Franklin Feedback Control Of Dynamic Systems 6th Pdf.rar
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Healthy ageing involves degeneration of the neuromuscular system which impacts movement control and proprioception. Yet the relationship between these sensory and motor deficits in upper limb reaching has not been examined in detail. Recently, we reported that age-related proprioceptive deficits were unrelated to accuracy in rapid arm movements, but whether this applied in motor tasks more heavily dependent on proprioceptive feedback was not clear. To address this, we have tested groups of younger and older adults on a force-field adaptation task under either full or limited visual feedback conditions and examined how performance was related to dynamic proprioceptive acuity. Adaptive performance was similar between the age groups, regardless of visual feedback condition, although older adults showed increased after-effects. Physically inactive individuals made larger systematic (but not variable) proprioceptive errors, irrespective of age. However, dynamic proprioceptive acuity was unrelated to adaptation and there was no consistent evidence of proprioceptive recalibration with adaptation to the force-field for any group. Finally, in spite of clear age-dependent loss of spatial working memory capacity, we found no relationship between memory capacity and adaptive performance or proprioceptive acuity. Thus, non-clinical levels of deficit in dynamic proprioception, due to age or physical inactivity, do not affect force-field adaptation, even under conditions of limited visual feedback that might require greater proprioceptive control.
However, those tasks emphasised speed, where it seems likely that sensory feedback control is minimised in favour of predictive, feedforward processes (Miall and Wolpert 1996; Wolpert et al. 1995). Thus, the question remains as to how sensory impairments might influence performance on tasks which require greater sensory feedback control (for review see Shadmehr et al. 2010). To perturb proprioceptive feedback specifically, external forces can be applied during discrete targeted movements (Krakauer et al. 1999; Sarlegna et al. 2010; Shadmehr and Mussa-Ivaldi 1994). Unlike tasks with visual feedback perturbation (Anguera et al. 2011; Bock 2005; Buch et al. 2003; Contreras-Vidal et al. 2002; Hegele and Heuer 2010; Seidler 2006; Vandevoorde and Orban de Xivry 2019), a number of studies have indicated a minimal role of ageing in the ability to adapt movements to novel force environments (Cesqui et al. 2008; Huang and Ahmed 2014; Rajeshkumar and Trewartha 2019; Reuter et al. 2018; Trewartha et al. 2014). Nonetheless, several age-dependent performance predictors have been highlighted, including increased muscle co-contraction (Huang and Ahmed 2014), reduced central processing of kinematic errors (Reuter et al. 2018) and reduced spatial working memory capacity (Trewartha et al. 2014). Furthermore, younger adults demonstrate a tight relationship between proprioceptive perception and motor performance when adapting to novel force-fields (Haith et al. 2008; Mattar et al. 2013; Ohashi et al. 2019; Ostry et al. 2010). Moreover, whilst adaptation to forces is possible in younger adults without visual feedback of hand position (Franklin et al. 2007; Lefumat et al. 2015; Scheidt et al. 2005), all previous studies with older adults have included either full (Cesqui et al. 2008; Huang and Ahmed 2014; Rajeshkumar and Trewartha 2019; Trewartha et al. 2014) or early visual feedback (first half of the movement; Reuter et al. 2018). Hence, the interactions of age and proprioceptive acuity on dynamic motor adaptation remains poorly understood, and the contributions of visual and proprioceptive feedback to motor adaptation have not been dissociated.
We have therefore investigated the relationship between dynamic proprioception and force-field adaptation in older and younger adults. Participants were given either full or limited visual feedback during force-field adaptation, and dynamic proprioceptive assessments were made before and at intervals throughout the adaptation task. Spatial working memory capacity and physical activity status were also examined, collectively providing a comprehensive overview of reach adaptation to novel field dynamics and its interaction with proprioceptive acuity across the lifespan.
Since the baseline (P1) proprioceptive assessment was made prior to exposure to the visual feedback condition, these data were separately analysed in two-way ANOVAs that included only age group and physical activity status (active or inactive) as between-subjects factors. Physical activity indices were converted to z-scores within the two age groups, and used as a predictor of adaptation extent in multiple linear regression models that controlled for age and visual feedback condition grouping. Finally, spatial working memory scores were analysed in mixed ANOVAs with a between-subjects factor of age group and within-subjects factor of memory load (6, 8 or 10 tiles).
We aimed to investigate the relationship of dynamic proprioception with adaptation to novel dynamic forces, in older and younger adults. We found that the level of adaptation was similar between the age groups, regardless of visual feedback limitations, although older adults showed increased after-effects of force production. Surprisingly, we found systematic (but not variable) proprioceptive errors were larger in physically inactive participants, regardless of age. However, there was no association between baseline proprioceptive acuity and adaptation, nor any consistent evidence of proprioceptive recalibration. Finally, despite clear age-related deficits in spatial working memory capacity there was no relation of this cognitive measure with adaptation. Taken together, we find little evidence to support a relationship between dynamic upper limb proprioception and adaptation to novel field dynamics in either older or younger adults.
This study adds to the increasing, but still limited, number of reports indicating a minimal effect of ageing on reach adaptation to novel forces (Cesqui et al. 2008; Rajeshkumar and Trewartha 2019; Reuter et al. 2018; Trewartha et al. 2014). In addition, we demonstrate this finding holds true under conditions of limited visual feedback (providing only distance information during movement, and terminal error), conditions which might emphasise proprioceptive control. Whereas studies of force-field adaptation in the ageing population are still scarce, there is a wealth of research which has focused on visuomotor transformations in this group (usually a rotated or altered gain hand position feedback; Anguera et al. 2011; Bock 2005; Buch et al. 2003; Contreras-Vidal et al. 2002; Hegele and Heuer 2010; Seidler 2006; Vandevoorde and Orban de Xivry 2019). Although the magnitudes of age-specific deficits reported in these studies are mixed, a recurring observation is that performance is most impaired for older adults when the perturbation is salient and requires greater reliance on explicit strategies for adaptation (Buch et al. 2003; Cressman et al. 2010; Hegele and Heuer 2010, 2013; McNay and Willingham 1998). Converging evidence suggests this is directly related to age-dependent cognitive decline and in particular spatial working memory capacity (Anguera et al. 2011; Uresti-Cabrera et al. 2015; Vandevoorde and Orban de Xivry 2019; Wolpe et al. 2020; for review see Seidler et al. 2010), which has been directly associated with the explicit component of adaptation (Christou et al. 2016). Despite clear evidence of reduced spatial working memory capacity in our sample of older adults, we did not find any association of this cognitive measure with adaptation. One interpretation of these data might, therefore, be that force-field adaptation relies less on explicit strategies than do visuomotor rotation tasks. Specifically, this could explain why older adults appear to rely more on implicit adaptation processes (Vandevoorde and Orban de Xivry 2019; Wolpe et al. 2020) but do not present notable deficits in force-field adaptation, which also appears to be unrelated to spatial working memory impairments. This is not to say that force-field adaptation relies only on implicit processes. Indeed, whilst better documented for visuomotor tasks (Benson et al. 2011; Mazzoni and Krakauer 2006; Neville and Cressman 2018; Taylor et al. 2014; Werner et al. 2015), recent work has sought to measure the explicit component of force-field adaptation (Schween et al. 2020) and the fast and slow processes of motor adaptation distinguished within force-field tasks (Smith et al. 2006) have been shown to be closely related to explicit and implicit learning on visuomotor tasks respectively (McDougle et al. 2015). However, the lack of any relationship with age or with age-related cognitive decline suggests explicit strategies may be reduced in force adaptation compared with visuomotor paradigms. Nevertheless, this interpretation of results was beyond the immediate scope of this study; further research will be necessary to test this hypothesis directly.
Stat6 is the major transcription factor responsible for the induction of M2 genes during macrophage M2 polarization14. Considering the critical negative regulatory role of M2-prone TAMs in regulating antitumor immunity4,5,6, the study of Stat6 transcriptional modulation may promote the identification of therapeutic targets for cancer immunotherapy. The present study showed that in healthy conditions with high levels of Trim24, the Th2 cytokine IL-4 can induce Stat6 acetylation by ubiquitinated CBP, which is mediated by its association with Trim24. Stat6 acetylation compromised the transcriptional activity of M2 genes and thus restrained macrophage M2 polarization and potentiated antitumor immunity. However, in the tumor microenvironment, activated Stat6 could directly mediate the transcriptional suppression of Trim24 in M2-polarized macrophages, in which low levels of Trim24 were insufficient to mediate CBP ubiquitination and Stat6 acetylation. In this case, Stat6-mediated Trim24 downregulation further promoted M2 polarization and impaired antitumor immune function, forming a positive feedback loop to contribute to the immunosuppressive protumor niche (Supplementary Fig. 8). Here, we identified the first acetylation modification in Stat6 to curtail its transcriptional activity, through which macrophage M2 polarization and antitumor immunity were controlled. 2b1af7f3a8