Neurons have a striking tendency to engage in oscillatory activities. One important type of oscillatory activity prevalent in the motor system occurs in the beta frequency band, at about 20 Hz. It is ...manifest during the maintenance of tonic contractions and is suppressed prior to and during voluntary movement 1–7. This and other correlative evidence suggests that beta activity might promote tonic contraction, while impairing motor processing related to new movements 3, 8, 9. Hence, bursts of beta activity in the cortex are associated with a strengthening of the motor effects of sensory feedback during tonic contraction and with reductions in the velocity of voluntary movements 9–11. Moreover, beta activity is increased when movement has to be resisted or voluntarily suppressed 7, 12, 13. Here we use imperceptible transcranial alternating-current stimulation to entrain cortical activity at 20 Hz in healthy subjects and show that this slows voluntary movement. The present findings are the first direct evidence of causality between any physiological oscillatory brain activity and concurrent motor behavior in the healthy human and help explain how the exaggerated beta activity found in Parkinson's disease can lead to motor slowing in this illness 14.
Neuroimaging studies help us better understand the pathophysiology and symptoms of Parkinson's disease (PD). In several of these studies, diffusion tensor imaging (DTI) was used to investigate ...structural changes in cerebral tissue. Although data have been provided as regards to specific brain areas, a whole brain meta-analysis is still missing.
We compiled 39 studies in this meta-analysis: 14 used fractional anisotropy (FA), 1 used mean diffusivity (MD), and 24 used both indicators. These studies comprised 1855 individuals, 1087 with PD and 768 healthy controls. Regions of interest were classified anatomically (subcortical structures; white matter; cortical areas; cerebellum). Our statistical analysis considered the disease effect size (D
) as the main variable; the heterogeneity index (I
) and Pearson's correlations between the D
and co-variables (demographic, clinical and MRI parameters) were also calculated.
Our results showed that FA-D
and MD-D
were able to distinguish between patients and healthy controls. Significant differences, indicating degenerations, were observed within the substantia nigra, the corpus callosum, and the cingulate and temporal cortices. Moreover, some findings (particularly in the corticospinal tract) suggested opposite brain changes associated with PD. In addition, our results demonstrated that MD-D
was particularly sensitive to clinical and MRI parameters, such as the number of DTI directions and the echo time within white matter.
Despite some limitations, DTI appears as a sensitive method to study PD pathophysiology and severity. The association of DTI with other MRI methods should also be considered and could benefit the study of brain degenerations in PD.
OBJECTIVE:To evaluate the safety and efficacy of unilateral Gamma Knife thalamotomy (GKT) for treatment of severe tremor with a prospective blinded assessment.
METHODS:Fifty patients (mean age74.5 ...years; 32 men) with severe refractory tremor (36 essential, 14 parkinsonian) were treated with unilateral GKT. Targeting of the ventral intermediate nucleus (Vim) was achieved with Leksell Gamma Knife with a single shot through a 4-mm collimator helmet. The prescription dose was 130 Gy. Neurologic and neuropsychological assessments including a single-blinded video assessment of the tremor severity performed by a movement disorders neurologist from another center were performed before and 12 months after treatment. MRI follow-up occurred at 3, 6, and 12 months.
RESULTS:The upper limb tremor score improved by 54.2% on the blinded assessment (p < 0.0001). All tremor components (rest, postural, and intention) were improved. Activities of daily living were improved by 72.2%. Cognitive functions remained unchanged. Following GKT, the median delay of improvement was 5.3 months (range 1–12 months). The only side effect was a transient hemiparesis associated with excessive edema around the thalamotomy in one patient.
CONCLUSION:This blinded prospective assessment demonstrates that unilateral GKT is a safe and efficient procedure for severe medically refractory tremor. Side effects were rare and transient in this study.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for patients with severe refractory tremor, GKT is well tolerated and effective in reducing tremor impairment.
In Parkinson's disease (PD), the effects of both L
and subthalamic deep brain stimulation (STN-DBS) are known to change cost-valuation. However, this was mostly studied through reward-effort task ...involving distal movements, while axial effort, less responsive to treatments, have been barely studied. Thus, our objective was to compare the influence of both L
and STN-DBS on cost-valuation between two efforts modalities: vowel production (as an example of axial movement) and hand squeezing (as an example of distal movement). Twelve PD patients were recruited to participate in this study. The task consisted in deciding whether to accept or reject trials based on a reward-effort trade-off. Participants performed two blocks with hand squeezing, and two with vowel production, in the four treatment conditions (L
On/Off; STN-DBS On/Off). We found that STN-DBS changed the ratio difference between hand and phonation efforts. Vowel production effort was estimated easier to perform with STN-DBS alone, and harder when associated with L
. The difference between hand and phonation efforts was correlated with quality of life in Off/Off and On L
alone conditions, and with impulsive assessment On STN-DBS alone. We highlighted that STN-DBS could introduce an imbalance between the actual motor impairments and their subjective costs. With this finding, we also suggest paying particular attention to the different treatment effects that should be expected for axial and distal movement dysfunctions.
Exaggerated activity in the beta band (13–35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in ...bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.
•Beta bursts are coupled across the basal-ganglia-cortical circuit•Phase coupling is greater during as opposed to outside of beta bursts•Pathological long beta bursts involve more long range synchronisation•Exaggerated circuit synchronisation may impact motor symptoms
The increasing number of MRI studies focused on prodromal Parkinson’s Disease (PD) demonstrates a strong interest in identifying early biomarkers capable of monitoring neurodegeneration. In this ...systematic review, we present the latest information regarding the most promising MRI markers of neurodegeneration in relation to the most specific prodromal symptoms of PD, namely isolated rapid eye movement (REM) sleep behavior disorder (iRBD). We reviewed structural, diffusion, functional, iron-sensitive, neuro-melanin-sensitive MRI, and proton magnetic resonance spectroscopy studies conducted between 2000 and 2023, which yielded a total of 77 relevant papers. Among these markers, iron and neuromelanin emerged as the most robust and promising indicators for early neurodegenerative processes in iRBD. Atrophy was observed in several regions, including the frontal and temporal cortices, limbic cortices, and basal ganglia, suggesting that neurodegenerative processes had been underway for some time. Diffusion and functional MRI produced heterogeneous yet intriguing results. Additionally, reduced glymphatic clearance function was reported. Technological advancements, such as the development of ultra-high field MRI, have enabled the exploration of minute anatomical structures and the detection of previously undetectable anomalies. The race to achieve early detection of neurodegeneration is well underway.
A partial loss of effectiveness of deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM) has been reported in some patients with essential tremor (ET), possibly due to ...habituation to permanent stimulation. This study focused on the evolution of VIM local-field potentials (LFPs) data over time to assess the long-term feasibility of closed-loop therapy based on thalamic activity. We performed recordings of thalamic LFPs in 10 patients with severe ET using the ACTIVA™ PC + S (Medtronic plc.) allowing both recordings and stimulation in the same region. Particular attention was paid to describing the evolution of LFPs over time from 3 to 24 months after surgery when the stimulation was Off. We demonstrated a significant decrease in high-beta LFPs amplitude during movements inducing tremor in comparison to the rest condition 3 months after surgery (1.91 ± 0.89 at rest vs. 1.27 ± 1.37 µV
/Hz during posture/action for N = 8/10 patients; p = 0.010), 12 months after surgery (2.92 ± 1.75 at rest vs. 2.12 ± 1.78 µV
/Hz during posture/action for N = 7/10 patients; p = 0.014) and 24 months after surgery (2.32 ± 0.35 at rest vs 0.75 ± 0.78 µV
/Hz during posture/action for 4/6 patients; p = 0.017). Among the patients who exhibited a significant decrease of high-beta LFP amplitude when stimulation was Off, this phenomenon was observed at least twice during the follow-up. Although the extent of this decrease in high-beta LFPs amplitude during movements inducing tremor may vary over time, this thalamic biomarker of movement could potentially be usable for closed-loop therapy in the long term.
Introduction
This study aims to reveal the feasibility and potential of molecular connectivity based on neurotransmission in comparison with the metabolic connectivity with an application to ...dopaminergic pathways. For this purpose, we propose to compare the neurotransmission connectivity findings using
123
I-FP-CIT SPECT and
18
F-FDOPA PET with the metabolic connectivity findings using
18
F-FDG PET.
Methods
18
F-FDG PET and
123
I-FP-CIT SPECT images from 47 subjects and
18
F-FDOPA PET images from 177 subjects, who had no neurological or psychiatric disorders, were studied. Interregional correlation analyses were performed at the group level to determine the midbrain’s connectivity via glucose metabolic rate using
18
F-FDG PET and via dopaminergic binding potential using
123
I-FP-CIT SPECT and
18
F-FDOPA PET. SPM-T maps of each radiotracer were generated, and masks used to highlight the significant differences obtained among the imaging modalities and targets.
Results
The three dopaminergic pathways (i.e., nigrostriatal, mesolimbic, and mesocortical) were identified by
18
F-FDG PET (1599 voxels, with a
T
max
value of 12.6),
123
I-FP-CIT SPECT (1120 voxels, with
T
max
value of 5.1), and
18
F-FDOPA PET (6054 voxels, with
T
max
value of 11.7) for a
T
voxel threshold of 5.10, 2.80, and 5.10, respectively. Using the same
T
voxel threshold of 5.10,
18
F-FDOPA PET showed more specific findings than
18
F-FDG PET with less voxels identified outside these pathways (− 9323 voxels), whereas no significant voxels were obtained with
123
I-FP-CIT SPECT at this threshold.
Conclusion
The present study illustrates the feasibility and interest in using molecular connectivity with
18
F-FDOPA PET for dopaminergic pathways. Such analyses could be applied to specific diseases involving the dopaminergic system.
OBJECTIVE:To confirm the efficacy and safety of deep brain stimulation (DBS) of the internal part of the globus pallidus in improving severe tardive dyskinesia (TD).
METHODS:Nineteen patients with ...severe pharmacoresistant TD were included. All were assessed at baseline and at 3, 6 (main outcome measure), and 12 months, and in the long term (6–11 years) for 14 patients, after bilateral pallidal DBS, using motor scales (Extrapyramidal Symptoms Rating Scale ESRS, Abnormal Involuntary Movement Scale AIMS), cognitive scales, and a psychiatric assessment. At 6 months, a double-blind ESRS evaluation was performed in the stimulation “on” and stimulation “off” conditions.
RESULTS:At 6 months, all patients had a decrease of more than 40% on the ESRS. The efficacy of the procedure was confirmed by a double-blind evaluation. This improvement was maintained at 12 months (ESRSdecrease of 58% 21%–81%; AIMSdecrease of 50% 7%–77%) and in the long term (ESRSdecrease of 60% 22%–90%; AIMSdecrease of 63% 14%–94%, n = 14). All the subscores of the ESRS (parkinsonism, dystonia, and chorea) and of the AIMS (facial, oral, extremities, and trunk movements) improved. Despite psychiatric comorbidities at baseline, cognitive and psychiatric tolerability of the procedure was excellent. No cognitive decline was observed and mood was improved in most of the patients.
CONCLUSIONS:Pallidal DBS procedure should be considered as a therapeutic option in disabling TD refractory to medical treatment.
CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that in patients with severe pharmacoresistant TD with implanted pallidal leads, the stimulation “on” condition significantly improved ESRS scores compared to the stimulation “off” condition.
Summary Background Despite optimum medical management, many patients with Parkinson's disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether ...methylphenidate—through its combined action on dopamine and noradrenaline reuptake—would improve gait disorders and freezing of gait in patients with advanced Parkinson's disease without dementia who also received subthalamic nucleus stimulation. Methods This multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinson's disease, severe gait disorders, and freezing of gait despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with ClinicalTrials.gov , number NCT00914095. Findings We screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps IQR 26–45), the patients in the methylphenidate group made fewer steps at 90 days (31 26–42, F(1, 62) =6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 SD 7·2 beats per min) and decrease in weight (mean 2·2 SD 1·8 kg) compared with the placebo group. Interpretation Methylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinson's disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinson's disease. The long term risk–benefit balance should be further studied. Funding French Ministry of Health and Novartis Pharma.
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