Precise cortical contributions to sensorimotor feedback control during reactive balance.

The role of the cortex in shaping automatic whole-body motor behaviors such as walking and balance is poorly understood. Gait and balance are typically mediated through subcortical circuits, with the cortex becoming engaged as needed on an individual basis by task difficulty and complexity. However, we lack a mechanistic understanding of how increased cortical contribution to whole-body movements shapes motor output. Here we use reactive balance recovery as a paradigm to identify relationships between hierarchical control mechanisms and their engagement across balance tasks of increasing difficulty in young adults. We hypothesize that parallel sensorimotor feedback loops engaging subcortical and cortical circuits contribute to balance-correcting muscle activity, and that the involvement of cortical circuits increases with balance challenge. We decomposed balance-correcting muscle activity based on hypothesized subcortically- and cortically-mediated feedback components driven by similar sensory information, but with different loop delays. The initial balance-correcting muscle activity was engaged at all levels of balance difficulty. Its onset latency was consistent with subcortical sensorimotor loops observed in the lower limb. An even later, presumed, cortically-mediated burst of muscle activity became additionally engaged as balance task difficulty increased, at latencies consistent with longer transcortical sensorimotor loops. We further demonstrate that evoked cortical activity in central midline areas measured using electroencephalography (EEG) can be explained by a similar sensory transformation as muscle activity but at a delay consistent with its role in a transcortical loop driving later cortical contributions to balance-correcting muscle activity. These results demonstrate that a neuromechanical model of muscle activity can be used to infer cortical contributions to muscle activity without recording brain activity. Our model may provide a useful framework for evaluating changes in cortical contributions to balance that are associated with falls in older adults and in neurological disorders such as Parkinson's disease.

Levodopa responsive freezing of gait is associated with reduced norepinephrine transporter binding in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a major cause of falling in Parkinson's disease (PD) and can be responsive or unresponsive to levodopa. Pathophysiology is poorly understood. OBJECTIVE: To examine the link between noradrenergic systems, the development of FOG in PD and its responsiveness to levodopa. METHODS: We examined norepinephrine transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[α-(2-methoxyphenoxy)benzyl]morpholine) in 52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize PD patients as non-freezing (NO-FOG, N = 16), levodopa responsive freezing (OFF-FOG, N = 10), and levodopa-unresponsive freezing (ONOFF-FOG, N = 21), and also included a non-PD FOG group, primary progressive freezing of gait (PP-FOG, N = 5). RESULTS: Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P = 0.021) and regionally in the frontal lobe, left and right thalamus, temporal lobe, and locus coeruleus, with the strongest effect in right thalamus (P = 0.038). Additional regions examined in a post hoc secondary analysis including the left and right amygdalae confirmed the contrast between OFF-FOG and NO-FOG (P = 0.003). A linear regression analysis identified an association between reduced NET binding in the right thalamus and more severe New FOG Questionnaire (N-FOG-Q) score only in the OFF-FOG group (P = 0.022). CONCLUSION: This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.

Cerebrospinal fluid levels of 5-HIAA and dopamine in people with HIV and depression.

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53 years versus 47 years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49 ng/mL versus 0.62 ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57 ng/mL versus 15.41 ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.

Referent Values for Commonly Used Clinical Mobility Tests in Black and White Adults Aged 50-95 Years.

OBJECTIVE: To estimate referent values for performance on clinical mobility tests conducted amongst racially diverse adults aged 50-95 years in the Southeast US. DESIGN: This is an observational study of community-dwelling older adults from diverse racial groups who participated in observational and rehabilitative studies conducted from 2011-2019. SETTING: Rehabilitation clinics around the greater metropolitan Atlanta, Georgia, region. PARTICIPANTS: A total of 314 adults (N=314; 222 women). Individuals were predominantly Black (n=121) or White (n=164), with some participants from other racial groups (n=29). INTERVENTIONS: Clinical and demographic data were collected at individual visits for each participant. MAIN OUTCOME MEASURES: Four Square Step Test (FSST), timed Up and Go (TUG) test, dual TUG test, 6-minute walk test (6MWT), 30-second chair stand, and gait speed were all used as assessments in each cohort. RESULTS: Performance slowly declines with increasing age, with a sharp drop in the ninth decade for preferred forward, backward, and fast gait speed; backward gait cadence; 6MWT, TUG test, dual-task TUG-Cognitive, and the 360° turn test. Declines were also seen in the eighth and ninth decades in the FSST. Among White participants, there were significant overall differences across age groups except in the assessment variable, preferred gait cadence. For Black individuals, there were significant overall differences across age groups for backward gait speed, fast gait speed, TUG-Cognitive, dual task, 6MWT, FSST, and 30-second chair stand. CONCLUSIONS: These data enrich current referent values for brief, commonly used clinical tests in a diverse, older Southeast US cohort. These data include representatives of the oldest old cohort. This study will support race- and age-specific fall prevention and mobility-enhancing therapeutic application among older patients in clinical practice.

Classifying Tremor Dominant and Postural Instability and Gait Difficulty Subtypes of Parkinson's Disease from Full-Body Kinematics.

Characterizing motor subtypes of Parkinson's disease (PD) is an important aspect of clinical care that is useful for prognosis and medical management. Although all PD cases involve the loss of dopaminergic neurons in the brain, individual cases may present with different combinations of motor signs, which may indicate differences in underlying pathology and potential response to treatment. However, the conventional method for distinguishing PD motor subtypes involves resource-intensive physical examination by a movement disorders specialist. Moreover, the standardized rating scales for PD rely on subjective observation, which requires specialized training and unavoidable inter-rater variability. In this work, we propose a system that uses machine learning models to automatically and objectively identify some PD motor subtypes, specifically Tremor-Dominant (TD) and Postural Instability and Gait Difficulty (PIGD), from 3D kinematic data recorded during walking tasks for patients with PD (MDS-UPDRS-III Score, 34.7 ± 10.5, average disease duration 7.5 ± 4.5 years). This study demonstrates a machine learning model utilizing kinematic data that identifies PD motor subtypes with a 79.6% F1 score (N = 55 patients with parkinsonism). This significantly outperformed a comparison model using classification based on gait features (19.8% F1 score). Variants of our model trained to individual patients achieved a 95.4% F1 score. This analysis revealed that both temporal, spectral, and statistical features from lower body movements are helpful in distinguishing motor subtypes. Automatically assessing PD motor subtypes simply from walking may reduce the time and resources required from specialists, thereby improving patient care for PD treatments. Furthermore, this system can provide objective assessments to track the changes in PD motor subtypes over time to implement and modify appropriate treatment plans for individual patients as needed.

An Explainable Spatial-Temporal Graphical Convolutional Network to Score Freezing of Gait in Parkinsonian Patients.

Freezing of gait (FOG) is a poorly understood heterogeneous gait disorder seen in patients with parkinsonism which contributes to significant morbidity and social isolation. FOG is currently measured with scales that are typically performed by movement disorders specialists (i.e., MDS-UPDRS), or through patient completed questionnaires (N-FOG-Q) both of which are inadequate in addressing the heterogeneous nature of the disorder and are unsuitable for use in clinical trials The purpose of this study was to devise a method to measure FOG objectively, hence improving our ability to identify it and accurately evaluate new therapies. A major innovation of our study is that it is the first study of its kind that uses the largest sample size (>30 h, N = 57) in order to apply explainable, multi-task deep learning models for quantifying FOG over the course of the medication cycle and at varying levels of parkinsonism severity. We trained interpretable deep learning models with multi-task learning to simultaneously score FOG (cross-validated F1 score 97.6%), identify medication state (OFF vs. ON levodopa; cross-validated F1 score 96.8%), and measure total PD severity (MDS-UPDRS-III score prediction error ≤ 2.7 points) using kinematic data of a well-characterized sample of N = 57 patients during levodopa challenge tests. The proposed model was able to explain how kinematic movements are associated with each FOG severity level that were highly consistent with the features, in which movement disorders specialists are trained to identify as characteristics of freezing. Overall, we demonstrate that deep learning models' capability to capture complex movement patterns in kinematic data can automatically and objectively score FOG with high accuracy. These models have the potential to discover novel kinematic biomarkers for FOG that can be used for hypothesis generation and potentially as clinical trial outcome measures.

Differentiating Parkinson Disease Subtypes Using Clinical Balance Measures.

BACKGROUND AND PURPOSE: People with Parkinson disease (PD) present phenotypes that are characterized as tremor-dominant (TD) or postural instability/gait difficulty (PIGD) subtypes. Differentiation of subtypes allows clinicians to predict disease course and adjust treatment. We examined whether brief mobility and balance measures can discriminate PIGD from TD phenotypes. METHODS: We performed a cross-sectional study with individuals with PD (n = 104). Blinded raters assessed participants with the Unified Parkinson's Disease Rating Scale (UPDRS) or Movement Disorders Society revision (MDS-UPDRS), and balance assessments: 360° turn test, one-leg stance, a reactive postural control test, and tandem walk. Participants were classified as PIGD or TD based on the UPDRS or MDS-UPDRS assessment results. Differences in balance variables between subtypes were assessed with univariate analyses. Receiver operating characteristic (ROC) curve analyses were performed to investigate the ability of balance variables to differentiate PD subtypes. RESULTS: No differences between subtypes were observed for tandem walk or reactive postural control. Participants with PIGD performed worse on number of steps and time to complete the 360° turn test and on one-leg stance time. ROC curves showed only the 360° turn test discriminated PIGD from TD with high specificity (0.84). Post hoc analyses revealed that the 360° turn test is the most discriminatory for classifying PD subtypes in early stages of the disease. ROC analyses based on combined models including both the 360° test and tandem walk test performance increased the specificity to 0.97. DISCUSSION AND CONCLUSIONS: The 360° turn test requires minimal time to administer and may be useful in mild-moderate PD for distinguishing PIGD from TD subtypes.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A295).

Increased neuromuscular consistency in gait and balance after partnered, dance-based rehabilitation in Parkinson's disease.

Here we examined changes in muscle coordination associated with improved motor performance after partnered, dance-based rehabilitation in individuals with mild to moderate idiopathic Parkinson's disease. Using motor module (a.k.a. muscle synergy) analysis, we identified changes in the modular control of overground walking and standing reactive balance that accompanied clinically meaningful improvements in behavioral measures of balance, gait, and disease symptoms after 3 wk of daily Adapted Tango classes. In contrast to previous studies that revealed a positive association between motor module number and motor performance, none of the six participants in this pilot study increased motor module number despite improvements in behavioral measures of balance and gait performance. Instead, motor modules were more consistently recruited and distinctly organized immediately after rehabilitation, suggesting more reliable motor output. Furthermore, the pool of motor modules shared between walking and reactive balance increased after rehabilitation, suggesting greater generalizability of motor module function across tasks. Our work is the first to show that motor module distinctness, consistency, and generalizability are more sensitive to improvements in gait and balance function after short-term rehabilitation than motor module number. Moreover, as similar differences in motor module distinctness, consistency, and generalizability have been demonstrated previously in healthy young adults with and without long-term motor training, our work suggests commonalities in the structure of muscle coordination associated with differences in motor performance across the spectrum from motor impairment to expertise.NEW & NOTEWORTHY We demonstrate changes in neuromuscular control of gait and balance in individuals with Parkinson's disease after short-term, dance-based rehabilitation. Our work is the first to show that motor module distinctness, consistency, and generalizability across gait and balance are more sensitive than motor module number to improvements in motor performance following short-term rehabilitation. Our results indicate commonalities in muscle coordination improvements associated with motor skill reacquisition due to rehabilitation and motor skill acquisition in healthy individuals.

Small forces that differ with prior motor experience can communicate movement goals during human-human physical interaction.

BACKGROUND: Physical interactions between two people are ubiquitous in our daily lives, and an integral part of many forms of rehabilitation. However, few studies have investigated forces arising from physical interactions between humans during a cooperative motor task, particularly during overground movements. As such, the direction and magnitude of interaction forces between two human partners, how those forces are used to communicate movement goals, and whether they change with motor experience remains unknown. A better understanding of how cooperative physical interactions are achieved in healthy individuals of different skill levels is a first step toward understanding principles of physical interactions that could be applied to robotic devices for motor assistance and rehabilitation. METHODS: Interaction forces between expert and novice partner dancers were recorded while performing a forward-backward partnered stepping task with assigned "leader" and "follower" roles. Their position was recorded using motion capture. The magnitude and direction of the interaction forces were analyzed and compared across groups (i.e. expert-expert, expert-novice, and novice-novice) and across movement phases (i.e. forward, backward, change of direction). RESULTS: All dyads were able to perform the partnered stepping task with some level of proficiency. Relatively small interaction forces (10-30N) were observed across all dyads, but were significantly larger among expert-expert dyads. Interaction forces were also found to be significantly different across movement phases. However, interaction force magnitude did not change as whole-body synchronization between partners improved across trials. CONCLUSIONS: Relatively small interaction forces may communicate movement goals (i.e. "what to do and when to do it") between human partners during cooperative physical interactions. Moreover, these small interactions forces vary with prior motor experience, and may act primarily as guiding cues that convey information about movement goals rather than providing physical assistance. This suggests that robots may be able to provide meaningful physical interactions for rehabilitation using relatively small force levels.

Balance, Body Motion, and Muscle Activity After High-Volume Short-Term Dance-Based Rehabilitation in Persons With Parkinson Disease: A Pilot Study.

BACKGROUND AND PURPOSE: The objectives of this pilot study were to (1) evaluate the feasibility and investigate the efficacy of a 3-week, high-volume (450 minutes per week) Adapted Tango intervention for community-dwelling individuals with mild-moderate Parkinson disease (PD) and (2) investigate the potential efficacy of Adapted Tango in modifying electromyographic (EMG) activity and center of body mass (CoM) displacement during automatic postural responses to support surface perturbations. METHODS: Individuals with PD (n = 26) were recruited for high-volume Adapted Tango (15 lessons, 1.5 hour each over 3 weeks). Twenty participants were assessed with clinical balance and gait measures before and after the intervention. Nine participants were also assessed with support-surface translation perturbations. RESULTS: Overall adherence to the intervention was 77%. At posttest, peak forward CoM displacement was reduced (4.0 ± 0.9 cm, pretest, vs 3.7 ± 1.1 cm, posttest; P = 0.03; Cohen's d = 0.30) and correlated to improvements on Berg Balance Scale (ρ = -0.68; P = 0.04) and Dynamic Gait Index (ρ = -0.75; P = 0.03). Overall antagonist onset time was delayed (27 ms; P = 0.02; d = 0.90) and duration was reduced (56 ms, ≈39%, P = 0.02; d = 0.45). Reductions in EMG magnitude were also observed (P < 0.05). DISCUSSION AND CONCLUSIONS: Following participation in Adapted Tango, changes in kinematic and some EMG measures of perturbation responses were observed in addition to improvements in clinical measures. We conclude that 3-week, high-volume Adapted Tango is feasible and represents a viable alternative to longer duration adapted dance programs.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A143).

Longitudinal prevalence of neurogenic orthostatic hypotension in the idiopathic Parkinson Progression Marker Initiative (PPMI) cohort.

BACKGROUND: Reported orthostatic hypotension (OH) prevalence in Parkinson's disease (PD) varies widely, with few studies evaluating specifically neurogenic-OH (nOH). The ratio of orthostatic heart rate (HR) to systolic blood pressure (SBP) change (Δ) is a valid screening method to stratify nOH/non-nOH but has had minimal epidemiologic application. OBJECTIVE: To estimate the prevalence of nOH and non-nOH in the PPMI using the ΔHR/ΔSBP ratio and examine associations between nOH and various motor and non-motor measures. METHODS: Longitudinal orthostatic vitals and motor and non-motor measures were extracted (baseline-month 48). Patients were consensus criteria classified as OH+/-, with ΔHR/ΔSBP sub-classification to nOH (ΔHR/ΔSBP < 0.5) or non-nOH (ratio ≥ 0.5). Prevalence was determined across visits. Independent linear mixed models tested associations between nOH/non-nOH and clinical variables. RESULTS: Of N = 907 PD with baseline orthostatic vitals, 3.9 % and 1.8 % exhibited nOH and non-nOH, respectively. Prevalence of nOH/non-nOH increased yearly (P = 0.012, chi-square), though with modest magnitude (baseline: 5.6 % [95 % CI: 4.3-7.3 %]; month 48: 8.6 % [6.4-11.5 %]). nOH patients were older than PD with no OH and nOH was associated with greater impairment of motor and independent functioning than non-nOH/OH- groups. Cognitive function and typical OH symptoms were worse in PD + OH, generally. CONCLUSIONS: nOH prevalence was greater than non-nOH in the PPMI early PD cohort, with modest prevalence increase over time. Our findings are consistent with prior studies of large cohorts that evaluated nOH, specifically. Those with early PD and nOH were likelier to be older and suffer from greater motor and functional impairment, but OH presence was generally associated with more cognitive impairment.

Impact of deep brain stimulation on gait in Parkinson disease: A kinematic study.

BACKGROUND: The effect of Deep Brain Stimulation (DBS) on gait in Parkinson's Disease (PD) is poorly understood. Kinematic studies utilizing quantitative gait outcomes such as speed, cadence, and stride length have shown mixed results and were done mostly before and after acute DBS discontinuation. OBJECTIVE: To examine longitudinal changes in kinematic gait outcomes before and after DBS surgery. METHOD: We retrospectively assessed changes in quantitative gait outcomes via motion capture in 22 PD patients before and after subthalamic (STN) or globus pallidus internus (GPi) DBS, in on medication state. Associations between gait outcomes and clinical variables were also assessed. RESULT: Gait speed reduced from 110.7 ± 21.3 cm/s before surgery to 93.6 ± 24.9 after surgery (7.7 ± 2.9 months post-surgery, duration between assessments was 15.0 ± 3.8 months). Cadence, step length, stride length, and single support time reduced, while total support time, and initial double support time increased. Despite this, there was overall improvement in the Movement Disorder Society-Unified Parkinson Disease Rating Scale-Part III score "on medication/on stimulation" score (from 19.8 ± 10.7-13.9 ± 8.6). Change of gait speed was not related to changes in levodopa dosage, disease duration, unilateral vs bilateral stimulation, or target nucleus. CONCLUSION: Quantitative gait outcomes in on medication state worsened after chronic DBS therapy despite improvement in other clinical outcomes. Whether these changes reflect the effects of DBS as opposed to ongoing disease progression is unknown.

Associations between music and dance relationships, rhythmic proficiency, and spatiotemporal movement modulation ability in adults with and without mild cognitive impairment.

Background: Personalized dance-based movement therapies may improve cognitive and motor function in individuals with mild cognitive impairment (MCI), a precursor to Alzheimer's disease. While age- and MCI-related deficits reduce individuals' abilities to perform dance-like rhythmic movement sequences (RMS)-spatial and temporal modifications to movement-it remains unclear how individuals' relationships to dance and music affect their ability to perform RMS. Objective: Characterize associations between RMS performance and music or dance relationships, as well as the ability to perceive rhythm and meter (rhythmic proficiency) in adults with and without MCI. Methods: We used wearable inertial sensors to evaluate the ability of 12 young adults (YA; age=23.9±4.2 yrs; 9F), 26 older adults without MCI (OA; age=68.1±8.5 yrs; 16F), and 18 adults with MCI (MCI; age=70.8±6.2 yrs; 10F) to accurately perform spatial, temporal, and spatiotemporal RMS. To quantify self-reported music and dance relationships and rhythmic proficiency, we developed Music (MRQ) and Dance Relationship Questionnaires (DRQ), and a rhythm assessment (RA), respectively. We correlated MRQ, DRQ, and RA scores against RMS performance for each group separately. Results: The OA and YA groups exhibited better MRQ and RA scores than the MCI group (p<0.006). Better MRQ and RA scores were associated with better temporal RMS performance for only the YA and OA groups (r2=0.18-0.41; p<0.045). DRQ scores were not associated with RMS performance in any group. Conclusions: Cognitive deficits in adults with MCI likely limit the extent to which music relationships or rhythmic proficiency improve the ability to perform temporal aspects of movements performed during dance-based therapies.

Life-long music and dance relationships inform impressions of music- and dance-based movement therapies in individuals with and without mild cognitive impairment.

Background: No effective therapies exist to prevent degeneration from Mild Cognitive Impairment (MCI) to Alzheimer's disease. Therapies integrating music and/or dance are promising as effective, non-pharmacological options to mitigate cognitive decline. Objective: To deepen our understanding of individuals' relationships (i.e., histories, experiences and attitudes) with music and dance that are not often incorporated into music- and dance-based therapeutic design, yet may affect therapeutic outcomes. Methods: Eleven older adults with MCI and five of their care partners/ spouses participated (4M/12F; Black: n=4, White: n=10, Hispanic/ Latino: n=2; Age: 71.4±9.6). We conducted focus groups and administered questionnaires that captured aspects of participants' music and dance relationships. We extracted emergent themes from four major topics, including: (1) experience and history, (2) enjoyment and preferences, (3) confidence and barriers, and (4) impressions of music and dance as therapeutic tools. Results: Thematic analysis revealed participants' positive impressions of music and dance as potential therapeutic tools, citing perceived neuropsychological, emotional, and physical benefits. Participants viewed music and dance as integral to their lives, histories, and identities within a culture, family, and/ or community. Participants also identified lifelong engagement barriers that, in conjunction with negative feedback, instilled persistent low self-efficacy regarding dancing and active music engagement. Questionnaires verified individuals' moderately-strong music and dance relationships, strongest in passive forms of music engagement (e.g., listening). Conclusions: Our findings support that individuals' music and dance relationships and the associated perceptions toward music and dance therapy may be valuable considerations in enhancing therapy efficacy, participant engagement and satisfaction for individuals with MCI.

Exploration of potential immune mechanisms in cervical dystonia.

BACKGROUND: Although there are many possible causes for cervical dystonia (CD), a specific etiology cannot be identified in most cases. Prior studies have suggested a relationship between autoimmune disease and some cases of CD, pointing to possible immunological mechanisms. OBJECTIVE: The goal was to explore the potential role of multiple different immunological mechanisms in CD. METHODS: First, a broad screening test compared neuronal antibodies in controls and CD. Second, unbiased blood plasma proteomics provided a broad screen for potential biologic differences between controls and CD. Third, a multiplex immunoassay compared 37 markers associated with immunological processes in controls and CD. Fourth, relative immune cell frequencies were investigated in blood samples of controls and CD. Finally, sequencing studies investigated the association of HLA DQB1 and DRB1 alleles in controls versus CD. RESULTS: Screens for anti-neuronal antibodies did not reveal any obvious abnormalities. Plasma proteomics pointed towards certain abnormalities of immune mechanisms, and the multiplex assay pointed more specifically towards abnormalities in T lymphocytes. Abnormal immune cell frequencies were identified for some CD cases, and these cases clustered together as a potential subgroup. Studies of HLA alleles indicated a possible association between CD and DRB1*15:03, which is reported to mediate the penetrance of autoimmune disorders. CONCLUSIONS: Altogether, the association of CD with multiple different blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of individuals with CD.

Statistically significant contrasts between EMG waveforms revealed using wavelet-based functional ANOVA.

We developed wavelet-based functional ANOVA (wfANOVA) as a novel approach for comparing neurophysiological signals that are functions of time. Temporal resolution is often sacrificed by analyzing such data in large time bins, increasing statistical power by reducing the number of comparisons. We performed ANOVA in the wavelet domain because differences between curves tend to be represented by a few temporally localized wavelets, which we transformed back to the time domain for visualization. We compared wfANOVA and ANOVA performed in the time domain (tANOVA) on both experimental electromyographic (EMG) signals from responses to perturbation during standing balance across changes in peak perturbation acceleration (3 levels) and velocity (4 levels) and on simulated data with known contrasts. In experimental EMG data, wfANOVA revealed the continuous shape and magnitude of significant differences over time without a priori selection of time bins. However, tANOVA revealed only the largest differences at discontinuous time points, resulting in features with later onsets and shorter durations than those identified using wfANOVA (P < 0.02). Furthermore, wfANOVA required significantly fewer (~1/4;×; P < 0.015) significant F tests than tANOVA, resulting in post hoc tests with increased power. In simulated EMG data, wfANOVA identified known contrast curves with a high level of precision (r(2) = 0.94 ± 0.08) and performed better than tANOVA across noise levels (P < <0.01). Therefore, wfANOVA may be useful for revealing differences in the shape and magnitude of neurophysiological signals (e.g., EMG, firing rates) across multiple conditions with both high temporal resolution and high statistical power.

Optimization of muscle activity for task-level goals predicts complex changes in limb forces across biomechanical contexts.

Optimality principles have been proposed as a general framework for understanding motor control in animals and humans largely based on their ability to predict general features movement in idealized motor tasks. However, generalizing these concepts past proof-of-principle to understand the neuromechanical transformation from task-level control to detailed execution-level muscle activity and forces during behaviorally-relevant motor tasks has proved difficult. In an unrestrained balance task in cats, we demonstrate that achieving task-level constraints center of mass forces and moments while minimizing control effort predicts detailed patterns of muscle activity and ground reaction forces in an anatomically-realistic musculoskeletal model. Whereas optimization is typically used to resolve redundancy at a single level of the motor hierarchy, we simultaneously resolved redundancy across both muscles and limbs and directly compared predictions to experimental measures across multiple perturbation directions that elicit different intra- and interlimb coordination patterns. Further, although some candidate task-level variables and cost functions generated indistinguishable predictions in a single biomechanical context, we identified a common optimization framework that could predict up to 48 experimental conditions per animal (n = 3) across both perturbation directions and different biomechanical contexts created by altering animals' postural configuration. Predictions were further improved by imposing experimentally-derived muscle synergy constraints, suggesting additional task variables or costs that may be relevant to the neural control of balance. These results suggested that reduced-dimension neural control mechanisms such as muscle synergies can achieve similar kinetics to the optimal solution, but with increased control effort (≈2×) compared to individual muscle control. Our results are consistent with the idea that hierarchical, task-level neural control mechanisms previously associated with voluntary tasks may also be used in automatic brainstem-mediated pathways for balance.

An integrated review of music cognition and rhythmic stimuli in sensorimotor neurocognition and neurorehabilitation.

This work reviews the growing body of interdisciplinary research on music cognition, using biomechanical, kinesiological, clinical, psychosocial, and sociological methods. The review primarily examines the relationship between temporal elements in music and motor responses under varying contexts, with considerable relevance for clinical rehabilitation. After providing an overview of the terminology and approaches pertinent to theories of rhythm and meter from the musical-theoretical and cognitive fields, this review focuses on studies on the effects of rhythmic sensory stimulation on gait, rhythmic cues' effect on the motor system, reactions to rhythmic stimuli attempting to synchronize mobility (i.e., musical embodiment), and the application of rhythm for motor rehabilitation for individuals with Parkinson's disease, stroke, mild cognitive impairment, Alzheimer's disease, and other neurodegenerative or neurotraumatic diseases. This work ultimately bridges the gap between the musical-theoretical and cognitive science fields to facilitate innovative research in which each discipline informs the other.

An explainable spatial-temporal graphical convolutional network to score freezing of gait in parkinsonian patients.

Freezing of gait (FOG) is a poorly understood heterogeneous gait disorder seen in patients with parkinsonism which contributes to significant morbidity and social isolation. FOG is currently measured with scales that are typically performed by movement disorders specialists (ie. MDS-UPDRS), or through patient completed questionnaires (N-FOG-Q) both of which are inadequate in addressing the heterogeneous nature of the disorder and are unsuitable for use in clinical trials The purpose of this study was to devise a method to measure FOG objectively, hence improving our ability to identify it and accurately evaluate new therapies. We trained interpretable deep learning models with multi-task learning to simultaneously score FOG (cross-validated F1 score 97.6%), identify medication state (OFF vs. ON levodopa; cross-validated F1 score 96.8%), and measure total PD severity (MDS-UPDRS-III score prediction error ≤ 2.7 points) using kinematic data of a well-characterized sample of N=57 patients during levodopa challenge tests. The proposed model was able to identify kinematic features associated with each FOG severity level that were highly consistent with the features that movement disorders specialists are trained to identify as characteristic of freezing. In this work, we demonstrate that deep learning models' capability to capture complex movement patterns in kinematic data can automatically and objectively score FOG with high accuracy. These models have the potential to discover novel kinematic biomarkers for FOG that can be used for hypothesis generation and potentially as clinical trial outcome measures.

Neuromelanin-sensitive MRI correlates of cognitive and motor function in Parkinson's disease with freezing of gait.

Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them in vivo. Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative and psychiatric conditions, including Parkinson's disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.