Amble Gait EEG Points at Complementary Cortical Networks Underlying Stereotypic Multi-Limb Co-ordination

BACKGROUND: Walking is characterized by stable antiphase relations between upper and lower limb movements. Such bilateral rhythmic movement patterns are neuronally generated at levels of the spinal cord and brain stem, that are strongly interconnected with cortical circuitries, including the Supplementary Motor Area (SMA). OBJECTIVE: To explore cerebral activity associated with multi-limb phase relations in human gait by manipulating mutual attunement of the upper and lower limb antiphase patterns. METHODS: Cortical activity and gait were assessed by ambulant EEG, accelerometers and videorecordings in 35 healthy participants walking normally and 19 healthy participants walking in amble gait, where upper limbs moved in-phase with the lower limbs. Power changes across the EEG frequency spectrum were assessed by Event Related Spectral Perturbation analysis and gait analysis was performed. RESULTS: Amble gait was associated with enhanced Event Related Desynchronization (ERD) prior to and during especially the left swing phase and reduced Event Related Synchronization (ERS) at final swing phases. ERD enhancement was most pronounced over the putative right premotor, right primary motor and right parietal cortex, indicating involvement of higher-order organization and somatosensory guidance in the production of this more complex gait pattern, with an apparent right hemisphere dominance. The diminished within-step ERD/ERS pattern in amble gait, also over the SMA, suggests that this gait pattern is more stride driven instead of step driven. CONCLUSION: Increased four-limb phase complexity recruits distributed networks upstream of the primary motor cortex, primarily lateralized in the right hemisphere. Similar parietal-premotor involvement has been described to compensate impaired SMA function in Parkinson’s disease bimanual antiphase movement, indicating a role as cortical support regions

Neural coupling between upper and lower limb muscles in Parkinsonian gait

OBJECTIVE: To explore to what extent neuronal coupling between upper and lower limb muscles during gait is preserved or affected in patients with Parkinson's Disease (PD). METHODS: Electromyography recordings were obtained from the bilateral deltoideus anterior and bilateral rectus femoris and biceps femoris muscles during overground gait in 20 healthy participants (median age 69 years) and 20 PD patients (median age 68.5 years). PD patients were able to walk independently (Hoehn and Yahr scale: Stage 2-3), had an equally distributed symptom laterality (6 left side, 7 both sides and 7 right side) and no cognitive problems or tremor dominant PD. Time-dependent directional intermuscular coherence analysis was employed to compare the neural coupling between upper and lower limb muscles between healthy participants and PD patients in three different directions: zero-lag (i.e. common driver), forward (i.e. shoulders driving the legs) and reverse component (i.e. legs driving the shoulders). RESULTS: Compared to healthy participants, PD patients exhibited (i) reduced intermuscular zero-lag coherence in the beta/gamma frequency band during end-of-stance and (ii) enhanced forward as well as reverse directed coherence in the alpha and beta/gamma frequency bands around toe-off. CONCLUSIONS: PD patients had a reduced common cortical drive to upper and lower limb muscles during gait, possibly contributing to disturbed interlimb coordination. Enhanced bidirectional coupling between upper and lower limb muscles on subcortical and transcortical levels in PD patients suggests a mechanism of compensation. SIGNIFICANCE: These findings provide support for the facilitating effect of arm swing instructions in PD gait

Enhanced arm swing improves Parkinsonian gait with EEG power modulations resembling healthy gait

BACKGROUND: The supplementary motor area (SMA) is implicated in stereotypic multi-limb movements such as walking with arm swing. Gait difficulties in Parkinson's Disease (PD) include reduced arm swing, which is associated with reduced SMA activity. OBJECTIVE: To test whether enhanced arm swing improves Parkinsonian gait and explore the role of the SMA in such an improvement. METHODS: Cortical activity and gait characteristics were assessed by ambulant EEG, accelerometers and video recordings in 27 PD patients with self-reported gait difficulties and 35 healthy participants when walking normally. Within these two groups, 19 PD patients additionally walked with enhanced arm swing and 30 healthy participants walked without arm swing. Power changes across the EEG frequency spectrum were assessed by Event Related Spectral Perturbation analysis of recordings from Fz over the putative SMA and gait analysis was performed. RESULTS: Baseline PD gait, characterized by reduced arm swing among other features, exhibited reduced within-step Event Related Desynchronization (ERD)/Synchronization (ERS) alternation (Fz; 20-50Hz), accompanied by a reduced step length and walking speed. All became similar to normal gait when patients walked with enhanced arm swing. When healthy controls walked without arm swing, their alternating ERD-ERS pattern decreased, mimicking baseline PD gait. CONCLUSION: Enhanced arm swing may serve as a driving force to overcome impaired gait control in PD patients by restoring reduced ERD-ERS alternation over the putative SMA. Accompanied by increased step length and walking speed, this provides a neural underpinning of arm swing as an effective rehabilitation concept for improving Parkinsonian gait

Pre-Movement Cortico-Muscular Dynamics Underlying Improved Parkinson Gait Initiation after Instructed Arm Swing

BACKGROUND: The supplementary motor area (SMA) is implicated in both motor initiation and stereotypic multi-limb movements such as walking with arm swing. Gait in Parkinson's disease exhibits starting difficulties and reduced arm swing, consistent with reduced SMA activity. OBJECTIVE: We tested whether enhanced arm swing could improve Parkinson gait initiation and assessed whether increased SMA activity during preparation might facilitate such improvement. METHODS: Effects of instructed arm swing on cortical activity, muscle activity and kinematics were assessed by ambulant EEG, EMG, accelerometers and video in 17 Parkinson patients and 19 controls. At baseline, all participants repeatedly started walking after a simple auditory cue. Next, patients started walking at this cue, which now meant starting with enhanced arm swing. EEG changes over the putative SMA and leg motor cortex were assessed by event related spectral perturbation (ERSP) analysis of recordings at Fz and Cz. RESULTS: Over the putative SMA location (Fz), natural PD gait initiation showed enhanced alpha/theta synchronization around the auditory cue, and reduced alpha/beta desynchronization during gait preparation and movement onset, compared to controls. Leg muscle activity in patients was reduced during preparation and movement onset, while the latter was delayed compared to controls. When starting with enhanced arm swing, these group differences virtually disappeared. CONCLUSION: Instructed arm swing improves Parkinson gait initiation. ERSP normalization around the cue indicates that the attributed information may serve as a semi-internal cue, recruiting an internalized motor program to overcome initiation difficulties

Intermuscular coherence analysis in older adults reveals that gait related arm swing drives lower limb muscles via subcortical and cortical pathways

KEY POINTS: Gait related arm swing in humans supports efficient lower limb muscle activation, indicating a neural coupling between the upper and lower limbs during gait. Intermuscular coherence analyses of gait related electromyography from upper and lower limbs in twenty healthy participants identified significant coherence in alpha and beta/gamma bands indicating that upper and lower limbs share common subcortical and cortical drivers that coordinate the rhythmic four limb gait pattern. Additional directed connectivity analyses revealed that upper limb muscles drive and shape lower limb muscle activity during gait via subcortical and cortical pathways and to a lesser extent vice versa. Our results provide a neural underpinning that arm swing may serve as an effective rehabilitation therapy concerning impaired gait in neurological diseases. ABSTRACT: Human gait benefits from arm swing, as it enhances efficient lower limb muscle activation in healthy participants as well as patients suffering from neurological impairment. The underlying neuronal mechanisms of such coupling between upper and lower limbs remain poorly understood. The aim of the present study was to examine this coupling by intermuscular coherence analysis during gait. Additionally, directed connectivity analysis of this coupling enabled to assess whether gait related arm swing indeed drives lower limb muscles. To that end, electromyography recordings were obtained from four lower limb muscles and two upper limb muscles bilaterally, during gait, of twenty healthy participants (mean age 67 years, SD 6.8). Intermuscular coherence analysis revealed functional coupling between upper and lower limb muscles in the alpha and beta/gamma band during muscle specific periods of the gait cycle. These effects in the alpha and beta/gamma bands point at involvement of subcortical and cortical sources, respectively, that commonly drive the rhythmic four limb gait pattern in an efficiently coordinated fashion. Directed connectivity analysis revealed that upper limb muscles drive and shape lower limb muscle activity during gait via subcortical and cortical pathways and to a lesser extent vice versa. This indicates that gait related arm swing reflects the recruitment of neuronal support for optimizing the cyclic movement pattern of the lower limbs. These findings thus provide a neural underpinning for arm swing to potentially serve as an effective rehabilitation therapy concerning impaired gait in neurological diseases. This article is protected by copyright. All rights reserved

Time-dependent directional intermuscular coherence analysis reveals that forward and backward arm swing equally drive the upper leg muscles during gait initiation

BACKGROUND: Human bipedal gait benefits from arm swing, as it drives and shapes lower limb muscle activity in healthy participants as well as patients suffering from neurological impairment. Also during gait initiation, arm swing instructions were found to facilitate leg muscle recruitment. RESEARCH QUESTION: The aim of the present study is to exploit the directional decomposition of coherence to examine to what extent forward and backward arm swing contribute to leg muscle recruitment during gait initiation. METHODS: Ambulant electromyography (EMG) from shoulder muscles (deltoideus anterior and posterior) and upper leg muscles (biceps femoris and rectus femoris) was analysed during gait initiation in nineteen healthy participants (median age of 67 ± 12 (IQR) years). To assess to what extent either deltoideus anterior or posterior muscles were able to drive upper leg muscle activity during distinct stages of the gait initiation process, time dependent intermuscular coherence was decomposed into directional components based on their time lag (i.e. forward, reverse and zero-lag). RESULTS: Coherence from the forward directed components, representing shoulder muscle signals leading leg muscle signals, revealed that deltoideus anterior (i.e. forward arm swing) and deltoideus posterior (i.e. backward arm swing) equally drive upper leg muscle activity during the gait initiation process. SIGNIFICANCE: The presently demonstrated time dependent directional intermuscular coherence analysis could be of use for future studies examining directional coupling between muscles or brain areas relative to certain gait (or other time) events. In the present study, this analysis provided neural underpinning that both forward and backward arm swing can provide neuronal support for leg muscle recruitment during gait initiation and can therefore both serve as an effective gait rehabilitation method in patients with gait initiation difficulties

Parkinson's disease-related perfusion and glucose metabolic brain patterns identified with PCASL-MRI and FDG-PET imaging

AbstractIntroductionUnder normal conditions, the spatial distribution of resting cerebral blood flow and cerebral metabolic rate of glucose are closely related. A relatively new magnetic resonance (MR) technique, pseudo-continuous arterial spin labeling (PCASL), can be used to measure regional brain perfusion. We identified a Parkinson's disease (PD)-related perfusion and metabolic covariance pattern in the same patients using PCASL and FDG-PET imaging and assessed (dis)similarities in the disease-related pattern between perfusion and metabolism in PD patients.MethodsNineteen PD patients and seventeen healthy controls underwent [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. Of 14 PD patients and all healthy controls PCASL-MRI could be obtained. Data were analyzed using scaled subprofile model/principal component analysis (SSM/PCA).ResultsUnique Parkinson's disease-related perfusion and metabolic covariance patterns were identified using PCASL and FDG-PET in the same patients. The PD-related metabolic covariance brain pattern is in high accordance with previously reports. Also our disease-related perfusion pattern is comparable to the earlier described perfusion pattern. The most marked difference between our perfusion and metabolic patterns is the larger perfusion decrease in cortical regions including the insula.ConclusionWe identified PD-related perfusion and metabolic brain patterns using PCASL and FDG-PET in the same patients which were comparable with results of existing research. In this respect, PCASL appears to be a promising addition in the early diagnosis of individual parkinsonian patients

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Consensus molecular subtype classification of colorectal adenomas

Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 ‘metabolic subtype’, which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the ‘MSI immune’ subtype. Eight adenomas (13%) were classified as the ‘canonical’ CMS2. No adenomas were classified as the ‘mesenchymal’ CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening