In Parkinson's disease (PD), the human brain is capable of producing motor commands, but appears to require greater than normal subjective effort, particularly for the more-affected side. What is the ...nature of this subjective effort and can it be altered? We used an isometric task in which patients produced a goal force by engaging both arms, but were free to assign any fraction of that force to each arm. The patients preferred their less-affected arm, but only in some directions. This preference was correlated with lateralization of signal-dependent noise: the direction of force for which the brain was less willing to assign effort to an arm was generally the direction for which that arm exhibited greater noise. Therefore, the direction-dependent noise in each arm acted as an implicit cost that discouraged use of that arm. To check for a causal relationship between noise and motor cost, we used bilateral transcranial direct current stimulation of the motor cortex, placing the cathode on the more-affected side and the anode on the less-affected side. This stimulation not only reduced the noise on the more-affected arm, it also increased the willingness of the patients to assign force to that arm. In a 3 d double-blind study and in a 10 d repeated stimulation study, bilateral stimulation of the two motor cortices with cathode on the more-affected side reduced noise and increased the willingness of the patients to exert effort. This stimulation also improved the clinical motor symptoms of the disease.
In Parkinson's disease, patients are less willing to assign force to their affected arm. Here, we find that this pattern is direction dependent: directions for which the arm is noisier coincide with directions for which the brain is less willing to assign force. We hypothesized that if we could reduce the noise on the affected arm, then we may increase the willingness for the brain to assign force to that arm. We found a way to do this via noninvasive cortical stimulation. In addition to reducing effort costs associated with the affected arm, the cortical stimulation also improved clinical motor symptoms of the disease.
Objective: Fluctuations in response to levodopa in Parkinson's disease (PD) are difficult to treat as tools to monitor temporal patterns of symptoms are hampered by several challenges. The objective ...was to use wearable sensors to quantify the dose response of tremor, bradykinesia, and dyskinesia in individuals with PD. Methods: Thirteen individuals with PD and fluctuating motor benefit were instrumented with wrist and ankle motion sensors and recorded by video. Kinematic data were recorded as subjects completed a series of activities in a simulated home environment through transition from off to on medication. Subjects were evaluated using the unified Parkinson disease rating scale motor exam (UPDRS-III) at the start and end of data collection. Algorithms were applied to the kinematic data to score tremor, bradykinesia, and dyskinesia. A blinded clinician rated severity observed on video. Accuracy of algorithms was evaluated by comparing scores with clinician ratings using a receiver operating characteristic (ROC) analysis. Results: Algorithm scores for tremor, bradykinesia, and dyskinesia agreed with clinician ratings of video recordings (ROC area > 0.8). Summary metrics extracted from time intervals before and after taking medication provided quantitative measures of therapeutic response (p <; 0.01). Radar charts provided intuitive visualization, with graphical features correlated with UPDRS-III scores (R = 0.81). Conclusion: A system with wrist and ankle motion sensors can provide accurate measures of tremor, bradykinesia, and dyskinesia as patients complete routine activities. Significance: This technology could provide insight on motor fluctuations in the context of daily life to guide clinical management and aid in development of new therapies.
In the last half-century, Parkinson's disease (PD) has played a historical role in demonstrating our ability to translate preclinical scientific advances in pathology and pharmacology into highly ...effective clinical therapies. Yet, as highly efficacious symptomatic treatments were successfully developed and adopted in clinical practice, PD remained a progressive disease without a cure. In contrast with the success story of symptomatic therapies, the lack of translation of disease-modifying interventions effective in preclinical models into clinical success has continued to accumulate failures in the past two decades. The ability to stop, prevent or mitigate progression in PD remains the "holy grail" in PD science at the present time. The large number of high-quality disease modification clinical trials in the past two decades with its lessons learned, as well as the growing knowledge of PD molecular pathology should enable us to have a deeper understanding of the reasons for past failures and what we need to do to reach better outcomes. Periodic reviews and mini-reviews of the unsolved disease modification conundrum in PD are important, considering how this field is rapidly evolving along with our views and understanding of the possible explanations.
Purpose of Review
According to the amyloid cascade hypothesis, removing amyloid beta (Aβ) should cure Alzheimer’s disease (AD). In the past three decades, many agents have been tested to try to lower ...Aβ production, prevent Aβ aggregation, and dissolve Aβ deposits. However, the paucity in definitive preventative or curative properties of these agents in clinical trials has resulted in more avant-garde approaches to therapeutic investigations. Immunotherapy has become an area of focus for research on disease-modifying therapies for neurodegenerative diseases. In this review, we highlight the current clinical development landscape of monoclonal antibody (mAb) therapies that target Aβ plaque formation and removal in AD.
Recent Findings
Multiple potential disease-modifying therapeutics for AD are in active development. Targeting Aβ with mAbs has the potential to treat various stages of AD: prodromal, prodromal to mild, mild, and mild to moderate. Monoclonal antibodies discussed here include aducanumab, lecanemab, solanezumab, crenezumab, donanemab, and gantenerumab.
Summary
The final decision by the FDA regarding the approval of aducanumab will offer valuable insight into the trajectory of drug development for mAbs in AD and other neurodegenerative diseases. Future directions for improving the treatment of AD will include more inquiry into the efficacy of mAbs as disease-modifying agents that specifically target Aβ peptides and/or multimers. In addition, a more robust trial design for AD immunotherapy agents should improve outcomes such that objective measures of clinical efficacy will eventually lead to higher chances of drug approval.
Objective: The main obstacle in interpreting EEG/MEG data in terms of brain connectivity is the fact that because of volume conduction, the activity of a single brain source can be observed in many ...channels. Here, we present an approach which is insensitive to false connectivity arising from volume conduction.
Methods: We show that the (complex) coherency of non-interacting sources is necessarily real and, hence, the imaginary part of coherency provides an excellent candidate to study brain interactions. Although the usual magnitude and phase of coherency contain the same information as the real and imaginary parts, we argue that the Cartesian representation is far superior for studying brain interactions. The method is demonstrated for EEG measurements of voluntary finger movement.
Results: We found: (a) from 5 s before to movement onset a relatively weak interaction around 20 Hz between left and right motor areas where the contralateral side leads the ipsilateral side; and (b) approximately 2–4 s after movement, a stronger interaction also at 20 Hz in the opposite direction.
Conclusions: It is possible to reliably detect brain interaction during movement from EEG data.
Significance: The method allows unambiguous detection of brain interaction from rhythmic EEG/MEG data.
Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function ...improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.
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