Emergent Functional Network Effects in Parkinson Disease.

Everyday communication is carried out concurrently with other tasks. Therefore, determining how dual tasks interfere with newly learned speech motor skills can offer insight into the cognitive mechanisms underlying speech motor learning in Parkinson disease (PD). The current investigation examines a recently learned speech motor sequence under dual-task conditions. A previously learned sequence of 6 monosyllabic nonwords was examined using a dual-task paradigm. Participants repeated the sequence while concurrently performing a visuomotor task, and performance on both tasks was measured in single- and dual-task conditions. The younger adult group exhibited little to no dual-task interference on the accuracy and duration of the sequence. The older adult group exhibited variability in dual-task costs, with the group as a whole exhibiting an intermediate, though significant, amount of dual-task interference. The PD group exhibited the largest degree of bidirectional dual-task interference among all the groups. These data suggest that PD affects the later stages of speech motor learning, as the dual-task condition interfered with production of the recently learned sequence beyond the effect of normal aging. Because the basal ganglia is critical for the later stages of motor sequence learning, the observed deficits may result from the underlying neural dysfunction associated with PD.

Parkinson's disease (PD) patients and the 6-hydroxydopamine (6-OHDA) lesioned rat model share blink abnormalities. In view of the evolutionarily conserved organization of blinking, characterization of blink reflex circuits in rodents may elucidate the neural mechanisms of PD reflex abnormalities. We examine the extent of this shared pattern of blink abnormalities by measuring blink reflex excitability, blink reflex plasticity, and spontaneous blinking in 6-OHDA lesioned rats. We also investigate whether 130-Hz subthalamic nucleus deep brain stimulation (STN DBS) affects blink abnormalities, as it does in PD patients. Like PD patients, 6-OHDA-lesioned rats exhibit reflex blink hyperexcitability, impaired blink plasticity, and a reduced spontaneous blink rate. At 130 Hz, but not 16 Hz, STN DBS eliminates reflex blink hyperexcitability and restores both short- and long-term blink plasticity. Replicating its lack of effect in PD patients, 130-Hz STN DBS does not reinstate a normal temporal pattern or rate to spontaneous blinking in 6-OHDA lesioned rats. These data show that the 6-OHDA lesioned rat is an ideal model system for investigating the neural bases of reflex abnormalities in PD and highlight the complexity of PD's effects on motor control, by showing that dopamine depletion does not affect all blink systems via the same neural mechanisms.

The vesicular monoamine transporter can protect against toxins that induce an acute parkinsonian syndrome. It has been hypothesized that cytoplasmic dopamine has subacute toxic effects in Parkinson Disease (PD) leading to neuronal death and clinical symptoms. Regulatory polymorphisms in the brain form of the vesicular monoamine transporter (VMAT2) which affect its quantitative expression might therefore serve as genetic risk factors for PD. We have screened the promoter region of the gene for VMAT2 (SLC18A2) and identified several novel polymorphisms that form discrete haplotypes. We have tested the common halpotypes in SLC18A2 for functional effects in reporter gene assays and found that there are several gain-of-function haplotypes that display significantly increased transcriptional activity from the reference element. These gain-of-function haplotypes were tested for association with PD and found to confer a protective effect that was selective for females. This finding is consistent with the prediction that increased sequestration of dopamine in secretory vesicles by VMAT2 is protective for PD.

Curcumin neuroprotective effects in Parkinson disease during pregnancy

Parkinson Disease's Effect on Mortality Eclipses Heart Disease and Other Common Illnesses of the Elderly

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

Many studies have demonstrated that the pathophysiology and clinical symptoms of Parkinson's disease (PD) are inhomogeneous. However, the symptom-specific intrinsic neural activities underlying the PD subtypes are still not well understood. Here, 15 tremor-dominant PD patients, 10 non-tremor-dominant PD patients, and 20 matched normal controls (NCs) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI). Functional brain networks were constructed based on randomly generated anatomical templates with and without the cerebellum. The regional network efficiencies (i.e., the local and global efficiencies) were further measured and used to distinguish subgroups of PD patients (i.e., with tremor-dominant PD and non-tremor-dominant PD) from the NCs using linear discriminant analysis. The results demonstrate that the subtype-specific functional networks were small-world-organized and that the network regional efficiency could discriminate among the individual PD subgroups and the NCs. Brain regions involved in distinguishing between the study groups included the basal ganglia (i.e., the caudate and putamen), limbic regions (i.e., the hippocampus and thalamus), the cerebellum, and other cerebral regions (e.g., the insula, cingulum, and calcarine sulcus). In particular, the performances of the regional local efficiency in the functional network were better than those of the global efficiency, and the performances of global efficiency were dependent on the inclusion of the cerebellum in the analysis. These findings provide new evidence for the neurological basis of differences between PD subtypes and suggest that the cerebellum may play different roles in the pathologies of different PD subtypes. The present study demonstrated the power of the combination of graph-based network analysis and discrimination analysis in elucidating the neural basis of different PD subtypes.

Midbrain dopaminergic (mDA) neurons are essential for motor control, reward processing, emotional regulation and motivation. The degeneration of these neurons, seen in Parkinson’s disease (PD), disrupts fine motor control, leading to symptoms such as bradykinesia, rigidity, and tremor. To date, there is no cure for Parkinson’s Disease (PD), and the mechanisms underlying dopaminergic neuron degeneration remain elusive. Current cell therapies focus on replenishing the degenerated dopaminergic neurons, by transplantation of dopaminergic neurons derived from human pluripotent stem cells (PSCs). Nevertheless, these therapies face post-transplantation challenges such as low cell survival, consistent dopamine release, and co-development of an undesired cell population such as serotonergic neurons leading to hyperkinesia. Midbrain organoids generated from PD hiPSCs offer a promising platform to investigate PD pathomechanisms and discover novel therapeutic approaches. This study aimed to establish a PD model in a novel midbrain organoid and employ optogenetics to control mDA neuron activity and thus dopamine release. We developed a robust mBENO protocol featuring bona fide midbrain dopaminergic neurons within a functional neuronal-glial network resembling the human midbrain/basal ganglia. The composition of mBENO was characterized by temporal transcriptomic analysis and morphological analyses after immunofluorescence labelling, while its function was assessed through local field potential recordings and dopamine content measurements. Neurotransmitter administration confirmed the presence of a functional neuronal network harboring dopaminergic, GABAergic, cholinergic and glutamatergic neurons. Next, we genome engineered and established a PD mBENO model by introducing a SNP found in PD patients, the α-synuclein (SNCA) A30P mutation. SNCA A30P did not impair the differentiation potential but led to dopaminergic neuron loss by D90 and electrophysiological hyperexcitability resembling basal ganglia dysfunction in PD patients. This SNCA A30P mBENO model provides a valuable system to investigate PD pathomechanisms, disease progression, as well as potential therapeutic targets. mBENO could potentially serve as a cell source for cell replacement therapies, offering better cell survival and retention in patients compared to singularized cell injections. Furthermore, to control dopamine secretion we engineered an optogenetic cell line, SynfChrimson, which expresses a stably integrated, fast, red light activatable channel (f-Chrimson), under the control of a synapsin promotor in the AAVS1 locus. Multielectrode array analysis confirmed that the SynfChrimson cell line exhibits neuron specific light-evoked activation. Implanting optogenetically controlled mDA neurons along with a medical device could potentially overcome the challenges of fine-tuning dopamine release in PD therapy. In conclusion, we present a novel midbrain organoid model, which recapitulates the human midbrain in cellular composition and function. We demonstrate that the A30P mBENO exhibits mDA neuron loss and hyperexcitability, functionally modeling PD. The A30P mBENO holds promise as a tool to investigate pathomechanisms and pharmaceutical targets in the future.

Conventional transcranial electrical stimulation (tES) is a non-invasive method to modulate brain activity and has been extensively used in the treatment of Parkinson’s disease (PD). Despite promising prospects, the efficacy of conventional tES in PD treatment is highly variable across different studies. Therefore, many have tried to optimize tES for an improved therapeutic efficacy by developing novel tES intervention strategies. Until now, these novel clinical interventions have not been discussed or reviewed in the context of PD therapy. In this review, we focused on the efficacy of these novel strategies in PD mitigation, classified them into three categories based on their distinct technical approach to circumvent conventional tES problems. The first category has novel stimulation modes to target different modulating mechanisms, expanding the rang of stimulation choices hence enabling the ability to modulate complex brain circuit or functional networks. The second category applies tES as a supplementary intervention for PD hence amplifies neurological or behavioral improvements. Lastly, the closed loop tES stimulation can provide self-adaptive individualized stimulation, which enables a more specialized intervention. In summary, these novel tES have validated potential in both alleviating PD symptoms and improving understanding of the pathophysiological mechanisms of PD. However, to assure wide clinical used of tES therapy for PD patients, further large-scale trials are required.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by topological abnormalities in large-scale functional brain networks, which are commonly analyzed using undirected correlations in the activation signals between brain regions. This approach assumes simultaneous activation of brain regions, despite previous evidence showing that brain activation entails causality, with signals being typically generated in one region and then propagated to other ones. To address this limitation, here, we developed a new method to assess whole-brain directed functional connectivity in participants with PD and healthy controls using antisymmetric delayed correlations, which capture better this underlying causality. Our results show that whole-brain directed connectivity, computed on functional magnetic resonance imaging data, identifies widespread differences in the functional networks of PD participants compared with controls, in contrast to undirected methods. These differences are characterized by increased global efficiency, clustering, and transitivity combined with lower modularity. Moreover, directed connectivity patterns in the precuneus, thalamus, and cerebellum were associated with motor, executive, and memory deficits in PD participants. Altogether, these findings suggest that directional brain connectivity is more sensitive to functional network differences occurring in PD compared with standard methods, opening new opportunities for brain connectivity analysis and development of new markers to track PD progression.

There is a huge heterogeneity of magnetic resonance imaging findings in Parkinson's disease (PD) with impulse control disorders (ICDs) studies. Here, we hypothesized that brain regions identified by structural and functional imaging studies of PD with ICDs could be reconciled in a common network. In this study, an initial systematic literature review was conducted to collect and evaluate whole-brain functional and structural magnetic resonance imaging studies related to PD with ICDs. We subsequently utilized the Human Connectome Project (HCP) dataset (n = 1,093) and a novel functional connectivity network mapping (FCNM) technique to identify a common brain network affected in PD with ICDs. A total of 19 studies with 25 contrasts, incorporating 345 individuals with PD and ICDs, and 787 individuals with PD without ICDs were included in the analysis. By using the HCP dataset and a novel FCNM technique, we ultimately identified that the aberrant neural networks predominantly involve the default mode network (middle and inferior temporal gyrus, anterior cingulate cortex, angular gyrus) and subcortical network (caudate nucleus). This study suggests that the heterogeneous neuroimaging findings in PD with ICDs can be attributed to shared abnormalities in the default mode and subcortical networks. These dysfunctions are associated with impaired self-regulation, decision-making, and heightened impulsivity in PD with ICDs. Our findings integrate diverse neuroimaging results from previous studies, providing a clearer understanding of the neurobiological mechanisms underlying PD with ICDs at a network level.

Towards precision functional brain network mapping in Parkinson’s disease

The mutations of the glucocerebrosidase (GBA) gene are the greatest genetic risk factor for Parkinson's disease (PD). The mechanism underlying the association between GBA mutations and PD has not been fully elucidated. Using resting-state functional magnetic resonance imaging and graph theory analysis to investigate the disrupted topological organization in PD patients with GBA mutation (GBA-PD). Eleven GBA-PD patients, 11 noncarriers with PD, and 18 healthy controls (HCs) with a similar age and sex distribution were recruited. Individual whole-brain functional connectome was constructed, and the global and nodal topological disruptions were calculated among groups. Partial correlation analyses between the clinical features of patients with PD and topological alterations were performed. The GBA-PD group showed prominently decreased characteristic path length (Lp) and increased global efficiency (Eg) compared to HCs at the global level; a significantly increased nodal betweenness centrality in the medial prefrontal cortex (mPFC) and precuneus within the default mode network, and precentral gyrus within the sensorimotor network, while a significantly decreased betweenness centrality in nodes within the cingulo-opercular network compared to the noncarrier group at the regional level. The altered nodal betweenness centrality of mPFC was positively correlated with fatigue severity scale scores in all patients with PD. The preliminary pilot study found that GBA-PD patients had a higher functional integration at the global level. The nodal result of the mPFC is congruent with the potential fatigue pathology in PD and is suggestive of a profound effect of GBA mutations on the clinical fatigue in patients with PD.

Iron-related nigral degeneration influences functional topology mediated by striatal dysfunction in Parkinson's disease

Background. It may be possible to use attention-based exercise to decrease demands associated with walking in Parkinson’s disease (PD), and thus improve dual task walking ability. For example, an external focus of attention (focusing on the effect of an action on the environment) may recruit automatic control processes degenerated in PD, whereas an internal focus (limb movement) may recruit conscious (nonautomatic) control processes. Thus, we aimed to investigate how externally and internally focused exercise influences dual task walking and symptom severity in PD. Methods. Forty-seven participants with PD were randomized to either an Externally (n = 24) or Internally (n = 23) focused group and completed 33 one-hour attention-based exercise sessions over 11 weeks. In addition, 16 participants were part of a control group. Before, after, and 8 weeks following the program (pre/post/washout), gait patterns were measured during single and dual task walking (digit-monitoring task, ie, walking while counting numbers announced by an audio-track), and symptom severity (UPDRS-III) was assessed ON and OFF dopamine replacement. Pairwise comparisons (95% confidence intervals [CIs]) and repeated-measures analyses of variance were conducted. Results. Pre to post: Dual task step time decreased in the external group (Δ = 0.02 seconds, CI 0.01-0.04). Dual task step length (Δ = 2.3 cm, CI 0.86-3.75) and velocity (Δ = 4.5 cm/s, CI 0.59-8.48) decreased (became worse) in the internal group. UPDRS-III scores (ON and OFF) decreased (improved) in only the External group. Pre to washout: Dual task step time (P = .005) and percentage in double support (P = .014) significantly decreased (improved) in both exercise groups, although only the internal group increased error on the secondary counting task (ie, more errors monitoring numbers). UPDRS-III scores in both exercise groups significantly decreased (P = .001). Conclusions. Since dual task walking improvements were found immediately, and 8 weeks after the cessation of an externally focused exercise program, we conclude that externally focused exercise may improve on functioning of automatic control networks in PD. Internally focused exercise hindered dual tasking ability. Overall, externally focused exercise led to greater rehabilitation benefits in dual tasking and motor symptoms compared with internally focused exercise.