Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease.

OBJECTIVE: To assess the effects of focal motor cortex stimulation on motor performance and cortical excitability in patients with Parkinson's disease (PD). METHODS: Repetitive transcranial magnetic stimulation (rTMS) was performed on the left motor cortical area corresponding to the right hand in 12 'off-drug' patients with PD. The effects of subthreshold rTMS applied at 0.5 Hz (600 pulses) or at 10 Hz (2000 pulses) using a 'real' or a 'sham' coil were compared to those obtained by a single dose of l-dopa. The assessment included a clinical evaluation by the Unified Parkinson's Disease Rating Scale and timed motor tasks, and a neurophysiological evaluation of cortical excitability by single- and paired-pulse TMS techniques. RESULTS: 'Real' rTMS at 10 or 0.5 Hz, but not 'sham' stimulation, improved motor performance. High-frequency rTMS decreased rigidity and bradykinesia in the upper limb contralateral to the stimulation, while low-frequency rTMS reduced upper limb rigidity bilaterally and improved walking. Concomitantly, 10 Hz rTMS increased intracortical facilitation, while 0.5 Hz rTMS restored intracortical inhibition. CONCLUSIONS: Low- and high-frequency rTMS of the primary motor cortex lead to significant but differential changes in patients with PD both on clinical and electrophysiological grounds. The effects on cortical excitability were opposite to previous observations made in healthy subjects, suggesting a reversed balance of cortical excitability in patients with PD compared to normals. However, the underlying mechanisms of these changes remain to determine, as well as the relationship with clinical presentation and response to l-dopa therapy. SIGNIFICANCE: The present study gives some clues to appraise the role of the primary motor cortex in PD. Clinical improvement induced by rTMS was too short-lasting to consider therapeutic application, but these results support the perspective of the primary motor cortex as a possible target for neuromodulation in PD.     

Effect of daily repetitive transcranial magnetic stimulation on motor performance in Parkinson's disease.

Previous studies in patients with Parkinson's disease have reported that a single session of repetitive transcranial magnetic stimulation (rTMS) can improve some or all of the motor symptoms for 30 to 60 minutes. A recent study suggested that repeated sessions of rTMS lead to effects that can last for at least 1 month. Here we report data that both confirm and extend this work. Fifty-five unmedicated PD patients were classified into four groups: two groups (early and late PD) received 25 Hz rTMS bilaterally on the motor arm and leg areas; other groups acted as control for frequency (10 Hz) and for site of stimulation (occipital stimulation). All patients received six consecutive daily sessions (3,000 pulses for each session). The first two groups then received a further three booster sessions (3 consecutive days of rTMS) after 1, 2, and 3 months, while the third group had only one additional session after the first month. Unified Parkinson's Disease Rating Scale (UPDRS), walking time, key-tapping speed, and self-assessment scale were measured for each patient before and after each rTMS session and before and after the monthly sessions. Compared to occipital stimulation, 25 Hz rTMS over motor areas improved all measures in both early and late groups; the group that received 10 Hz rTMS improved more than the occipital group but less than the 25 Hz groups. The effect built up gradually during the sessions and was maintained for 1 month after, with a slight reduction in efficacy. Interestingly, the effect was restored and maintained for the next month by the booster sessions. We conclude that 25 Hz rTMS can lead to cumulative and long-lasting effects on motor performance.     

Statistic rCBF study of extrapyramidal disorders]

We studied regional cerebral blood flow (rCBF) in 16 patients with Parkinson's disease (PD), 2 patients with dementia with Lewy bodies (DLB), 2 patients with progressive supranuclear palsy (PSP), 2 patients with striatonigral degeneration, and 16 normal volunteers, using Three-dimensional stereotactic surface projections (3 D-SSP). Decreased rCBF in PD patients was shown in the posterior parietal and occipital cortex. Decreased rCBF in DLB was shown in the frontal, parietal and occipital cortex with relative sparing of the sensorimotor cortex. Decreased rCBF in PSP was shown in the frontal cortex. Decreased rCBF in SND was shown in the frontal cortex and cerebellum. Statistic rCBF analysis using 3 D-SSP was a useful measure for the early differential diagnosis of extrapyramidal disorders.     

Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients.

BACKGROUND: High (10-20 Hz) and low frequency (1-5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits. METHODS: Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using (15)O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test. RESULTS: Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L > R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related (r = -.78, p <.005, n = 10) such that individuals who improved with one frequency worsened with the other. CONCLUSIONS: These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.     

0.2-Hz repetitive transcranial magnetic stimulation has no add-on effects as compared to a realistic sham stimulation in Parkinson's disease.

To study the efficacy of 0.2-Hz repetitive transcranial magnetic stimulation (rTMS) on Parkinson's disease (PD), 85 patients with PD were enrolled into three groups: 1). motor cortical, 2). occipital, and 3). sham stimulation. A round coil was centered over the vertex in motor cortical stimulation, and over the inion in occipital stimulation. In one session, 100 stimuli of 0.2-Hz rTMS at an intensity of 1.1 times active motor threshold (AMT) were given. In sham stimulation, electric currents were given with electrodes fixed on the head to mimic the sensation in real stimulation. Each session was carried out once a week for the first 8 weeks. The Unified Parkinson Disease Rating Scale (UPDRS), Hamilton Rating Scale for Depression (HRSD) and subjective score (visual analogue scale) were assessed. There were no significant differences in clinical features among the three groups. Total and motor score of UPDRS were improved to the same extent by rTMS over Cz, inion, and sham stimulation. HRSD was improved by rTMS over Cz and sham stimulation in the same manner. Subjective score was not significantly improved by any methods of stimulation. 0.2-Hz rTMS at an intensity of 1.1 x AMT has only a placebo effect on PD. Our realistic sham stimulation maneuver must produce powerful placebo effects as a real stimulation.     

Comparison of monophasic versus biphasic stimulation in rTMS over premotor cortex: SEP and SPECT studies

OBJECTIVE: To optimize the clinical uses of repetitive transcranial magnetic stimulation (rTMS), we compared the effects of rTMS on somatosensory-evoked potentials (SEPs) and regional cerebral blood flow (rCBF) using different phases (monophasic vs. biphasic) or frequencies (0.2Hz vs. 0.8Hz) of stimulation. METHODS: In the first experiment, different phases were compared (0.2Hz monophasic vs. 0.2Hz biphasic). Biphasic 1Hz or sham condition served as controls. The second experiment was to explore the effect of frequencies (0.2Hz vs. 0.8Hz) using the monophasic stimulation. Substhreshold TMS was applied 250 times over the left premotor cortex. Single photon emission computed tomography (SPECT) was performed before and after monophasic 0.2Hz or biphasic 1Hz rTMS. RESULTS: Monophasic rTMS of both 0.2 and 0.8Hz significantly increased the ratio of N30 amplitudes as compared with sham rTMS, whereas biphasic stimulation showed no significant effects. SPECT showed increased rCBF in motor cortices after monophasic 0.2Hz rTMS, but not after biphasic 1Hz stimulation. CONCLUSIONS: Monophasic rTMS exerted more profound effects on SEPs and rCBF than biphasic rTMS over the premotor cortex. SIGNIFICANCE: Monophasic rTMS over the premotor cortex could be clinically more useful than biphasic rTMS.     

Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: I. Effects of primary motor cortex rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) affects the excitability of the motor cortex and is thought to influence activity in other brain areas as well. We combined the administration of varying intensities of 1-Hz rTMS of the motor cortex with simultaneous positron emission tomography (PET) to delineate local and distant effects on brain activity. METHODS: Ten healthy subjects received 1-Hz rTMS to the optimal position over motor cortex (M1) for producing a twitch in the right hand at 80, 90, 100, 110, and 120% of the twitch threshold, while regional cerebral blood flow (rCBF) was measured using H(2)(15)O and PET. Repetitive transcranial magnetic stimulation (rTMS) was delivered in 75-pulse trains at each intensity every 10 min through a figure-eight coil. The regional relationship of stimulation intensity to normalized rCBF was assessed statistically. RESULTS: Intensity-dependent rCBF increases were produced under the M1 stimulation site in ipsilateral primary auditory cortex, contralateral cerebellum, and bilateral putamen, insula, and red nucleus. Intensity-dependent reductions in rCBF occurred in contralateral frontal and parietal cortices and bilateral anterior cingulate gyrus and occipital cortex. CONCLUSIONS: This study demonstrates that 1-Hz rTMS delivered to the primary motor cortex (M1) produces intensity-dependent increases in brain activity locally and has associated effects in distant sites with known connections to M1.     

Placebo-controlled study of rTMS for the treatment of Parkinson's disease.

The objective of this study is to assess the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) for gait and bradykinesia in patients with Parkinson's disease (PD). In a double-blind placebo-controlled study, we evaluated the effects of 25 Hz rTMS in 18 PD patients. Eight rTMS sessions were performed over a 4-week period. Four cortical targets (left and right motor and dorsolateral prefrontal cortex) were stimulated in each session, with 300 pulses each, 100% of motor threshold intensity. Left motor cortex (MC) excitability was assessed using motor evoked potentials (MEPs) from the abductor pollicis brevis. During the 4 weeks, times for executing walking and complex hand movements tests gradually decreased. The therapeutic rTMS effect lasted for at least 1 month after treatment ended. Right-hand bradykinesia improvement correlated with increased MEP amplitude evoked by left MC rTMS after individual sessions, but improvement overall did not correlate with MC excitability. rTMS sessions appear to have a cumulative benefit for improving gait, as well as reducing upper limb bradykinesia in PD patients. Although short-term benefit may be due to MC excitability enhancement, the mechanism of cumulative benefit must have another explanation.     

Effects of DBS,premotor rTMS,and levodopa on motor function and silent period in advanced Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used and highly effective treatment for patients with advanced Parkinson's disease (PD). Repetitive TMS (rTMS) applied to motor cortical areas has also been shown to improve symptoms in PD and modulate motor cortical excitability. Here, we compared clinical and neurophysiological effects of STN stimulation with those of 1 Hz rTMS given to the dorsal premotor cortex (PMd) and those following intake of levodopa in a group of PD patients with advanced disease. Ten PD patients were studied on 2 consecutive days before and after surgery. Clinical effects were determined using the UPDRS motor score. Motor thresholds, motor‐evoked potential (MEP) amplitudes during slight voluntary contraction, and the cortical silent periods (SP) were measured using TMS. Before surgery effects of levodopa and 1 Hz PMd rTMS and after surgery those of STN stimulation with or without additional levodopa were determined. Levodopa significantly improved clinical symptoms and increased the SP duration. STN stimulation improved clinical symptoms without changing the SP duration. In contrast, 1 Hz PMd rTMS was not effective clinically but normalized the SP duration. Whereas levodopa had widespread effects at different levels of an abnormally active motor network in PD, STN stimulation and PMd rTMS led to either clinical improvement or SP normalization, i.e., only partially reversed abnormal motor network activity. © 2009 Movement Disorder Society     

Repetitive transcranial magnetic stimulation to improve mood and motor function in Parkinson's disease

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can produce lasting changes in excitability and activity in cortical regions underneath the stimulation coil (local effect), but also within functionally connected cortical or subcortical regions (remote effects). Since the clinical presentation of Parkinson's disease (PD) is related to abnormal neuronal activity within the basal ganglia and cortical regions, including the primary motor cortex, the premotor cortex and the prefrontal cortex, several studies have used rTMS to improve brain function in PD. Here, we review the studies that have investigated the possible therapeutic effects of rTMS on mood and motor function in PD patients. We highlight some methodological inconsistencies and problems, including the difficulty to define the most effective protocol for rTMS or to establish an appropriate placebo condition. We finally propose future directions of research that may help to improve the therapeutic efficacy of rTMS in PD.     

Effect of high frequency repetitive transcranial magnetic stimulation on reaction time,clinical features and cognitive functions in patients with Parkinson’s disease

The aim of the present study was to investigate the effects of one session of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the left dorsal premotor cortex (PMd) and left dorsolateral prefrontal cortex (DLPFC) on choice reaction time in a noise-compatibility task, and cognitive functions in patients with Parkinson’s disease (PD). Clinical motor symptoms of PD were assessed as well. Ten patients with PD entered a randomized, placebo-controlled study with a crossover design. Each patient received 10 Hz stimulation over the left PMd and DLPFC (active stimulation sites) and the occipital cortex (OCC; a control stimulation site) in the OFF motor state, i.e. at least after 12 h of dopaminergic drugs withdrawal. Frameless stereotaxy was used to target the optimal position of the coil. For the evaluation of reaction time, we used a noise-compatibility paradigm. A short battery of neuropsychological tests was performed to evaluate executive functions, working memory, and psychomotor speed. Clinical assessment included a clinical motor evaluation using part III of the Unified Parkinson’s Disease Rating Scale. Statistical analysis revealed no significant effect of rTMS applied over the left PMd and/or DLPFC in patients with PD in any of the measured parameters. In this study, we did not observe any effect of one session of high frequency rTMS applied over the left PMd and/or DLPFC on choice reaction time in a noise-compatibility task, cognitive functions, or motor features in patients with PD. rTMS applied over all three stimulated areas was well tolerated and safe in terms of the cognitive and motor effects.     

Alterations of regional cerebral blood flow and oxygen metabolism in Parkinson's disease

Regional cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2) were determined in six normals, six unilateral Parkinson's disease (PD) patients, and eight bilateral PD patients. In the unilateral patients, rCBF and rCMRO2 in the basal ganglia contralateral to the symptomatic limbs was 13% higher than on the other side (p less than 0.01); in the frontal cortex it was 8% lower than the other side, suggesting abnormal neuronal function in both regions. The bilateral PD patients had a widespread decrease (20%) in rCBF unaccompanied by comparable changes in rCMRO2, suggesting vasoconstriction due to loss of dopaminergic innervation of blood vessels in more advanced PD patients.     

Observation of EEG coherence after repetitive transcranial magnetic stimulation.

OBJECTIVE: The effects before and after repetitive transcranial magnetic stimulation (rTMS) on EEG activity were investigated. METHODS: Nineteen healthy subjects received two trains (10 Hz, 100% of motor threshold, 3 s/train) of rTMS to the left frontal area. Directed coherence and ordinary coherence were calculated from EEG epochs recorded before and after (1 approximately 3 and 3 approximately 5 min) rTMS. The results were compared and demonstrated on maps. RESULTS: Directed coherence between cortical areas increased after rTMS (F=5.62, P<0.005), with the intra-hemispheric change being more pronounced than the inter-hemispheric change. Connections from the stimulated site to other sites were selectively reinforced. In contrast, ordinary coherence did not change after the stimulation. rTMS did not influence the dominant frequency at which maximal coherence was calculated. Differences in the directed coherence with opposite directions after rTMS were significantly correlated with the differences before rTMS (r=0.88, 0.89, P<0.001). CONCLUSIONS: (1) rTMS can enhance the connections between cortical areas, especially connections between the stimulated cortex and other sites in the brain. (2) Comparing with connections from the parietal area to frontal area, connections from the frontal area to parietal area are obviously improved by rTMS in both hemispheres. (3) The effects of rTMS can last for several minutes. Therefore, the necessity of EEG monitoring in rTMS studies is suggested.     

Left prefrontal-repetitive transcranial magnetic stimulation (rTMS) and regional cerebral glucose metabolism in normal volunteers

Repetitive transcranial magnetic stimulation (rTMS) holds promise as a probe into the pathophysiology and possible treatment of neuropsychiatric disorders. To explore its regional effects, we combined rTMS with positron emission tomography (PET). Fourteen healthy volunteers participated in a baseline 18-fluorodeoxyglucose (FDG) PET scan. During a second FDG infusion on the same day, seven subjects received 30 min of 1 Hz rTMS at 80% of motor threshold to left prefrontal cortex, and seven other subjects received sham rTMS under identical conditions. Global and normalized regional cerebral glucose metabolic rates (rCMRglu) from the active and sham conditions were compared to baseline and then to each other. Sham, but not active 1 Hz rTMS, was associated with significantly increased global CMRglu. Compared to baseline, active rTMS induced normalized decreases in rCMRglu in right prefrontal cortex, bilateral anterior cingulate, basal ganglia (L>R), hypothalamus, midbrain, and cerebellum. Increases in rCMRglu were seen in bilateral posterior temporal and occipital cortices. Sham rTMS compared to baseline resulted in isolated normalized decreases in rCMRglu in left dorsal anterior cingulate and left basal ganglia, and increases in posterior association and occiptal regions. Differences between the 1 Hz active versus sham changes from baseline revealed that active rTMS induced relative decrements in rCMRglu in the left superior frontal gyrus and increases in the cuneus (L>R). One Hertz rTMS at 80% motor threshold over the left prefrontal cortex in healthy subjects compared to sham rTMS in another group (each compared to baseline) induced an area of decreased normalized left prefrontal rCMRglu not directly under the stimulation site, as well as increases in occipital cortex. While these results are in the predicted direction, further studies using other designs and higher intensities and frequencies of rTMS are indicated to better describe the local and distant changes induced by rTMS.     

Cholinergic enhancement improves performance on working memory by modulating the functional activity in distinct brain regions: a positron emission tomography regional cerebral blood flow study in healthy humans

Previously, we have shown that physostigmine, an acetylcholinesterase inhibitor, improved performance on a working memory for faces task, as reflected by reduced reaction time (RT), and reduced task-specific regional cerebral blood flow (rCBF) in right prefrontal cortex and, further, that these reductions in RT and right frontal rCBF were significantly correlated. Here we investigated the relation between the effects of physostigmine on task performance and task-specific functional brain response throughout the cortex by examining correlations between physostigmine-related changes in rCBF in all brain areas and changes in RT. In subjects who received an infusion of physostigmine, reduced RT correlated (p<0.001) positively with reduced rCBF in right frontal cortex, left temporal cortex, anterior cingulate, and left hippocampus; and correlated with increased rCBF in medial occipital visual cortex. In subjects who received a placebo infusion of saline, no significant correlations between changes in RT and cortical rCBF were observed. The results show that cholinergically induced improvements in working memory performance are related to alterations in neural activity in multiple cortical regions, including increased neural activity in regions associated with early perceptual processing and decreased neural activity in regions associated with attention, memory encoding, and memory maintenance.     

Motor cortex stimulation for levodopa-resistant akinesia: case report.

We treated a patient with levodopa-resistant akinesia with motor cortex stimulation (MCS), and she showed dramatic improvement more than 1 year. On admission, the patient presented severe akinesia and gait disturbance without tremor and rigidity, and did not respond to levodopa test. The patient was suspected pure akinesia and progressive supranuclear palsy. First, high-frequency rTMS of primary motor cortex was examined, and showed the dramatic improvement. Next, chronic subdural electrodes were implanted over the motor cortex bilaterally. One year after surgery, the Unified Parkinson's Disease Rating Scale had improved remarkably, and she could walk four times faster than before. The H2 15O PET study showed a significant increase of rCBF in the left SMA and right dorsolateral prefrontal cortex after bilateral MCS. MCS may be an alternative treatment for patients with akinesia, including those with PD, and particularly for levodopa-resistant patients, who respond well to rTMS.     

Effects of acute repetitive transcranial magnetic stimulation on dopamine release in the rat dorsolateral striatum

Animal studies have shown that descending pathways from the frontal cortex modulate dopamine (DA) release in the striatum. This modulation is thought to be relevant to the pathophysiology of Parkinson's disease. In human, repetitive transcranial magnetic stimulation (rTMS) can result in functional changes in the cortex. The present study intended to clarify the effects of acute rTMS treatment using various stimulation intensities on the extracellular DA concentrations in the rat dorsolateral striatum. The frontal brain of each rat received acute rTMS treatment, which consisted of 500 stimuli from 20 trains in a day. Each train was applied at 25 Hz for 1 s with 1-min intervals between trains. The neurochemical effects of acute rTMS treatment were investigated by determining the extracellular concentrations of DA in the rat dorsolateral striatum using in vivo microdialysis. Acute rTMS treatment of the frontal brain using the stimulation intensity of almost 110% motor threshold (MT) markedly and continuously increased the extracellular DA concentrations in the rat dorsolateral striatum. The present study demonstrates that acute rTMS treatment of the frontal brain affects the DAergic neuronal system in the rat dorsolateral striatum, and may have therapeutic implications for Parkinson's disease.     

Repetitive transcranial magnetic stimulation has a beneficial effect on bradykinesia in Parkinson's disease

The effect of focal 5 Hz repetitive transcranial magnetic stimulation (rTMS) of the motor hand area (M1) on bradykinesia was studied in 12 unmedicated patients with Parkinson's disease (PD). On 2 separate days, a real-rTMS was applied to M1 contralaterally to the more severely affected limb or a frontal sham-rTMS was applied 3 cm anteriorly to Fz in a random order. Stimulus intensity was 10% below resting motor threshold. Before and 20 min after rTMS, patients performed 15 consecutive pointing movements with the index finger contralaterally to the stimulated M1. Compared with sham-rTMS, real-rTMS over the contralateral M1 caused a significant decrease in total movement time without affecting end-point accuracy. Our data provide evidence that 5 Hz rTMS over M1 can improve bradykinesia in PD patients beyond the time of magnetic stimulation.     

Heterogeneous factors in dementia with Parkinson's disease: IMP-SPECT study

BACKGROUND: Nature of the dementing process in Parkinson's disease, and particularly its relationship with Alzheimer's disease, diffuse Lewy body disease or frontal dementia remains controversial. OBJECTIVE: We hypothesize that origins of dementia in Parkinson's disease are heterogeneous, so we compared cortical regional cerebral blood flow (rCBF) between Parkinson's disease patients with and without dementia. PATIENTS: Forty consecutive patients with Hoehn-Yahr stage III or IV Parkinson's disease were used (13 patients had dementia (PDD group), and 27 patients had no dementia (PDND group)). RESULTS: There were significant rCBF reductions in the left parietal association cortex and left frontal association cortex in PDD. Multiple logistic regression analysis demonstrated that only rCBF of the left frontal association cortex was significant. PDD patients were divided into three groups according to rCBF patterns: frontal hypoperfusion group, Alzheimer's disease-like group, and diffuse Lewy body disease-like group. CONCLUSIONS: Controversial study results involving PDD patients may be mainly due to heterogeneity in dementing processes in Parkinson's disease.     

Functional connectivity revealed by single-photon emission computed tomography (SPECT) during repetitive transcranial magnetic stimulation (rTMS) of the motor cortex.

OBJECTIVE: In the present study, we studied effects of 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the left primary motor cortex (M1) on regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT). METHODS: SPECT measurements were carried out under two experimental conditions: real and sham stimulation. In sham stimulation, to exclude other components besides currents in the brain in rTMS, we applied sound and electrical stimulation to the skin of the head. 99mTc-ethyl cysteinate dimer was injected during the real or sham stimulation. Images were analyzed with the statistical parametric mapping software (SPM99). Relative differences in adjusted rCBF between two conditions were determined by a voxel-by-voxel paired t test. RESULTS: 1 Hz rTMS at an intensity of 1.1 x active motor threshold evoked increase of rCBF in the contralateral (right) cerebellar hemisphere. Reduction of rCBF was observed in the contralateral M1, superior parietal lobule (most probably corresponding to PE area in the monkey) (Rizzolatti G, Luppino G, Matelli M. Electroenceph clin Neurophysiol 1998;106:283-296), inferior parietal lobule (PF area in the monkey (Rizzolatti et al., 1998)), dorsal and ventral premotor areas (dPM, vPM) and supplementary motor area (SMA). CONCLUSIONS: Increase of rCBF in the contralateral cerebellum must reflect facilitatory connection between the motor cortex and contralateral cerebellum. Reduced rCBF in the contralateral M1 may be produced by transcallosal inhibitory effect of the left motor cortical activation. CBF decrease in the right PM, SMA and parietal cortex may reflect some secondary effects. Low frequency rTMS at an intensity of around threshold for active muscles can evoke rCBF changes. Significance: We demonstrated that rCBF changes could be elicited even by low frequency rTMS at such a low intensity as the threshold for an active muscle. Combination of rTMS and SPECT is one of powerful tools to study interareal connection within the human brain.