage. · Pubmed #19398020 No free full text.

Abstract: Depression is the most frequent psychiatric disorder in Parkinson's disease (PD). Although evidence suggests that depression in PD is related to the degenerative process that underlies the disease, further studies are necessary to better understand the neural basis of depression in this population of patients. In order to investigate neuronal alterations underlying the depression in PD, we studied thirty-six patients with idiopathic PD. Twenty of these patients had the diagnosis of major depression disorder and sixteen did not. The two groups were matched for PD motor severity according to Unified Parkinson Disease Rating Scale (UPDRS). First we conducted a functional magnetic resonance imaging (fMRI) using an event-related parametric emotional perception paradigm with test retest design. Our results showed decreased activation in the left mediodorsal (MD) thalamus and in medial prefrontal cortex in PD patients with depression compared to those without depression. Based upon these results and the increased neuron count in MD thalamus found in previous studies, we conducted a region of interest (ROI) guided voxel-based morphometry (VBM) study comparing the thalamic volume. Our results showed an increased volume in mediodorsal thalamic nuclei bilaterally. Converging morphological changes and functional emotional processing in mediodorsal thalamus highlight the importance of limbic thalamus in PD depression. In addition this data supports the link between neurodegenerative alterations and mood regulation.

Boggio PS, Khoury LP, Martins DC, Martins OE, de Macedo EC, Fregni F. · Center for Health and Biological Sciences, Mackenzie Presbyterian University, São Paulo, Brazil. · J Neurol Neurosurg Psychiatry. · Pubmed #18977813 No free full text.

Abstract: Several studies have reported that transcranial direct current stimulation (tDCS), a non-invasive method of neuromodulation, enhances some aspects of working memory in healthy and Parkinson disease subjects. The aim of this study was to investigate the impact of anodal tDCS on recognition memory, working memory and selective attention in Alzheimer disease (AD). Ten patients with diagnosis of AD received three sessions of anodal tDCS (left dorsolateral prefrontal cortex, left temporal cortex and sham stimulation) with an intensity of 2 mA for 30 min. Sessions were performed in different days in a randomised order. The following tests were assessed during stimulation: Stroop, Digit Span and a Visual Recognition Memory task (VRM). The results showed a significant effect of stimulation condition on VRM (p = 0.0085), and post hoc analysis showed an improvement after temporal (p = 0.01) and prefrontal (p = 0.01) tDCS as compared with sham stimulation. There were no significant changes in attention as indexed by Stroop task performance. As far as is known, this is the first trial showing that tDCS can enhance a component of recognition memory. The potential mechanisms of action and the implications of these results are discussed.

Cardoso EF, Fregni F, Martins Maia F, Boggio PS, Luis Myczkowski M, Coracini K, Lopes Vieira A, Melo LM, Sato JR, Antonio Marcolin M, Rigonatti SP, Cruz AC, Reis Barbosa E, Amaro E. · NIF, LIM-44, Department of Radiology, University of São Paulo, São Paulo, Brazil. · Int J Neuropsychopharmacol. · Pubmed #17708780 No free full text.

Abstract: The mechanisms underlying the effects of antidepressant treatment in patients with Parkinson's disease (PD) are unclear. The neural changes after successful therapy investigated by neuroimaging methods can give insights into the mechanisms of action related to a specific treatment choice. To study the mechanisms of neural modulation of repetitive transcranial magnetic stimulation (rTMS) and fluoxetine, 21 PD depressed patients were randomized into only two active treatment groups for 4 wk: active rTMS over left dorsolateral prefrontal cortex (DLPFC) (5 Hz rTMS; 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20 mg/d. Event-related functional magnetic resonance imaging (fMRI) with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time-point. The two groups of treatment had a significant, similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right DLPFC and brain activity increases in left DLPFC and anterior cingulate gyrus compared to baseline. In contrast, after fluoxetine treatment, there were brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups vs. time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network.

Boggio PS, Ferrucci R, Rigonatti SP, Covre P, Nitsche M, Pascual-Leone A, Fregni F. · Department of Experimental Psychology, University of Sao Paulo, Sao Paulo, Brazil; Núcleo de Neurociências, Mackenzie University, Sao Paulo, Brazil. · J Neurol Sci. · Pubmed #16843494 No free full text.

Abstract: OBJECTIVES: Cognitive impairment is a common feature in Parkinson's disease (PD) and is an important predictor of quality of life. Past studies showed that some aspects of cognition, such as working memory, can be enhanced following dopaminergic therapy and transcranial magnetic stimulation. The aim of our study was to investigate whether another form of noninvasive brain stimulation, anodal transcranial direct current stimulation (tDCS), which increases cortical excitability, is associated with a change in a working memory task performance in PD patients. METHODS: We studied 18 patients (12 men and 6 women) with idiopathic PD. The patients performed a three-back working memory task during active anodal tDCS of the left dorsolateral prefrontal cortex (LDLPFC), anodal tDCS of the primary motor cortex (M1) or sham tDCS. In addition, patients underwent two different types of stimulation with different intensities: 1 and 2 mA. RESULTS: The results of this study show a significant improvement in working memory as indexed by task accuracy, after active anodal tDCS of the LDLPFC with 2 mA. The other conditions of stimulation: sham tDCS, anodal tDCS of LDLPFC with 1 mA or anodal tDCS of M1 did not result in a significant task performance change. CONCLUSION: tDCS may exert a beneficial effect on working memory in PD patients that depends on the intensity and site of stimulation. This effect might be explained by the local increase in the excitability of the dorsolateral prefrontal cortex.

Fregni F, Boggio PS, Santos MC, Lima M, Vieira AL, Rigonatti SP, Silva MT, Barbosa ER, Nitsche MA, Pascual-Leone A. · Harvard Center for Non-Invasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. · Mov Disord. · Pubmed #16817194 No free full text.

Abstract: Electrical stimulation of deep brain structures, such as globus pallidus and subthalamic nucleus, is widely accepted as a therapeutic tool for patients with Parkinson's disease (PD). Cortical stimulation either with epidural implanted electrodes or repetitive transcranial magnetic stimulation can be associated with motor function enhancement in PD. We aimed to study the effects of another noninvasive technique of cortical brain stimulation, transcranial direct current stimulation (tDCS), on motor function and motor-evoked potential (MEP) characteristics of PD patients. We tested tDCS using different electrode montages [anodal stimulation of primary motor cortex (M1), cathodal stimulation of M1, anodal stimulation of dorsolateral prefrontal cortex (DLPFC), and sham-stimulation] and evaluated the effects on motor function--as indexed by Unified Parkinson's Disease Rating Scale (UPDRS), simple reaction time (sRT) and Purdue Pegboard test--and on corticospinal motor excitability (MEP characteristics). All experiments were performed in a double-blinded manner. Anodal stimulation of M1 was associated with a significant improvement of motor function compared to sham-stimulation in the UPDRS (P < 0.001) and sRT (P = 0.019). This effect was not observed for cathodal stimulation of M1 or anodal stimulation of DLPFC. Furthermore, whereas anodal stimulation of M1 significantly increased MEP amplitude and area, cathodal stimulation of M1 significantly decreased them. There was a trend toward a significant correlation between motor function improvement after M1 anodal-tDCS and MEP area increase. These results confirm and extend the notion that cortical brain stimulation might improve motor function in patients with PD.

Fregni F, Ono CR, Santos CM, Bermpohl F, Buchpiguel C, Barbosa ER, Marcolin MA, Pascual-Leone A, Valente KD. · Harvard Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. · Neurology. · Pubmed #16769932 No free full text.

Abstract: BACKGROUND: Although depression is highly prevalent in Parkinson disease (PD), little is known about the neural correlates associated with depression and antidepressant treatment in PD. OBJECTIVE: To examine the effects of fluoxetine and repetitive transcranial magnetic stimulation (rTMS) on regional cerebral blood flow (rCBF) using SPECT in patients with PD and depression. METHODS: Twenty-six patients were enrolled into two groups: One received active rTMS and placebo medication and the other sham rTMS and fluoxetine 20 mg/day. Brain SPECT was performed at baseline and after 2 and 8 weeks. Changes in rCBF were compared across timepoints and correlated with clinical scores. In addition, baseline rCBF of these patients was compared with that of 29 healthy, age-matched subjects. RESULTS: At baseline, patients with PD and depression showed significantly lower rCBF in the left prefrontal cortex, posterior cingulate gyrus, left insula, and right parietal cortex when compared with healthy controls. Both treatments induced significant clinical improvement and increases in rCBF in the posterior cingulate gyrus and decreases in rCBF in the right medial frontal gyrus. These changes were significantly correlated to the clinical outcome. Furthermore, the comparison between these two treatments revealed that whereas rTMS treatment was associated with an increased perfusion in the right and left prefrontal cortex, fluoxetine treatment was associated with a relative rCBF increase in the occipital lobe. CONCLUSION: Depression in patients with Parkinson disease is correlated with a dysfunction of the frontal-limbic network that can be modulated by two different antidepressant therapies.

Dias AE, Barbosa ER, Coracini K, Maia F, Marcolin MA, Fregni F. · Department of Neurology and Psychiatry, University of Sao Paulo, Sao Paulo, Brazil. · Acta Neurol Scand. · Pubmed #16411969 No free full text.

Abstract: OBJECTIVE: To investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on vocal function in Parkinson's disease (PD). MATERIAL AND METHODS: Two different sets of rTMS parameters were investigated on 30 patients with PD: active or sham 15 Hz rTMS of the left dorsolateral prefrontal cortex (LDLPFC) (110% of motor threshold (MT), 3000 pulses per session) and active 5 Hz rTMS of the primary motor cortex (M1)-mouth area (90% MT, 2250 pulses per session). A blind rater evaluated speech characteristics (acoustic and perceptual analysis of voice) and voice-related quality of life (V-RQOL). RESULTS: rTMS of LDLPFC resulted in mood amelioration and subjective improvement of the V-RQOL only (71.9% improvement, P < 0.001), but not in objective measures such as fundamental frequency (P = 0.86) and voice intensity (P = 0.99). On the other hand, rTMS of M1-mouth induced a significant improvement of the fundamental frequency (12.9% for men and 7.6% for women, P < 0.0001) and voice intensity (20.6%, P < 0.0001). CONCLUSIONS: Our findings provide initial evidence that rTMS of the primary motor cortex might yield a beneficial effect on vocal function in PD.

Boggio PS, Fregni F, Bermpohl F, Mansur CG, Rosa M, Rumi DO, Barbosa ER, Odebrecht Rosa M, Pascual-Leone A, Rigonatti SP, Marcolin MA, Araujo Silva MT. · Department of Experimental Psychology, Institute of Psychology, University of Sao Paulo, Sao Paulo, SP, Brazil. · Mov Disord. · Pubmed #15895421 No free full text.

Abstract: Previous studies show that cognitive functions are more impaired in patients with Parkinson's disease (PD) and depression than in nondepressed PD patients. We compared the cognitive effects of two types of antidepressant treatments in PD patients: fluoxetine (20 mg/day) versus repetitive transcranial magnetic stimulation (rTMS, 15 Hz, 110% above motor threshold, 10 daily sessions) of the left dorsolateral prefrontal cortex. Twenty-five patients with PD and depression were randomly assigned either to Group 1 (active rTMS and placebo medication) or to Group 2 (sham rTMS and fluoxetine). A neuropsychological battery was assessed by a rater blind to treatment arm at baseline and 2 and 8 weeks after treatment. Patients in both groups had a significant improvement of Stroop (colored words and interference card) and Hooper and Wisconsin (perseverative errors) test performances after both treatments. Furthermore, there were no adverse effects after either rTMS or fluoxetine in any neuropsychological test of the cognitive test battery. The results show that rTMS could improve some aspects of cognition in PD patients similar to that of fluoxetine. The mechanisms for this cognitive improvement are unclear, but it is in the context of mood improvement.