Cannabidiol-enriched oil for adult patients with drug-resistant epilepsy: Prospective clinical and electrophysiological study.

OBJECTIVE: Cannabidiol-enriched oil (CBDO) is being used increasingly to improve seizure control in adult patients with drug-resistant epilepsy (DRE), despite the lack of large-scale studies supporting its efficacy in this patient population. We aimed to assess the effects of add-on CBDO on seizure frequency as well as on gait, cognitive, affective, and sleep-quality metrics, and to explore the electrophysiological changes in responder and non-responder DRE patients treated with add-on CBDO. METHODS: We prospectively recruited adult DRE patients who were treated with add-on CBDO. Patients were evaluated prior to treatment and following 4 weeks of a maintenance daily dose of ≈260 mg CBD and ≈12 mg Δ9-tetrahydrocannabinol (THC). The outcome measures included seizure response to CBDO (defined as ≥50% decrease in seizures compared to pre-CBDO baseline), gait testing, Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS), and sleep-quality questionnaire assessments. Patients underwent electroencephalography (EEG) recording during rest as well as event-related potentials (ERPs) during visual Go/NoGo task while sitting and while walking. RESULTS: Nineteen patients were recruited, of which 16 finished pre- and post-CBDO assessments. Seven patients (43.75%) were responders demonstrating an average reduction of 82.4% in seizures, and nine patients (56.25%) were non-responders with an average seizure increase of 30.1%. No differences in demographics and clinical parameters were found between responders and non-responders at baseline. However, responders demonstrated better performance in the dual-task walking post-treatment (p = .015), and correlation between increase in MoCA and seizure reduction (r = .810, p = .027). Post-CBDO P300 amplitude was lower during No/Go-sitting in non-responders (p = .028) and during No/Go-walking in responders (p = .068). SIGNIFICANCE: CBDO treatment can reduce seizures in a subset of patients with DRE, but could aggravate seizure control in a minority of patients; yet we found no specific baseline clinical or electrophysiological characteristics that are associated with response to CBDO. However, changes in ERPs in response to treatment could be a promising direction to better identify patients who could benefit from CBDO treatment.

Validity of the Short Weekly Calendar Planning Activity in patients with Parkinson disease and nonmanifesting LRRK2 and GBA carriers.

BACKGROUND AND PURPOSE: Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short Weekly Calendar Planning Activity (WCPA-10)'s known-group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined. METHODS: The study included 73 participants: 22 with idiopathic PD (iPD) who do not carry any of the founder GBA mutations or LRRK2-G2019S, 29 nonmanifesting carriers of the G2019S-LRRK2 (n = 14) and GBA (n = 15) mutations, and 22 HCs. Known-group validity was determined using the WCPA-10, convergent validity by also using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT), and ecological validity by using the WCPA-10, Schwab and England Activities of Daily Living Scale (SE ADL), and Physical Activity Scale for the Elderly (PASE). RESULTS: Known-group validity of the WCPA-10 was established for the iPD group only; they followed fewer rules (p = 0.020), were slower (p = 0.003) and less efficient (p = 0.001), used more strategies (p = 0.017) on the WCPA-10, and achieved significantly lower CTT scores (p < 0.001) than the HCs. The nonmanifesting carriers and HCs were similar on all cognitive tests. Convergent and ecological validity of the WCPA-10 were partially established, with few correlations between WCPA-10 outcome measures and the MoCA (r = 0.50, r = 0.41), CTT-2 (r = 0.43), SE ADL (r = 0.41), and PASE (r = 0.54, r = 0.46, r = 0.31). CONCLUSIONS: This study affirms the known-group validity for most (four) WCPA-10 scores and partially confirms its convergent and ecological validity for PD.

Task-Related Reorganization of Cognitive Network in Parkinson's Disease Using Electrophysiology.

BACKGROUND: Cognitive deficits in Parkinson's disease (PD) patients are well described, however, their underlying neural mechanisms as assessed by electrophysiology are not clear. OBJECTIVES: To reveal specific neural network alterations during the performance of cognitive tasks in PD patients using electroencephalography (EEG). METHODS: Ninety participants, 60 PD patients and 30 controls underwent EEG recording while performing a GO/NOGO task. Source localization of 16 regions of interest known to play a pivotal role in GO/NOGO task was performed to assess power density and connectivity within this cognitive network. The connectivity matrices were evaluated using a graph-theory approach that included measures of cluster-coefficient, degree, and global-efficiency. A mixed-model analysis, corrected for age and levodopa equivalent daily dose was performed to examine neural changes between PD patients and controls. RESULTS: PD patients performed worse in the GO/NOGO task (P < 0.001). The power density was higher in δ and θ bands, but lower in α and ß bands in PD patients compared to controls (interaction group × band: P < 0.001), indicating a general slowness within the network. Patients had more connections within the network (P < 0.034) than controls and these were used for graph-theory analysis. Differences between groups in graph-theory measures were found only in cluster-coefficient, which was higher in PD compared to controls (interaction group × band: P < 0.001). CONCLUSIONS: Cognitive deficits in PD are underlined by alterations at the brain network level, including higher δ and θ activity, lower α and ß activity, increased connectivity, and segregated network organization. These findings may have important implications on future adaptive deep brain stimulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Paroxysmal Slow-Wave Events Are Uncommon in Parkinson's Disease.

Background: Parkinson's disease (PD) is currently considered to be a multisystem neurodegenerative disease that involves cognitive alterations. EEG slowing has been associated with cognitive decline in various neurological diseases, such as PD, Alzheimer's disease (AD), and epilepsy, indicating cortical involvement. A novel method revealed that this EEG slowing is composed of paroxysmal slow-wave events (PSWE) in AD and epilepsy, but in PD it has not been tested yet. Therefore, this study aimed to examine the presence of PSWE in PD as a biomarker for cortical involvement. Methods: 31 PD patients, 28 healthy controls, and 18 juvenile myoclonic epilepsy (JME) patients (served as positive control), underwent four minutes of resting-state EEG. Spectral analyses were performed to identify PSWEs in nine brain regions. Mixed-model analysis was used to compare between groups and brain regions. The correlation between PSWEs and PD duration was examined using Spearman's test. Results: No significant differences in the number of PSWEs were observed between PD patients and controls (p > 0.478) in all brain regions. In contrast, JME patients showed a higher number of PSWEs than healthy controls in specific brain regions (p < 0.023). Specifically in the PD group, we found that a higher number of PSWEs correlated with longer disease duration. Conclusions: This study is the first to examine the temporal characteristics of EEG slowing in PD by measuring the occurrence of PSWEs. Our findings indicate that PD patients who are cognitively intact do not have electrographic manifestations of cortical involvement. However, the correlation between PSWEs and disease duration may support future studies of repeated EEG recordings along the disease course to detect early signs of cortical involvement in PD.

Differences in EEG Event-Related Potentials during Dual Task in Parkinson's Disease Carriers and Non-Carriers of the G2019S-LRRK2 Mutation.

BACKGROUND: The G2019S-LRRK2 gene mutation is a common cause of hereditary Parkinson's disease (PD), associated with a higher frequency of the postural instability gait difficulty (PIGD) motor phenotype yet with preserved cognition. This study investigated neurophysiological changes during motor and cognitive tasks in PD patients with and without the G2019S-LRRK2 mutation. METHODS: 33 iPD patients and 22 LRRK2-PD patients performed the visual Go/NoGo task (VGNG) during sitting (single-task) and walking (dual-task) while wearing a 64-channel EEG cap. Event-related potentials (ERP) from Fz and Pz, specifically N200 and P300, were extracted and analyzed to quantify brain activity patterns. RESULTS: The LRRK2-PD group performed better in the VGNG than the iPD group (group*task; p = 0.05). During Go, the iPD group showed reduced N2 amplitude and prolonged N2 latency during walking, whereas the LRRK2-PD group showed only shorter latency (group*task p = 0.027). During NoGo, opposite patterns emerged; the iPD group showed reduced N2 and increased P3 amplitudes during walking while the LRRK2-PD group demonstrated increased N2 and reduced P3 (N2: group*task, p = 0.010, P3: group*task, p = 0.012). CONCLUSIONS: The LRRK2-PD group showed efficient early cognitive processes, reflected by N2, resulting in greater neural synchronization and prominent ERPs. These processes are possibly the underlying mechanisms for the observed better cognitive performance as compared to the iPD group. As such, future applications of intelligent medical sensing should be capable of capturing these electrophysiological patterns in order to enhance motor-cognitive functions.

Tossing and Turning in Bed: Nocturnal Movements in Parkinson's Disease.

BACKGROUND: Sleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum. OBJECTIVES: We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication. METHODS: A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [H&Y] stage 1 = 47, H&Y stage 2 = 181, H&Y stage 3 = 77) and 205 healthy controls continuously wore a tri-axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright -time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements. RESULTS: Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; H&Y stage 1, 7.3 ± 0.9 hours; H&Y stage 2, 7.2 ± 1.3 hours; H&Y stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication. CONCLUSIONS: Using wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society.

Successful Negotiation of Anticipated and Unanticipated Obstacles in Young and Older Adults: Not All Is as Expected.

BACKGROUND: Tripping over an obstacle is one of the most common causes of falls among older adults; however, the impact of obstacle parameters and subject characteristics are not well described. OBJECTIVES: To evaluate age-associated changes in the ability to negotiate obstacles and the role of obstacle parameters (e.g., anticipated vs. unanticipated, height, and available response time [ART]), and subject characteristics. METHODS: Twenty healthy older adults (77.7 ± 3.4 years; 50% women) and 20 healthy young adults (29.3 ± 3.8 years; 50% women) underwent cognitive, gait, and balance testing before negotiating a computer-controlled obstacle course. The primary outcome measure was the ability to successfully negotiate the obstacles (without touching them). RESULTS: The success rate for all subjects was higher when the obstacle was anticipated (99.0 ± 2.8%) than when unanticipated (66.0 ± 20.2%; p < 0.001). The obstacle height had a significant effect on the success rate (p = 0.022); the success rate was lower when the obstacle height was lower. No significant interaction between group and obstacle height was observed (p = 0.096). ART had no significant effect on the success rate (p = 0.294) in both of the groups (ART × group, p = 0.136). However, a significant interaction between group, obstacle height, and ART was found (p = 0.013), reflecting a lower success rate in the older adults when the obstacles were low and unanticipated. In general, older adults demonstrated a trend towards a lower success rate in all types of obstacles compared to the young adults (p = 0.057). Among the older adults, the success rate in the anticipated obstacle condition was correlated with stride length (ρ = 0.600, p = 0.005), step time coefficient of variation (ρ = -0.635, p = 0.003), and gait speed (rho = 0.530, p = 0.016). Montreal Cognitive Assessment scores tended to be related to the difference in the success rate between the anticipated and unanticipated conditions. CONCLUSIONS: These findings support the idea that motor and, to some degree, cognitive functions are needed to successfully negotiate obstacles, and provide new insights into the ability of older adults to successfully negotiate obstacles. Furthermore, the present results suggest that when it comes to the physical properties of obstacles, not all is as expected, and low obstacles may impose a greater danger to tripping than obstacles that have a higher height.

Impaired dual tasking in Parkinson's disease is associated with reduced focusing of cortico-striatal activity.

See Bell et al. (doi:10.1093/awx063) for a scientific commentary on this article. Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro-anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This pattern of striatal activity may be explained by a loss of functional segregation between neighbouring striatal territories that occurs specifically in a dual task context.

Cerebral Imaging Markers of GBA and LRRK2 Related Parkinson's Disease and Their First-Degree Unaffected Relatives.

Cerebral atrophy has been detected in patients with Parkinson's disease (PD) both with and without dementia, however differentiation based on genetic status has thus far not yielded robust findings. We assessed cortical thickness and subcortical volumes in a cohort of PD patients and healthy controls carriers of the G2019S mutation in the LRRK2 gene and the common GBA mutations, in an attempt to determine whether genetic status influences structural indexes. Cortical thickness and subcortical volumes were computed and compared between six groups of participants; idiopathic PD, GBA-PD, LRRK2-PD, non-manifesting non-carriers (NMNC), GBA-non-manifesting carriers (NMC) and LRRK2-NMC utilizing the FreeSurfer software program. All participants were cognitively intact based on a computerized cognitive assessment battery. Fifty-seven idiopathic PD patients, 9 LRRK2-PD, 12 GBA-PD, 49 NMNC, 41 LRRK2-NMC and 14 GBA-NMC participated in this study. Lower volumes among patients with PD compared to unaffected participants were detected in bilateral hippocampus, nucleus accumbens, caudate, thalamus, putamen and amygdala and the right pallidum (p = 0.016). PD patients demonstrated lower cortical thickness indexes in a majority of regions assessed compared with non-manifesting participants. No differences in cortical thickness and subcortical volumes were detected within each of the groups of participants based on genetic status. Mutations in the GBA and LRRK2 genes are not important determinants of cortical thickness and subcortical volumes in both patients with PD and non-manifesting participants. PD is associated with a general reduction in cortical thickness and sub-cortical atrophy even in cognitively intact patients.

Prefrontal cortex activation during obstacle negotiation: What's the effect size and timing?

BACKGROUND: Obstacle negotiation is a daily activity that requires the integration of sensorimotor and cognitive information. Recent studies provide evidence for the important role of prefrontal cortex during obstacle negotiation. We aimed to explore the effects of obstacle height and available response time on prefrontal activation. METHODS: Twenty healthy young adults (age: 30.1 ±â€¯1.0 years; 50% women) walked in an obstacle course while negotiating anticipated and unanticipated obstacles at heights of 50 mm and 100 mm. Prefrontal activation was measured using a functional near-infrared spectroscopy system. Kinect cameras measured the obstacle negotiation strategy. Prefrontal activation was defined based on mean level of HbO2 before, during and after obstacle negotiation and the HbO2 slope from gait initiation and throughout the task. Changes between types of obstacles were assessed using linear-mix models and partial correlation analyses evaluated the relationship between prefrontal activation and the distance between the feet as the subjects traversed the obstacles. RESULTS: Different obstacle heights showed similar changes in prefrontal activation measures (p > 0.210). However, during unanticipated obstacles, the slope of the HbO2 response was steeper (p = 0.048), as compared to anticipated obstacles. These changes in prefrontal activation during negotiation of unanticipated obstacles were correlated with greater distance of the leading foot after the obstacles (r = 0.831, p = 0.041). CONCLUSIONS: These findings are the first to show that the pattern of prefrontal activation depends on the nature of the obstacle. More specifically, during unanticipated obstacles the recruitment of the prefrontal cortex is faster and greater than during negotiating anticipated obstacles. These results provide evidence of the important role of the prefrontal cortex and the ability of healthy young adults to tailor the activation pattern to different types of obstacles.

Addition of a non-immersive virtual reality component to treadmill training to reduce fall risk in older adults (V-TIME): a randomised controlled trial.

BACKGROUND: Age-associated motor and cognitive deficits increase the risk of falls, a major cause of morbidity and mortality. Because of the significant ramifications of falls, many interventions have been proposed, but few have aimed to prevent falls via an integrated approach targeting both motor and cognitive function. We aimed to test the hypothesis that an intervention combining treadmill training with non-immersive virtual reality (VR) to target both cognitive aspects of safe ambulation and mobility would lead to fewer falls than would treadmill training alone. METHODS: We carried out this randomised controlled trial at five clinical centres across five countries (Belgium, Israel, Italy, the Netherlands, and the UK). Adults aged 60-90 years with a high risk of falls based on a history of two or more falls in the 6 months before the study and with varied motor and cognitive deficits were randomly assigned by use of computer-based allocation to receive 6 weeks of either treadmill training plus VR or treadmill training alone. Randomisation was stratified by subgroups of patients (those with a history of idiopathic falls, those with mild cognitive impairment, and those with Parkinson's disease) and sex, with stratification per clinical site. Group allocation was done by a third party not involved in onsite study procedures. Both groups aimed to train three times per week for 6 weeks, with each session lasting about 45 min and structured training progression individualised to the participant's level of performance. The VR system consisted of a motion-capture camera and a computer-generated simulation projected on to a large screen, which was specifically designed to reduce fall risk in older adults by including real-life challenges such as obstacles, multiple pathways, and distracters that required continual adjustment of steps. The primary outcome was the incident rate of falls during the 6 months after the end of training, which was assessed in a modified intention-to-treat population. Safety was assessed in all patients who were assigned a treatment. This study is registered with ClinicalTrials.gov, NCT01732653. FINDINGS: Between Jan 6, 2013, and April 3, 2015, 302 adults were randomly assigned to either the treadmill training plus VR group (n=154) or treadmill training alone group (n=148). Data from 282 (93%) participants were included in the prespecified, modified intention-to-treat analysis. Before training, the incident rate of falls was similar in both groups (10·7 [SD 35·6] falls per 6 months for treadmill training alone vs 11·9 [39·5] falls per 6 months for treadmill training plus VR). In the 6 months after training, the incident rate was significantly lower in the treadmill training plus VR group than it had been before training (6·00 [95% CI 4·36-8·25] falls per 6 months; p<0·0001 vs before training), whereas the incident rate did not decrease significantly in the treadmill training alone group (8·27 [5·55-12·31] falls per 6 months; p=0·49). 6 months after the end of training, the incident rate of falls was also significantly lower in the treadmill training plus VR group than in the treadmill training group (incident rate ratio 0·58, 95% CI 0·36-0·96; p=0·033). No serious training-related adverse events occurred. INTERPRETATION: In a diverse group of older adults at high risk for falls, treadmill training plus VR led to reduced fall rates compared with treadmill training alone. FUNDING: European Commission.

When is Higher Level Cognitive Control Needed for Locomotor Tasks Among Patients with Parkinson's Disease?

Turning has been implicated as a complex task that requires both motor and cognitive resources. Accumulating evidence shows that patients with Parkinson's disease (PD) require more steps and more time to complete a turn, however, the role of the prefrontal cortex during turning is not clear. Forty nine patients with PD without freezing of gait (mean age 71.7 ± 1.0 years; 67% men, disease duration 9.7 ± 1.3 years) performed motor and cognitive tests. Prefrontal activation, specifically in Brodmann area 10 (BA10), during turning and usual walking was measured using functional near infrared spectroscopy (fNIRS). The patients with PD were further divided into two subgroups with high and low functional status based on limitations in community ambulation. General Linear Model analysis adjusted for age, gender, disease duration and turn duration was used to assess differences between tasks and subgroups of patients with PD. In addition, Pearson's correlation was performed to assess association between BA10 activation and motor and cognitive scores. Activation in BA10 increased during walking (p < 0.001), while it decreased during turning (p = 0.006). A comparison between the two subgroups of patients with PD revealed that patients with relatively better ambulation decreased prefrontal activation during turning, as compared to patients with relatively worse ambulation (p < 0.001). These findings are the first to show that BA10 plays a different role during turning and walking and that ambulation status may alter BA10 activation during turning. Higher prefrontal activation during turning in the subgroup of patients with relatively worse ambulation may reflect a compensatory attempt at improving performance.

Effects of aging on prefrontal brain activation during challenging walking conditions.

BACKGROUND: Deficits in cognitive domains, in particular, those related to the prefrontal cortex, contribute to diminished walking performance in complex conditions in older age. Studies using functional near infra-red spectroscopy (fNIRS) reported inconsistent findings of brain activation age-related changes in response to increased task demands. We aimed to study the effects of aging on gait and prefrontal activation in complex walking tasks with internal and external task demands. METHODS: Twenty-three healthy young adults (30.9±3.7yrs) and 20 healthy older adults (69.7±5.8yrs) participated in this study. Gait and prefrontal activation were assessed during three walking conditions: (1) usual walking, (2) dual tasking (internal task demands) and, (3) obstacle negotiation (external task demands). fNIRS measured changes in oxygenated hemoglobin concentrations in the prefrontal cortex. RESULTS: Several gait measures were worse in older compared to younger adults under all walking conditions (p<0.005). Even at the lowest level of challenge, older adults had significant increases in HbO2 levels during usual walking, relative to standing (p=0.006). Both groups showed increased activation during dual-task (p<0.002) and during obstacle negotiation (p<0.003). CONCLUSIONS: Prefrontal activation during walking is dependent on age and task properties and that older adults apparently rely more on cognitive resources even during usual walking task.

Increased frontal brain activation during walking while dual tasking: an fNIRS study in healthy young adults.

BACKGROUND: Accumulating evidence suggests that gait is influenced by higher order cognitive and cortical control mechanisms. Recently, several studies used functional near infrared spectroscopy (fNIRS) to examine brain activity during walking, demonstrating increased oxygenated hemoglobin (HbO2) levels in the frontal cortex during walking while subjects completed a verbal cognitive task. It is, however, still unclear whether this increase in activation was related to verbalization, if the response was specific to gait, or if it would also be observed during standing, a different motor control task. The aim of this study was to investigate whether an increase in frontal activation is specific to dual tasking during walking. METHODS: Twenty-three healthy young adults (mean 30.9 ± 3.7 yrs, 13 females) were assessed using an electronic walkway. Frontal brain activation was assessed using an fNIRS system consisting of two probes placed on the forehead of the subjects. Assessments included: walking in a self-selected speed; walking while counting forward; walking while serially subtracting 7s (Walking+S7); and standing while serially subtracting 7s (Standing+S7). Data was collected from 5 walks of 30 meters in each condition. Twenty seconds of quiet standing before each walk served as baseline frontal lobe activity. Repeated Measures Analysis of Variance (RM ANOVA) tested for differences between the conditions. RESULTS: Significant differences were observed in HbO2 levels between all conditions (p = 0.007). HbO2 levels appeared to be graded; walking alone demonstrated the lowest levels of HbO2 followed by walking+counting condition (p = 0.03) followed by Walking+S7 condition significantly increased compared to the two other walking conditions (p < 0.01). No significant differences in HbO2 levels were observed between usual walking and the standing condition (p = 0.38) or between standing with or without serial subtraction (p = 0.76). CONCLUSIONS: This study provides direct evidence that dual tasking during walking is associated with frontal brain activation in healthy young adults. The observed changes are apparently not a response to the verbalization of words and are related to the cognitive load during gait.

Virtual reality and motor imagery: promising tools for assessment and therapy in Parkinson's disease.

Motor imagery (MI) and virtual reality (VR) are two evolving therapeutic approaches that make use of cognitive function to study and enhance movement, in particular, balance and mobility of people with Parkinson's disease (PD). This review examines the literature on the use of VR and MI in the assessment of mobility and as a therapeutic intervention to improve balance and gait in patients with PD. A study was eligible for inclusion if MI or VR were used to assess motor or cognitive function to improve gait, balance, or mobility in patients with PD. Data were extracted on the following categories: participants; study design; intervention (type, duration, and frequency); and outcomes. Intervention studies were evaluated for quality using the Physiotherapy Evidence Database scale. Sixteen studies were identified; 4 articles used MI and 12 used VR for assessment and treatment of gait impairments in PD. The studies included small samples and were diverse in terms of methodology. Quality of the intervention trials varied from fair for VR to good for MI. The benefits of using MI and VR for assessment and treatment were noted. Encouraging findings on the potential benefits of using MI and VR in PD were found, although further good-quality research is still needed. Questions remain on the optimal use, content of interventions, and generalizability of findings across the different stages of the disease. The possible mechanisms underlying MI and VR and recommendations for future research and therapy are also presented.

Decreased aperiodic neural activity in Parkinson's disease and dementia with Lewy bodies.

Neural oscillations and signal complexity have been widely studied in neurodegenerative diseases, whereas aperiodic activity has not been explored yet in those disorders. Here, we assessed whether the study of aperiodic activity brings new insights relating to disease as compared to the conventional spectral and complexity analyses. Eyes-closed resting-state electroencephalography (EEG) was recorded in 21 patients with dementia with Lewy bodies (DLB), 28 patients with Parkinson's disease (PD), 27 patients with mild cognitive impairment (MCI) and 22 age-matched healthy controls. Spectral power was differentiated into its oscillatory and aperiodic components using the Irregularly Resampled Auto-Spectral Analysis. Signal complexity was explored using the Lempel-Ziv algorithm (LZC). We found that DLB patients showed steeper slopes of the aperiodic power component with large effect sizes compared to the controls and MCI and with a moderate effect size compared to PD. PD patients showed steeper slopes with a moderate effect size compared to controls and MCI. Oscillatory power and LZC differentiated only between DLB and other study groups and were not sensitive enough to detect differences between PD, MCI, and controls. In conclusion, both DLB and PD are characterized by alterations in aperiodic dynamics, which are more sensitive in detecting disease-related neural changes than the traditional spectral and complexity analyses. Our findings suggest that steeper aperiodic slopes may serve as a marker of network dysfunction in DLB and PD features.

Abnormal gait and motor cortical processing in drug-resistant juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is characterized by generalized seizures. Nearly 30% of JME patients are drug-resistant (DR-JME), indicating a widespread cortical dysfunction. Walking is an important function that necessitates orchestrated coordination of frontocentral cortical regions. However, gait alterations in JME have been scarcely investigated. Our aim was to assess changes in gait and motor-evoked responses in DR-JME patients. METHODS: Twenty-nine subjects (11 JME drug-responder, 8 DR-JME, and 10 healthy controls) underwent a gait analyses during usual walking and dual-task walking. Later, subjects underwent 64-channel EEG recordings while performing a simple motor task. We calculated the motor-evoked current source densities (CSD) at a priori chosen cortical regions. Gait and CSD measures were compared between groups and tasks using mixed model analysis. RESULTS: DR-JME patients demonstrated an altered gait pattern that included slower gait speed (p = .018), reduced cadence (p = .003), and smaller arm-swing amplitude (p = .011). The DR-JME group showed higher motor-evoked CSD in the postcentral gyri compared to responders (p = .049) and both JME groups showed higher CSD in the superior frontal gyri compared to healthy controls (p < .011). Moreover, higher CSD in the superior frontal gyri correlated with worse performance in dual-task walking (r > |-0.494|, p < .008). CONCLUSIONS: These alterations in gait and motor-evoked responses in DRE-JME patients reflect a more severe dysfunction of motor-cognitive neural processing in frontocentral regions, leading to poorer gait performance. Further studies are needed to investigate the predictive value of altered gait and cortical motor processing as biomarkers for poor response to treatment in JME and other epilepsy syndromes.

Effects of aging on cognitive and brain inter-network integration patterns underlying usual and dual-task gait performance.

Introduction: Aging affects the interplay between cognition and gait performance. Neuroimaging studies reported associations between gait performance and structural measures; however, functional connectivity (FC) analysis of imaging data can help to identify dynamic neural mechanisms underlying optimal performance. Here, we investigated the effects on divergent cognitive and inter-network FC patterns underlying gait performance during usual (UW) and dual-task (DT) walking. Methods: A total of 115 community-dwelling, healthy participants between 20 and 80 years were enrolled. All participants underwent comprehensive cognitive and gait assessments in two conditions and resting state functional MRI (fMRI) scans. Inter-network FC from motor-related to 6 primary cognitive networks were estimated. Step-wise regression models tested the relationships between gait parameters, inter-network FC, neuropsychological scores, and demographic variables. A threshold of p < 0.05 was adopted for all statistical analyses. Results: UW was largely associated with FC levels between motor and sustained attention networks. DT performance was associated with inter-network FC between motor and divided attention, and processing speed in the overall group. In young adults, UW was associated with inter-network FC between motor and sustained attention networks. On the other hand, DT performance was associated with cognitive performance, as well as inter-network connectivity between motor and divided attention networks (VAN and SAL). In contrast, the older age group (> 65 years) showed increased integration between motor, dorsal, and ventral attention, as well as default-mode networks, which was negatively associated with UW gait performance. Inverse associations between motor and sustained attention inter-network connectivity and DT performance were observed. Conclusion: While UW relies on inter-network FC between motor and sustained attention networks, DT performance relies on additional cognitive capacities, increased motor, and executive control network integration. FC analyses demonstrate that the decline in cognitive performance with aging leads to the reliance on additional neural resources to maintain routine walking tasks.

Neural activation in the prefrontal cortex during the digital clock drawing test measured with functional near-infrared spectroscopy in early stage Parkinson's disease.

INTRODUCTION: The clock drawing test (CDT) is a neuropsychological test for the screening of global cognitive functioning. The test requires use of multiple cognitive domains including executive functions, visuospatial abilities and semantic memory and can be a suitable tool for screening cognitive decline in participants in the early stages of Parkinson's Disease (PD). Behavioral performance on the CDT has been studied in depth, however, neural activation during real-time performance has not been extensively investigated. In this study we explored changes in prefrontal cortex (PFC) activation during the performance of CDT in participants with PD compared to healthy controls (HC) and assessed the correlations between PFC activation and CDT performance. METHODS: The study included 60 participants, 29 PD and 31 HC participants whom performed a digital CDT (DCTclock) in conjunction with a Functional Near-Infrared Spectroscopy (fNIRS) system measuring neural activation in the PFC. RESULTS: HbO2 signals derived from the fNIRS during the CDT revealed that PD participants showed more moderate slopes than the HC in the right hemisphere in the command (p = 0.042) and copy task (p = 0.009). Better score on the measurement of information processing correlated with steeper right hemisphere HbO2 slope in the copy task in the PD group (p = 0.003). CONCLUSION: Our results reflect slower PFC activation in participants with PD which correlates with behavioral measures. In addition, the findings of the study indicate the importance of performing the CDT copy task condition that detect early cognitive decline in participants with PD.

The interplay between structural and functional connectivity in early stage Parkinson's disease patients.

The mechanisms underlying cognitive disturbances in Parkinson's disease (PD) are poorly understood but likely to depend on the ongoing degenerative processes affecting structural and functional connectivity (FC). This pilot study examined patterns of FC alterations during a cognitive task using EEG and structural characteristics of white matter (WM) pathways connecting these activated regions in early-stage PD. Eleven PD patients and nine healthy controls (HCs) underwent EEG recording during an auditory oddball task and MRI scans. Source localization was performed and Gaussian mixture model was fitted to identify brain regions with high power during task performance. These areas served as seed regions for connectivity analysis. FC among these regions was assessed by measures of magnitude squared coherence (MSC), and phase-locking value (PLV), while structural connectivity was evaluated using fiber tracking based on diffusion tensor imaging (DTI). The paracentral lobule (PL), superior parietal lobule (SPL), superior and middle frontal gyrus (SMFG), parahippocampal gyrus, superior and middle temporal gyri (STG, MTG) demonstrated increased activation during task performance. Compared to HCs, PD showed lower FC between SMFG and PL and between SMFG and SPL in MSC (p = 0.012 and p = 0.036 respectively). No significant differences between the groups were observed in PLV and the measured DTI metrics along WM tracts. These findings demonstrate that in early PD, cognitive performance changes might be attributed to FC alterations, suggesting that FC is affected early on in the degenerative process, whereas structural damage is more prominent in advanced stages as a result of the disease burden accumulation.