Neurobiology of exercise in Parkinson's disease.

Physical activity can have positive effects on motor and non-motor symptoms in Parkinson's disease, but its benefits in terms of quality of life and function are uncertain and vary based on the specific forms of activities and interventions. We sought to assess the current evidence on the positive effects of physical activity in people with Parkinson's disease and more specifically in relation to its potential benefits for quality of life. This systematic review was conducted between January and April 2024 via the PubMed, Medline, and Scopus databases. Predetermined search criteria were used that included the following terms: "Parkinson's disease", "quality of life" and "physical activity". A total of 1669 articles were identified. After utilizing predetermined criteria, a total of fifteen articles met the selection criteria. Statistically significant improvements in quality of life were found in seven studies. Seven studies demonstrated a significant improvement in non-motor symptoms, while nine studies showed an improvement in motor symptoms. Despite heterogeneity in the study designs, interventions and clinical assessments, the articles identified in this review yielded mostly positive results in relation to physical activities. The findings reflect an improvement in motor and non-motor symptoms may translate to a better quality of life in people with Parkinson's disease.

Adapting to post-COVID19 research in Parkinson's disease: Lessons from a multinational experience

Introduction: Parkinson’s disease (PD) is a neurodegenerative disease, caused by an imbalance between the inhibitory action of dopamine and the excitatory action of acetylcholine due to dopamine restriction, characterized by motor and non-motor symptoms. The phytocannabinoid cannabidiol (CBD) may be effective for the treatment of symptoms in PD, offering better quality of life. Objectives: To verify the evidence for the efficacy of cannabidiol in the treatment of patients with PD about the improvement of quality of life. To analyze its applicability in controlling involuntary movements in PD patients. Methods: A search in the databases LILACS, BIREME, SCIELO, SCIENCE, EBSCO, PUBMED, using the bibliographic research method, and by means of integrative review. The descriptor cannabidiol was associated with the words: therapeutic use, parkinsonism, and quality of life. The selection included articles published between 2000 and 2020, in Portuguese, English and German languages. Results: Therapeutic effects of cannabidiol were promising in PD, such as neuroprotective action, reduction of motor symptoms, cognitive and quality of life improvement with few relevant adverse effects. Among the 16 articles, 8 demonstrate an improvement in symptoms and the others cite improvement in psychiatric and cognitive symptoms, thus reflecting that cannabidiol is a promising for quality of life improvement. Conclusion: Although cannabidiol has shown efficacy in the therapy of Parkinson’s patients in clinical and preclinical studies, there is still a need for further studies and investigations on the therapeutic effects of this compound. Thus, cannabidiol may become a first choice treatment for PD, promote patients and families a better living with the disease, and positive reflexes.

Subthalamic nucleus (STN) deep brain stimulation (DBS) can improve motor symptoms in Parkinson’s disease (PD), as well as potentially improving otherwise intractable comorbid depressive symptoms. To address the latter issue, we evaluated the severity of depressive symptoms along with the severity of motor symptoms in 18 PD patients (mean age, 58.4 ± 5.4 years; 9 males, 9 females; mean PD duration, 9.4 ± 4.4 years) with treatment-resistant depression (TRD) before and after approximately 1 year of STN-DBS treatment. Moreover, to gain more insight into the brain mechanism mediating the therapeutic action of STN-DBS, we utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess cerebral regional glucose metabolism in the patients at baseline and 1-year follow-up. Additionally, the baseline PET data from patients were compared with PET data from an age- and sex-matched control group of 16 healthy volunteers. Among them, 12 PD patients underwent post-operative follow-up PET scans. Results showed that the severity of both motor and depressive symptoms in patients with PD-TRD was reduced significantly at 1-year follow-up. Also, patients used significantly less antiparkinsonian medications and antidepressants at 1-year follow-up, as well as experiencing improved daily functioning and a better quality of life. Moreover, relative to the PET data from healthy controls, PD-TRD patients displayed widespread abnormalities in cerebral regional glucose metabolism before STN-DBS treatment, which were partially recovered at 1-year follow-up. Additionally, significant correlations were observed between the patients’ improvements in depressive symptoms following STN-DBS and post-operative changes in glucose metabolism in brain regions implicated in emotion regulation. These results support the view that STN-DBS provides a promising treatment option for managing both motor and depressive symptoms in patients who suffer from PD with TRD. However, the results should be interpreted with caution due to the observational nature of the study, small sample size, and relatively short follow-up.

Article Figures and data Abstract Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Pathological oscillations including elevated beta activity in the subthalamic nucleus (STN) and between STN and cortical areas are a hallmark of neural activity in Parkinson's disease (PD). Oscillations also play an important role in normal physiological processes and serve distinct functional roles at different points in time. We characterised the effect of dopaminergic medication on oscillatory whole-brain networks in PD in a time-resolved manner by employing a hidden Markov model on combined STN local field potentials and magnetoencephalography (MEG) recordings from 17 PD patients. Dopaminergic medication led to coherence within the medial and orbitofrontal cortex in the delta/theta frequency range. This is in line with known side effects of dopamine treatment such as deteriorated executive functions in PD. In addition, dopamine caused the beta band activity to switch from an STN-mediated motor network to a frontoparietal-mediated one. In contrast, dopamine did not modify local STN–STN coherence in PD. STN–STN synchrony emerged both on and off medication. By providing electrophysiological evidence for the differential effects of dopaminergic medication on the discovered networks, our findings open further avenues for electrical and pharmacological interventions in PD. Introduction Oscillatory activity serves crucial cognitive roles in the brain (Akam and Kullmann, 2010; Akam and Kullmann, 2014), and alterations of oscillatory activity have been linked to neurological and psychiatric diseases (Schnitzler and Gross, 2005). Different large-scale brain networks operate with their own oscillatory fingerprint and carry out specific functions (Keitel and Gross, 2016; Mellem et al., 2017; Vidaurre et al., 2018b). Given the dynamics of cognition, different brain networks need to be recruited and deployed flexibly. Hence, the duration for which a network is active, its overall temporal presence, and even the interval between the different activations of a specific network might provide a unique window to understanding brain functions. Crucially, alterations of these temporal properties or networks might be related to neurological disorders. In Parkinson's disease (PD), beta oscillations within the subthalamic nucleus (STN) and motor cortex (13–30 Hz) correlate with the motor symptoms of PD (Marreiros et al., 2013; van Wijk et al., 2016; West et al., 2018). Beta oscillations also play a critical role in communication in a healthy brain (Engel and Fries, 2010). (For the purposes of our paper, we refer to oscillatory activity or oscillations as recurrent but transient frequency-specific patterns of network activity, even though the underlying patterns can be composed of either sustained rhythmic activity, neural bursting, or both [Quinn et al., 2019]. Disambiguating the exact nature of these patterns is, however, beyond the scope of this work.) At the cellular level, loss of nigral dopamine neurons in PD leads to widespread changes in brain networks, to varying degrees across different patients. Dopamine loss is managed in patients via dopaminergic medication. Dopamine is a widespread neuromodulator in the brain (Gershman and Uchida, 2019), raising the question of whether each medication-induced change restores physiological oscillatory networks. In particular, dopaminergic medication is known to produce cognitive side effects in PD patients (Voon et al., 2009). According to the dopamine overdose hypothesis, a reason for these effects is the presence of excess dopamine in brain regions not affected in PD (MacDonald et al., 2011; MacDonald and Monchi, 2011). Previous task-based and neuroimaging studies in PD demonstrated frontal cognitive impairment due to dopaminergic medication (Cools et al., 2002; Ray and Strafella, 2010; MacDonald et al., 2011). Using resting-state whole-brain MEG analysis, network changes related to both motor and non-motor symptoms of PD have been described (Olde Dubbelink et al., 2013a; Olde Dubbelink et al., 2013b). However, these studies could not account for simultaneous STN–STN or cortico–STN activity affecting these networks, which would require combined MEG/electroencephalogram (EEG)–LFP recordings (Litvak et al., 2021). Such recordings are possible during the implantation of deep brain stimulation (DBS) electrodes, an accepted treatment in the later stages of PD (Volkmann et al., 2004; Deuschl et al., 2006; Kleiner-Fisman et al., 2006). Combined MEG–LFP studies in PD involving dopaminergic intervention report changes in beta and alpha band connectivity between specific cortical regions and the STN (Litvak et al., 2011; Hirschmann et al., 2013; Oswal et al., 2016). Decreased cortico–STN coherence under dopaminergic medication (ON) correlates with improved motor functions in PD (George et al., 2013). STN–STN intra-hemispheric oscillations positively correlate to motor symptom severity in PD without dopaminergic medication (OFF), whereas dopamine-dependent nonlinear phase relationships exist between inter-hemispheric STN–STN activity (West et al., 2016). Crucially, previous studies could not rule out the influence of cortico–STN connectivity on these inter-hemispheric STN–STN interactions. To further characterise the differential effects of dopaminergic medication and delineate pathological versus physiological-relevant spectral connectivity in PD, we study PD brain activity via a hidden Markov model (HMM), a data-driven learning algorithm (Vidaurre et al., 2016; Vidaurre et al., 2018b). Due to the importance of cortico–subcortical interactions in PD, we investigated these interactions with combined spontaneous whole-brain magnetoencephalography (MEG) and STN local field potentials (LFPs) recordings from PD patients. We study whole-brain connectivity including the STN using spectral coherence as a proxy for communication based on the communication through coherence hypothesis (Fries, 2005; Fries, 2015). This will allow us to delineate differences in communication OFF and ON medication. Furthermore, we extended previous work that was limited to investigating communication between specific pairs of brain areas (Litvak et al., 2011; George et al., 2013; Hirschmann et al., 2013). Moreover, we identified the temporal properties of the networks both ON and OFF medication. The temporal properties provide an encompassing view of network alterations in PD and the effect of dopamine on these networks. We found that cortico–cortical, cortico–STN, and STN–STN networks were differentially modulated by dopaminergic medication. For the cortico–cortical network, medication led to additional connections that can be linked to the side effects of dopamine. At the same time, dopamine changed the cortico–STN network towards a pattern more closely resembling physiological connectivity as reported in the PD literature. Within the third network, dopamine only had an influence on local STN–STN coherence. These results provide novel information on the oscillatory network connectivity occurring in PD and the differential changes caused by dopaminergic intervention. These whole-brain networks, along with their electrophysiological signatures, open up new potential targets for both electric and pharmacological interventions in PD. Results Under resting-state conditions in PD patients, we simultaneously recorded whole-brain MEG activity with LFPs from the STN using directional electrodes implanted for DBS. Using an HMM, we identified recurrent patterns of transient network connectivity between the cortex and the STN, which we henceforth refer to as an 'HMM state'. In comparison to classic sliding window analysis, an HMM solution can be thought of as a data-driven estimation of time windows of variable length (within which a particular HMM state was active): once we know the time windows when a particular state is active, we compute coherence between different pairs of regions for each of these recurrent states. Each HMM state itself is a multidimensional, time-delay embedded (TDE) covariance matrix across the whole brain, containing information about cross-regional coherence and power in the frequency domain. Additionally, the temporal evolution of the HMM states was determined. The PD data were acquired under medication (L-DOPA) OFF and ON conditions, which allowed us to delineate the physiological versus pathological spatio-spectral and temporal changes observed in PD. To allow the system to dynamically evolve, we use time delay embedding. Theoretically, delay embedding can reveal the state space of the underlying dynamical system (Packard et al., 1980). Thus, by delay-embedding PD time series OFF and ON medication, we uncover the differential effects of a neurotransmitter such as dopamine on underlying whole-brain connectivity. OFF medication, patients had on average a Unified Parkinson's Disease Rating Scale (UPDRS) part III of 29.24 ± 10.74. This was reduced by L-DOPA (176.5 ± 56.2 mg) to 19.47 ± 8.52, indicating an improvement in motor symptoms. Spontaneous brain activity in PD can be resolved into distinct states Using an HMM, we delineated cortico–subthalamic spectral changes from both global source-level cortical interactions as well as local STN–STN interactions. Three of the six HMM states could be attributed to physiologically interpretable connectivity patterns. We could not interpret the other three states within the current physiological frameworks both OFF and ON medication and they are therefore not considered in the following (see Figure 2—figure supplement 1). The connectivity between different brain regions for each state was visualised for the frequency modes shown in Figure 1. Figures 2–4 show the connectivity patterns for the three physiologically meaningful states in both the OFF (top row) and ON medication condition (bottom row). We refer to the state obtained in Figure 2 as the cortico–cortical state (Ctx–Ctx). This state was characterised mostly by local coherence within segregated networks OFF medication in the alpha and beta band. In contrast, there was a widespread increase in coherence across the brain from OFF to ON medication. Therefore, ON medication, the connectivity strength in the alpha and beta band was not significantly different from the mean noise level. Figure 3 displays the second state. A large proportion of spectral connections in this state enable cortico–STN communication via spectral coherence (Lalo et al., 2008; Litvak et al., 2011; Hirschmann et al., 2013; Oswal et al., 2013; van Wijk et al., 2016) and thus we labelled this as the cortico–STN state (Ctx–STN). This state was characterised by connectivity between multiple cortical regions and the STN OFF medication, but increased specificity of cortical–STN connectivity ON medication. Finally, Figure 4 shows the third state. Within this state, highly synchronous STN–STN spectral connectivity emerged, both OFF and ON medication and therefore we named it the STN–STN state (STN–STN). The spectral characteristics of this state largely remain unaffected under the influence of dopaminergic medication. In the following sections, we describe these three states in detail. Figure 1 Download asset Open asset Data-driven frequency modes. Each plotted curve shows a different spectral band. The x-axis represents frequency in Hz and the y-axis represents the weights obtained from the non-negative matrix factorisation (NNMF) in arbitrary units. The NNMF weights are like regression coefficients. The frequency resolution of the modes is 0.5 Hz. Panels A and B show the OFF and ON medication frequency modes, respectively. Source data are provided as Figure 1—source data 1–2. Figure 1—source data 1 Source data of Figure 1a. https://cdn.elifesciences.org/articles/66057/elife-66057-fig1-data1-v1.mat Download elife-66057-fig1-data1-v1.mat Figure 1—source data 2 Source data of Figure 1b. https://cdn.elifesciences.org/articles/66057/elife-66057-fig1-data2-v1.mat Download elife-66057-fig1-data2-v1.mat Figure 2 with 1 supplement see all Download asset Open asset Cortico–cortical state. The cortico–cortical state was characterised by a significant increase in coherence ON compared to OFF medication (see panel B). Due to this, no connections within the alpha and beta band ON medication were significantly higher than the mean (panel C). However, in the delta band, ON medication medial prefrontal–orbitofrontal connectivity emerged. (A and C) Each node in the circular graph represents a brain region based on the Mindboggle atlas. The regions from the atlas are listed in Table 1 along with their corresponding numbers that are used in the circular graph. The colour code in the circular graph represents a group of regions clustered according to the atlas (starting from node number 1) STN contacts (contacts 1, 2, 3 = right STN and contacts 4, 5, 6 = left STN), frontal, medial frontal, temporal, sensorimotor, parietal, and visual cortices. In the circular graph, only the significant connections (p<0.05; corrected for multiple comparisons, IntraMed analysis) are displayed as black curves connecting the nodes. The circles from left to right represent the delta/theta, alpha, and beta bands. Panel A shows results for OFF medication data and panel C for the ON medication condition. For every circular graph, we also show a corresponding top view of the brain with the connectivity represented by yellow lines and the red dot represents the anatomical seed vertex of the brain region. Only the cortical connections are shown. Panel B shows the result for inter-medication analysis (InterMed) for the cortico–cortical state. In each symmetric matrix, every row and column corresponds to a specific atlas cluster denoted by the dot colour on the side of the matrix. Each matrix entry is the result of the InterMed analysis where OFF medication connectivity between ith row and jth column was compared to the ON medication connectivity between the same connections. A cell is white if the comparison mentioned on top of the matrix (either ON >OFF or OFF >ON) was significant at a threshold of p<0.05. The connectivity maps of states 4–6 are provided in Figure 2—figure supplement 1. Source data are provided as Figure 2—source data 1–3. Figure 2—source data 1 Source data of Figure 2a. https://cdn.elifesciences.org/articles/66057/elife-66057-fig2-data1-v1.mat Download elife-66057-fig2-data1-v1.mat Figure 2—source data 2 Source data of Figure 2b. https://cdn.elifesciences.org/articles/66057/elife-66057-fig2-data2-v1.mat Download elife-66057-fig2-data2-v1.mat Figure 2—source data 3 Source data of Figure 2c. https://cdn.elifesciences.org/articles/66057/elife-66057-fig2-data3-v1.mat Download elife-66057-fig2-data3-v1.mat Figure 3 Download asset Open asset Cortico–STN state. For the general description, see the note to Figure 2. The cortico–STN state was characterised by preservation of spectrally selective cortico–STN connectivity ON medication. Also, ON medication, a sensorimotor–frontoparietal network emerged. Source data are provided as Figure 3—source data 1–3. Figure 3—source data 1 Source data of Figure 3a. https://cdn.elifesciences.org/articles/66057/elife-66057-fig3-data1-v1.mat Download elife-66057-fig3-data1-v1.mat Figure 3—source data 2 Source data of Figure 3b. https://cdn.elifesciences.org/articles/66057/elife-66057-fig3-data2-v1.mat Download elife-66057-fig3-data2-v1.mat Figure 3—source data 3 Source data of Figure 3c. https://cdn.elifesciences.org/articles/66057/elife-66057-fig3-data3-v1.mat Download elife-66057-fig3-data3-v1.mat Figure 4 Download asset Open asset STN–STN state. For the general description, see the note to Figure 2. The STN–STN state was characterised by preservation of STN–STN coherence in the alpha and beta band OFF versus ON medication. STN–STN theta/delta coherence was no longer significant ON medication. Source data are provided as Figure 4—source data 1–3. Figure 4—source data 1 Source data of Figure 4a. https://cdn.elifesciences.org/articles/66057/elife-66057-fig4-data1-v1.mat Download elife-66057-fig4-data1-v1.mat Figure 4—source data 2 Source data of Figure 4b. https://cdn.elifesciences.org/articles/66057/elife-66057-fig4-data2-v1.mat Download elife-66057-fig4-data2-v1.mat Figure 4—source data 3 Source data of Figure 4c. https://cdn.elifesciences.org/articles/66057/elife-66057-fig4-data3-v1.mat Download elife-66057-fig4-data3-v1.mat Table 1 Regions of the Mindboggle atlas used. STN, subthalamic nucleus; Vis, visual; Par, parietal; Smtr, sensory motor; Tmp, temporal; Mpf, medial prefrontal; Frnt, frontal; Ctx, cortex. The colour code is for the ring figures presented as part of the results. STN1Contact one rightSmtr-Ctx12Postcentral2Contact two right13Precentral3Contact three rightTmp-Ctx14Middle temporal1Contact four left15Superior temporal2Contact five leftMpf-Ctx16Caudal middle frontal3Contact six left17Medial orbitofrontalVis-Ctx4CuneusFrnt-Ctx18Insula5Lateral occipital19Lateral orbitofrontal6Lingual20Pars opercularisPar-Ctx7Inferior parietal21Pars orbitalis8Para central22Pars triangularis9Precuneus23Rostral middlefrontal10Superior parietal24Superior frontal11Supramarginal Ctx–Ctx state is characterised by increased frontal coherence due to elevated dopamine levels Supporting the dopamine overdose hypothesis in PD (Kelly et al., 2009; MacDonald and Monchi, 2011), we identified a delta/theta oscillatory network involving intra-hemispheric connections between the lateral and medial orbitofrontal cortex as well as the pars orbitalis. The delta/theta network emerged between the lateral and medial orbitofrontal as well as left and right pars orbitalis cortex ON medication (p<0.05, Figure 2C delta). On the contrary, OFF medication no significant connectivity was detected in the delta/theta band. In the alpha and beta band OFF medication there was significant connectivity within the frontal regions, STN, and to a limited extent in the posterior parietal regions (p<0.05, Figure 2A). Another effect of excess dopamine was significantly increased connectivity of frontal cortex and temporal cortex both with the STN and multiple cortical regions across all frequency modes (p<0.01, Figure 2 delta, alpha, and beta). The change in sensorimotor–STN connectivity primarily took place in the alpha band with an increased ON medication. Sensorimotor–cortical connectivity was increased ON medication across multiple cortical regions in both the alpha and beta band (p<0.01, Figure 2 alpha and beta). However, STN–STN coherence remained unchanged OFF versus ON medication across all frequency modes. Viewed together, the Ctx–Ctx state captured increased coherence across the cortex ON medication within the alpha and beta band. This, however, implies that ON medication, no connectivity strength was significantly higher than the mean noise level within the alpha or beta band. ON medication, significant coherence emerged in the delta/theta band primarily between different regions of the orbitofrontal cortex. Dopaminergic medication selectively reduced connectivity in the Ctx–STN state Our analysis revealed that the Ctx–STN state ON medication was characterised by selective cortico–STN spectral connectivity and an overall shift in cortex-wide activity towards physiologically relevant network connectivity. In particular, ON medication, connectivity between STN and cortex became more selective in the alpha and beta band. OFF medication, STN–pre-motor (sensory), STN–frontal, and STN–parietal connectivity was present (p<0.05, Figure 3A alpha and beta). Importantly, coherence OFF medication was significantly larger than ON medication between STN and sensorimotor, STN and temporal, and STN and frontal cortices (p<0.05 for all connections, Figure 3B alpha and beta). Furthermore, ON medication, in the alpha band only the connectivity between temporal, parietal, and medial orbitofrontal cortical regions and the STN was preserved (p<0.05, Figure 3C alpha). Finally, ON medication, a sensorimotor–frontoparietal network emerged (p<0.05, Figure 3C beta), where sensorimotor, medial prefrontal, frontal, and parietal regions were no longer connected to the STN, but instead directly communicated with each other in the beta band. Hence, there was a transition from STN-mediated sensorimotor connectivity to the cortex OFF medication to a more direct cortico–cortical connectivity ON medication. Simultaneously to STN–cortico and cortico–cortical, STN–STN connectivity changed. In the ON condition, STN–STN connectivity was significantly different from the mean noise level across all three frequency modes (p<0.05, Figure 3C). But on the other hand, there was no significant change in the STN–STN connectivity OFF versus ON medication (p=0.21 delta/theta; p=0.25 alpha; p=0.10 beta; Figure 3B). To summarise, coherence decreased ON medication across a wide range of cortical regions both at the cortico–cortical and cortico–STN level. Still, significant connectivity was selectively preserved in a spectrally specific manner ON medication both at the cortico–cortical (sensorimotor–frontoparietal network) and the cortico–STN levels. The most surprising aspect of this state was the emergence of bilateral STN–STN coherence ON medication across all frequency modes. Dopamine selectively modifies delta/theta oscillations within the STN–STN state In this STN–STN state, dopaminergic intervention had only a limited effect on STN–STN connectivity. OFF medication, STN–STN coherence was present across all three frequency modes (p<0.05, Figure 4A), while ON medication, significant STN–STN coherence emerged only in the alpha and beta band (p<0.05, Figure 4C alpha and beta). ON medication, STN–STN delta/theta connectivity strength was not significantly different from the mean noise level (p<0.05, Figure 4C delta). OFF compared to ON medication, coherence was reduced across the entire cortex both at the inter-cortical and the STN–cortex level across all frequency modes. The most affected areas were similar to the ones in the Ctx–STN state, in other words, the sensorimotor, frontal, and temporal regions. Their coherence with the STN was also significantly reduced, ON compared to OFF medication (STN–sensorimotor, p<0.01 delta/theta, beta; p<0.05 alpha; STN–temporal, p<0.01 delta/theta, alpha, beta; and STN–frontal, p<0.01 delta/theta, alpha and beta; Figure 4B). In summary, STN–STN connectivity was not significantly altered OFF to ON medication. At the same time, coherence decreased from OFF to ON medication at both the cortico–cortical and the cortico–STN level. Therefore, only significant STN–STN connectivity existed both OFF and ON medication, while cortico–STN or cortico–cortical connectivity changes remained at the mean noise level. States with a generic coherence decrease have longer lifetimes Using the temporal properties of the identified networks, we investigated whether states showing a shift towards physiological connectivity patterns lasted longer ON medication. A state that is physiological should exhibit increased lifetime and/or should occur more often ON medication. An example of the state time courses is shown in Figure 5. Figure 5 Download asset Open asset Example of a probability time course for the six hidden Markov model (HMM) states OFF medication. Note that within the main text of the paper, we are only discussing the first three states. The connectivity maps of states 4–6 are provided in Figure 2—figure supplement 1. Source data are provided as Figure 5—source data 1–2. Figure 5—source data 1 Probability time course first half in relation to Figure 5. https://cdn.elifesciences.org/articles/66057/elife-66057-fig5-data1-v1.mat Download elife-66057-fig5-data1-v1.mat Figure 5—source data 2 Probability time course second half in relation to Figure 5. Download Figure shows the temporal properties for the three states for both the OFF and ON medication on the temporal properties of the HMM states revealed an effect of HMM states on the interval of and lifetime was no effect of medication (L-DOPA) on and lifetime had a significant effect on the interval of Finally, we found an between the HMM states and medication on the interval of and lifetime But there was no between HMM states and medication on Figure 6 Download asset Open asset properties of states. Panel A shows the for the three states for the cortico–cortical cortico–STN and the STN–STN (STN–STN). Each represents the mean for a state and the represents ON medication data and OFF medication Panel B shows the mean interval of of the three states ON and OFF medication. Panel C shows the lifetime for the three states. Figure are used for in are not The y-axis of each the same as the main Source data are provided as Figure data Figure data 1 Source data of Figure OFF medication. Download Figure data 2 Source data of Figure ON medication. Download Figure data 3 Source data of Figure OFF medication. Download Figure data 4 Source data of Figure ON medication. Download Figure data 5 Source data of Figure OFF medication. Download Figure data 6 Source data of Figure ON medication. Download We on the results. OFF medication, the STN–STN state was the one with the lifetime Ctx, STN–STN The Ctx–STN state OFF medication had the lifetime all three states Ctx–STN and the interval between of Ctx–STN Ctx–STN The interval between was for the Ctx–Ctx state OFF medication Ctx–Ctx The for the STN–STN and Ctx–STN states was but significantly higher than for the Ctx–Ctx state STN–STN Ctx–STN ON medication, the comparison between temporal properties of all three states the same levels as OFF medication, for the lifetime of the Ctx–STN state, which was no longer significantly different from that of the Ctx–Ctx state Within each medication condition, the states their temporal characteristics to each medication conditions, significant changes were present in the temporal properties of the states. The lifetimes for both the STN–STN and Ctx–STN state were significantly increased by medication but the lifetime for the Ctx–Ctx state was not significantly by medication. The Ctx–Ctx state was even often ON medication ON >OFF The interval between remained unchanged for the STN–STN and Ctx–STN states. The for all three states was not significantly changed from OFF to ON medication. In summary, the cortico–cortical state was often compared to the other two states both OFF and ON medication. The cortico–STN and STN–STN states showing physiologically relevant spectral connectivity lasted significantly longer ON medication. Discussion In this we simultaneously recorded into time-resolved states to reveal distinct spectral communication patterns. We identified three states distinct coherence patterns ON and OFF a cortico–cortical, a cortico–STN, and a STN–STN state. Our results a of neural activity to in connectivity patterns in which coherence under the effect of dopaminergic medication and which selective cortico–STN connectivity and STN–STN Only within the Ctx–Ctx state did coherence increase under dopaminergic medication. These results are in line with the multiple effects of dopaminergic medication reported in and task-based PD studies et al., 2009; West et al., 2016; et al., The differential effect of dopamine allowed us to delineate pathological and

In Parkinson's disease, safinamide and zonisamide are novel monoamine oxidase-B inhibitors with a dual mechanism of action involving the inhibition of sodium and calcium channels and the subsequent release of glutamate. The aim of this systematic review and meta-analysis was to examine the efficacy and safety of both drugs compared with placebo on motor symptoms, cognitive function, and quality of life in patients with Parkinson's disease. We searched MEDLINE, EMBASE, Cochrane Central, Scopus, PsycINFO, and trials registries up to March 2023 for randomized controlled trials of adults with Parkinson's disease administered either safinamide or zonisamide and published in English. We excluded single-arm trials or if neither the efficacy nor safety outcomes of interest were reported. Primary outcomes were the change from baseline in Unified Parkinson's Disease Rating Scale section III (UPDRS-III) and serious adverse events. Secondary outcomes included a change from baseline in OFF-time, Parkinson's Disease Questionnaire 39 to evaluate quality of life, and Mini-Mental State Examination for cognitive function assessment. The meta-analysis was conducted using Review Manager 5.4.1. Random-effect models were used to calculate the pooled mean differences (MDs) and risk ratios with 95% confidence intervals (CIs). Subgroup analyses by medication, doses, Parkinson's disease stage, and risk of bias were conducted. We assessed the risk of bias using the Cochrane's risk of bias tool. Sensitivity analysis was conducted, and publication bias were evaluated. This meta-analysis was not externally funded, and the protocol is available on the Open Science Framework Registration ( https://doi.org/10.17605/OSF.IO/AMNP5 ). Of 3570 screened citations, 16 trials met inclusion criteria (4314 patients with Parkinson's disease). Ten safinamide trials were conducted in several countries. Six zonisamide trials were included, five of which were conducted in Japan and one in India. UPDRS Part III scores were significantly lower with both monoamine oxidase-B inhibitors than with placebo (MD = - 2.18; 95% CI - 2.88 to - 1.49; I 2 =63%; n = 14 studies). A subgroup analysis showed a significant improvement in UPDRS-III in safinamide (MD = - 2.10; 95% CI - 3.09 to - 1.11; I2 = 71%; n = 8 studies) and zonisamide (MD = - 2.31; 95% CI - 3.35 to - 1.27; I2 = 52%; n = 6 studies) compared with placebo. Monoamine oxidase-B inhibitors significantly decreased OFF-time compared with placebo. No significant differences in cognitive function (Mini-Mental State Examination), whereas an improvement in quality of life (Parkinson's Disease Questionnaire 39 scores) was observed. There was no significant difference in incidence rates of serious adverse events among all examined doses of zonisamide and safinamide compared with placebo. Two trials were reported as a high risk of bias and sensitivity analyses confirmed the primary analysis results. Evidence suggests that novel monoamine oxidase-B inhibitors not only improve motor symptoms but also enhance patients' quality of life. The meta-analysis showed that both medications have a similar safety profile to placebo with regard to serious adverse events. The overall findings emphasize the effectiveness of safinamide and zonisamide in the treatment of Parkinson's disease as adjunct therapy. Further long-term studies examining the impact of these medications on motor and non-motor symptoms are necessary.

Parkinson's disease is caused by the progressive degeneration of nerve cells that produce dopamine, a neurotransmitter essential for motor coordination. The most common symptoms of Parkinson's disease are resting tremors, muscle rigidity, slow voluntary movements and postural instability. Furthermore, the disease can cause cognitive, emotional, sensory and autonomic changes. There are two main types of neurosurgery for Parkinson's disease: ablative surgery and deep brain stimulation (DBS). Objective: to evaluate the impact of neurosurgery for Parkinson's disease in improving motor symptoms, reducing medication side effects, preserving cognitive functions and improving patients' quality of life. Methodology: followed the PRISMA checklist. The databases used were PubMed, Scielo, Web of Science and Google Scholar. The descriptors used were: “Parkinson's disease”, “neurosurgery”, “ablation”, “deep brain stimulation” and “outcome”. The inclusion criteria were: articles that compared the two types of neurosurgery for Parkinson's disease (ablative surgery and deep brain stimulation), that evaluated clinical outcomes (motor symptoms, medication side effects, cognitive functions and quality of life) and that used standardized scales to measure these outcomes. The exclusion criteria were: articles that did not compare the two types of neurosurgery for Parkinson's disease, that did not evaluate the clinical outcomes of interest, that used non-validated or inadequate scales to measure these outcomes. Results: 15 studies were selected. Both types of neurosurgery for Parkinson's disease have been effective in improving patients' motor symptoms, especially tremors, rigidity, and bradykinesia. However, deep brain stimulation had an advantage over ablative surgery in terms of reducing medication side effects, such as motor fluctuations and dyskinesias. Deep brain stimulation was also safer and less invasive than ablative surgery, presenting fewer complications such as hemorrhage, infection, neurological deficits, and cognitive or psychiatric changes. However, deep brain stimulation showed greater improvement than ablative surgery, especially in physical, emotional and social aspects of quality of life. Conclusion: neurosurgery for Parkinson's disease is a valid therapeutic option for patients who do not respond adequately to drug treatment or who have intolerable side effects. Among the two main types of neurosurgery for Parkinson's disease, deep brain stimulation appears to be superior to ablative surgery in terms of efficacy, safety, and impact on patients' quality of life.

Efficacy of repetitive transcranial magnetic stimulation in Parkinson's disease: A systematic review and meta-analysis of randomised controlled trials.

Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings.

Implicaciones clínicas y terapéuticas de la acupuntura en la enfermedad de Parkinson: una revisión exploratoria

Monotherapy with monoamine oxidase B (MAO-B) inhibitors enhances the level of endogenous dopamine in treatment for Parkinson's disease (PD) and provides some benefits. Certain neuropsychiatric functions are also regulated by central dopaminergic activity. To investigate the relationship of the efficacy of monotherapy with MAO-B inhibitors on motor symptoms in PD with baseline cognitive function. Outcomes were examined for 27 consecutive drug-naïve PD patients who received initial treatment with a MAO-B inhibitor (selegiline: 11, rasagiline: 16). Selegiline was titrated to an optimal dose. The dose of rasagiline was fixed at 1mg/day. Motor symptoms were assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III before treatment and after the efficacy reached a plateau within 19weeks after drug initiation, and the % improvement in motor symptoms was calculated. Pre-treatment cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). Correlations of % improvement in motor symptoms and baseline cognitive assessments were examined using Spearman correlation coefficients and multiple regression analysis. In all patients, the mean % improvement in motor symptoms was 46.5% (range 0-83.3%). Spearman correlation coefficients showed the % improvement in motor symptoms was correlated with FAB (r = 0.631, p < 0.001). In multiple regression analysis with patient background factors as independent variables, only FAB was associated with improvement in motor symptoms in the MAO-B group. Better FAB scores predict a significant improvement in motor symptoms with treatment with MAO-B inhibitors, suggesting high activity of endogenous dopamine.

AimsAlthough subthalamic nucleus deep brain stimulation (STN-DBS) is effective in patients with advanced Parkinson’s disease (PD), its physiological mechanisms remain unclear. Because STN-DBS is effective in patients with PD whose motor symptoms are dramatically alleviated by L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the higher preoperative catecholamine levels might be related to the better clinical outcome after surgery. We aimed to examine the correlation between the preoperative catecholamine levels and postoperative clinical outcome after subthalamic nucleus deep brain stimulation. The effectiveness of STN-DBS in the patient who responded well to dopaminergic medication suggest the causal link between the dopaminergic system and STN-DBS. We also examined how catecholamine levels were modulated after subthalamic stimulation.MethodsIn total 25 patients with PD were enrolled (Mean age 66.2 ± 6.7 years, mean disease duration 11.6 ± 3.7 years). Mean levodopa equivalent doses were 1032 ± 34.6 mg before surgery. Cerebrospinal fluid and plasma catecholamine levels were measured an hour after oral administration of antiparkinsonian drugs before surgery. The mean Unified Parkinson’s Disease Rating Scale scores (UPDRS) and the Parkinson’s disease Questionnaire-39 (PDQ-39) were obtained before and after surgery. Of the 25 patients, postoperative cerebrospinal fluid and plasma were collected an hour after oral administration of antiparkinsonian drugs during on stimulation at follow up in 11 patients.ResultsMean levodopa equivalent doses significantly decreased after surgery with improvement in motor functions and quality of life. The preoperative catecholamine levels had basically negative correlations with postoperative motor scores and quality of life, suggesting that higher preoperative catecholamine levels were related to better outcome after STN-DBS. The preoperative plasma levels of L-DOPA had significantly negative correlations with postoperative UPDRS- III score in off phase three months after STN-DBS. The preoperative cerebrospinal fluid (CSF) 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) levels had significantly negative correlations with postoperative UPDRS- III score in off phase one year after STN-DBS and the preoperative CSF homovanilic acid (HVA) levels had significant negative correlations with postoperative UPDRS- III score in on phase three months after STN-DBS. In PDQ-39 SI (summary index), preoperative plasma dopamine (DA) level had significantly negative correlations with postoperative PDQ-39 SI one year after STN-DBS suggesting that higher preoperative plasma DA level resulted in better quality of life (QOL) one year after STN-DBS. The stepwise multiple linear regression study revealed that higher preoperative plasma HVA levels had negative influence on the postoperative motor symptoms (i.e., increase in the score of UPDRS), whereas higher preoperative CSF L-DOPA levels had positive influence on the postoperative motor symptoms and QOL (decrease in the score of UPDRS and PDQ-39 SI) The catecholamine levels were not significantly reduced postoperatively in 11 patients despite the significant reduction in levodopa equivalent doses. Unexpectedly, CSF HVA levels significantly increased from 0.00089±0.0003 ng/μl to 0.002±0.0008 ng/μl after STN-DBS.ConclusionThe preoperative catecholamine levels might affect the postoperative motor symptoms and quality of life. The catecholamine levels were not significantly reduced postoperatively despite the significant reduction in levodopa equivalent doses.

Emerging non-invasive therapeutic approaches targeting hypocholinergic neural systems in Parkinson's disease.

BackgroundParkinson's disease is (PD) a progressive neurodegenerative disorder. This study investigated the effects of an individualized nutritional intervention based on the Ketoflex 12/3 protocol, in addition to standard medical treatment, on motor and non-motor symptoms in PD.Methods40 individuals with PD were included in the study, and participants were randomly assigned to intervention and control. All individuals were classified according to inflammatory, glycotoxic, toxic, and vascular biotypes. The intervention group was assigned a plant-rich diet with a low glycemic index, consistent with ketogenic principles, free of inflammatory effects, and including intermittent fasting. The primary endpoint was the change in motor symptoms measured by the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) from baseline to six months. Secondary endpoints included apathy (Starkstein Apathy Scale), activities of daily living (ADL/IADL), and gastrointestinal function (Bristol stool scale).ResultsCompared with the control group, the intervention group showed a significantly greater improvement in motor symptoms as measured by UPDRS-III (-11.0 vs +2.1 points from baseline to six months; p < 0.001). Significant between-group differences were also observed for secondary endpoints, including apathy (Starkstein Apathy Scale), activities of daily living (ADL/IADL), and gastrointestinal function (Bristol stool scale), all favoring the intervention group. Spearman correlation analyses revealed significant negative correlations with ADL and UPDRS-III scores, particularly in individuals with an inflammatory phenotype.ConclusionsThe findings suggest an individualized nutritional approach may contribute to improvement in both motor and non-motor symptoms in PD. Larger, multi-center trials with extended follow-up are needed.

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.