University of Groningen
Neural control of balance in increasingly difficult standing tasks
Nandi, Tulika
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Nandi, T. (2019). Neural control of balance in increasingly difficult standing tasks. University of Groningen.
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Chapter 6
General discussion
For almost 150 years it has been known that the quality of standing balance, especially in tasks which are more difficult compared to quiet standing, tells us a lot about neuromus-cular control [1–3]. We now know that several brain areas [4–6], including the cortex [7–9] are involved in standing balance control. However, much is yet to be learnt about how cortical inputs tune muscle activation in increasingly difficult standing tasks. This thesis attempted to address three major questions related to cortical control of standing balance in increasingly difficult tasks (Figure 1). First, what cortical neurophysiological processes (inhibition and facilitation) contribute to standing balance control and do they correlate with sway dynamics? Chapters 2 and 3 demonstrated that corticospinal excitability is cor-related with sway velocity. However, though cortical inhibition and facilitation are clearly modulated in response to increasing task difficulty, these measures are independent of sway velocity. Second, does the cortex contribute to the common inputs underlying muscle synergies supporting stiffness and/ or reciprocal control, and are these inputs specific to the biomechanical demands of each task? Chapter 4 showed that the task difficulty related increases in cortical inputs favor reciprocal control. Additionally, the common inputs to specific pairs of muscles are in line with the biomechanical demands of each task. Lastly, what factors can explain individual differences in neural control of increasingly difficult standing tasks? Chapter 5 along with supplementary analysis of data from chapter 3, provides preliminary evidence that self-reported confidence and intrinsic neural excitability may drive individual differences in standing balance control. These findings are discussed in further detail in the following sections.
1. effeCT of TAsk diffiCulTy oN siNgle musCle NeurAl
exCiTAbiliTy
This thesis adds to a growing body of evidence demonstrating that neural input to lower extremity muscles, indexed using corticospinal excitability, increases with increasing task difficulty [10,11] (chapters 2 & 3). Additionally, unlike studies examining anteroposterior or direction unspecific manipulations, we found an association between corticospinal excitability and ML sway velocity, confirming our suspicion that ML compared to AP sway requires greater active neural control. These findings also support the hypothesis that with increasing task difficulty greater neural inputs are required to tune muscle activation and consequently support the well documented increase in sway velocity [12–14].
Previous studies have concluded that a decrease in cortical GABAa inhibition contributes to the task difficulty related increase in corticospinal excitability [10,11] and consequent increase in muscle activation. Though GABAa inhibition decreases with increasing diffi-culty, the associations between inhibition, and muscle activation and sway are either weak
figur e 1: Panel A : Experimental tasks in or der of incr easing difficulty (top to bottom). In chapters 3 and 4, the most difficult tasks wer e tandem and one leg (left column), while in
chapters 2 and 5, a step or spring wer
e used to incr
ease difficulty (right column).
Panel B : Ef fect of task difficulty on cortical excitability of single muscles – with incr easing difficulty , intracortical GABAa inhibition decr eases, GABAb inhibition incr eases and facilitation decr eases. Panel C : Ef fect of task difficulty on common cortical inputs to multiple muscles – with incr easing difficulty , agonist-agonist common inputs incr ease while agonist-antagonist common inputs r
emain low (below statistical significance) in all tasks.
Panel D : Individual dif fer ences in cortical contr ol of standing tasks – task-difficulty related changes (incr ease or decr ease) in single muscle excitability ar e pr oportional to each individual’
s standing balance confidence and excitability in the contr
ol wide stance condition.
m ain conclusion - the cortex plays a role in the higher or der planning and pr ocessing requir ed for determining muscle activation patter ns in incr easingly difficult standing tasks.
(rho=0.27, chapter 2) or absent (chapter 3). Given the extensive evidence from a variety of muscles and tasks, it cannot be disputed that release of GABAa inhibition is important for increasing muscle activation [15,16]. However, inhibition often decreases before the onset of muscle activation [17–19]. Therefore, we suspect that in standing, the task difficulty related release of inhibition serves as a preparatory process for upcoming muscle activa-tion, in addition to setting current muscle activation. This idea is discussed further at the end of this section.
The task difficulty related decrease in intracortical facilitation and GABAb inhibition appear to be counter-productive to the overall goal of increasing corticospinal excitability. We confirmed a decrease in intracortical facilitation in two different muscles (chapters 2 and 3). Additionally, this finding is in agreement with the lower facilitation observed in standing compared to sitting[20]. Therefore, this apparent decrease in excitability is unlikely to be a spurious finding. Physiologically, such a finding is entirely plausible since corticospinal excitability is a net resultant of spinal excitability and, inhibitory and facilitatory inputs from different brain areas including the cortex. However, the question is, what drives this ap-parent decrease in excitability and does it have a biomechanical or functional significance? An important aspect of standing balance control is the ability to respond appropriately to perturbations [21–23]. When using TMS, it is possible that neural processes reflect prepara-tion for the upcoming TMS induced perturbaprepara-tion, in addiprepara-tion to control of muscle activaprepara-tion and sway. In difficult compared to easier tasks the TMS pulse is more likely to compromise balance. Based on observations of neural and muscular responses to perturbations, along with the effect of concurrent cognitive processes, it has been proposed that the cortex plays an important role in context-specific preparation for responding to perturbations [24]. Indeed, recent evidence shows that corticospinal excitability increases and GABAa inhibition decreases when a perturbation is expected in standing[25,26]. Such a subliminal increase in excitability likely prepares the neuromuscular system for faster and/ or larger muscle activation. Additionally, upper extremity studies show that movement preparation involves simultaneous inhibitory and excitatory processes [18,19]. We speculate that the task difficulty related decrease in cortical excitability contributes to preparatory processes required for improving response speed and accuracy[27] and ensuring appropriate co-ordination between muscles [28].
2. effeCT of TAsk diffiCulTy oN CommoN NeurAl iNPuT To
mulTiPle musCles
Functional synergy analyses suggest that in standing, reciprocal control mediated by agonist-agonist (AG-AG) co-activation is favored over stiffness control mediated by agonist-antagonist (AG-ANT) co-activation [29–31]. In chapter 4, we show that common neural inputs to groups of lower extremity muscles also favor reciprocal over stiffness control and add to the growing evidence suggesting that common input is a neural mecha-nism underlying the formation of functional synergies [32–35]. These findings are also in line with animal studies and theoretical models which suggest that cortical activation and especially beta oscillations, which we examined for detecting cortical common inputs, drive functional muscle synergies [36–38].
In line with our main premise of greater cortical involvement in control of difficult tasks, we expected cortical common inputs to increase with increasing difficulty. Our findings prompt a more nuanced interpretation than initially expected. Cortical common inputs increase with increasing difficulty, but specifically favor reciprocal control. Branched inputs from individual cortical motor neurons to multiple muscles usually target agonist-agonist muscles [39]. Also, cortical neurons are preferentially activated during movements in one direction and may in fact inhibit antagonistic movements [40]. Therefore, it is possible that the differential effect of task difficulty on cortical inputs to agonist and agonist-antagonist muscle groups is driven by anatomical and physiological properties of cortical neurons. Also, reciprocal control allows for more flexible movement patterns [41,42] and it is logical that descending cortical inputs are involved in such complex control which re-quires ongoing evaluation of sensory information. On the other hand, subcortical common inputs increased with task difficulty but favored stiffness control. Since stiffness control requires less online feedback and adjustment of efferent commands, it is logical that it is supported by the relatively more stereotypical subcortical inputs.
A closer look at specific pairs, within the AG-AG and AG-ANT groups, reveals that task dif-ficulty related modulation of common inputs is guided by the biomechanical demands of each task. First, in the difficult tasks, which preferentially challenge mediolateral balance, pairs of invertors or evertors receive greater common input than mixed invertor-evertor pairs. Such an organization of common inputs can support the greater mediolateral torques required to maintain balance in these tasks. Second, a peak in 10 Hz common input has previously been observed only when examining common inputs to bilateral muscles in standing [43,44]. Interestingly, we observed a 10 Hz peak only in the easier tasks in which symmetrical muscle activity was required in both legs. These findings also explain why
previous studies have found a differential effect of task on common inputs to different muscles pairs [45,46].
3. iNdividuAl differeNCes iN NeurAl CoNTrol of sTANdiNg
bAlANCe
This thesis presents some preliminary evidence pointing towards potential underlying causes for individual differences in neural control of balance. We found that the task difficulty related modulation of intracortical facilitation (ICF) is dependent on each partici-pant’s balance confidence (chapter 5) and intrinsic neural excitability (chapter 3). Specifi-cally, individuals who report relatively higher confidence demonstrate higher intrinsic ICF and a larger task difficulty related decrease in ICF. Primary motor cortex (M1) excitability measured using TMS can reflect inputs to M1 from other brain areas [47,48] and ICF in particular is believed to reflect long range connections between M1 and other brain areas, including the prefrontal cortex [49,50]. This may explain why a cognitive attribute like confidence influences balance control through modulation of ICF, rather than GABAa inhibition which likely reflects short range connections [50]. Additionally, since experience with balance related activities leads to an increase in confidence, we hypothesize that the high intrinsic facilitation in confident individuals is due to experience related neuroplastic-ity. This finding is also in line with the higher spinal excitability observed in situations where participants express high confidence [51]. However, higher facilitation seems contrary to the relatively lower sway area and velocity observed in more confident individuals (chapter 5). As discussed in section 6.1, we speculate that the observed facilitation reflects other balance related goals besides setting current muscle activation and sway. Further work is required to determine if and how the observed intrinsic excitability and task difficulty related modulation translates to a performance advantage in confident individuals. In addition to ICF, we found some individual differences in cortical GABAb inhibition. Specifically, a subset of participants demonstrated atypical facilitation in response to the long interval intracortical inhibition (LICI) protocol used to measure GABAb inhibition. This subset of participants also demonstrated a task difficulty related decrease in facilitation (or emergence of inhibition) which was proportional to the intrinsic facilitation observed in the control condition (chapter 3). When LICI is elicited using a 100 ms inter-stimulus interval, as we did, pre-synaptic GABAb receptors may be activated leading to a decrease in release of GABA [52,53], and consequent decrease in or abolition of inhibition. Though this is a possible mechanism explaining the observed facilitation, it is unclear why facilitation emerges only in some participants. Also, we cannot rule out the possibility that in these participants the LICI protocol did not probe GABAb neurons but activated other neurons
instead. That said, compared to GABAa, much less is known about the role of GABAb inhibition in motor control in general [54] and balance control in particular. To the best of our knowledge, ours was the first study to examine LICI in standing. Since the same participants reliably demonstrated a decrease in LICI on two different days, and across four different comparisons, we believe that our findings encourage further examination of the functional significance of LICI modulation in balance control.
4. meThodologiCAl sTreNgThs ANd limiTATioNs
The dual approach of this thesis i.e., examining M1 neurophysiological processes target-ing starget-ingle muscles and cortical versus subcortical common inputs to multiple muscles, allows us to make stronger conclusions compared to a single approach. This is further complemented by our preliminary analysis of factors driving individual differences in the neural inputs to muscles. However, before making any conclusions, it is important to draw attention to some strengths and limitations of the methods. One main limitation is that both methods cannot be used to measure neural activity in areas like the cerebellum or basal ganglia, which are known to be important for balance control. Theoretically, this limitation could be overcome in future studies by combining TMS with other techniques like fMRI. However, since it is technically challenging to examine upright postures using most neuroimaging equipment, it is also worthwhile to explore other options. For instance, we may ask the question whether EMG-EMG coherence in certain frequency ranges is associated with cerebellum or basal ganglia activation revealed using fMRI, during non-postural tasks. Based on the outcomes, EMG-EMG analysis could subsequently be used to make inferences about brain areas involved in standing balance control.
Muscle activation is determined by the firing pattern of spinal alpha motor neurons. Tran-scranial magnetic stimulation (TMS) allowed us to measure the excitability of groups of cortical inhibitory or facilitatory neurons which tune the descending inputs to alpha motor neurons. Such descending inputs may tune current muscle activation but could also lead to subliminal excitability changes which reflect a readiness (or lack thereof) to activate a muscle. Also, due to practical time constraints, it is difficult to measure neural excitability of more than one muscle, even though it is well known that individual M1 pyramidal neurons can synapse on alpha motor neurons targeting more than one muscle [55]. On the other hand, EMG-EMG coherence was used to examine neural inputs to pairs or groups of muscles. This method allowed us to examine neural inputs that drive the current firing pattern of alpha motor neurons [56], but not to make inferences about subliminal excit-ability changes. Also, cortical and subcortical neural inputs could be distinguished but specific cortical neuron groups or neurophysiological processes could not be examined. Given these strengths and limitations, we discuss how the information gleaned from the
two methods relate to each other, and how they contribute to our broader understanding of standing balance control.
5. hoW does This Thesis Add To our uNdersTANdiNg of
NeurAl CoNTrol of sTANdiNg bAlANCe?
This thesis adds to the growing body of literature which confirms that cortical involvement in standing balance control increases with increasing task difficulty [7–11]. The outstanding question is, what is the role of the cortex in standing balance control? Theoretically, stereo-typical subcortical inputs can tune the muscle activation necessary for maintaining balance in standing. Indeed, in early studies, when cortical inputs were surgically interrupted, animals were still able to stand independently [57,58]. However, in humans with cortical lesions, balance related muscle activation is stereotypical and does not adapt to changing task contexts. Therefore, in quiet standing, balance may be maintained with minimal or no cortical intervention. But, in difficult tasks, the cortical involvement is necessary for higher order planning and preparation which must be tailored to the current biomechanical and environmental conditions. Several findings presented in this thesis support this argument. First, as discussed in section 6.1, with increasing task difficulty, there is a subliminal change in excitability of both inhibitory and facilitatory cortical neurons. Since the TMS pulse causes an expected perturbation, such subliminal excitability changes likely reflect planning and preparation through alteration of descending inputs to alpha motor neurons. These descending inputs can ensure that the response to the perturbation is appropriate for the initial conditions i.e., the biomechanical configuration before the perturbation occurred [24]. Though this thesis did not determine whether the observed subliminal changes trans-late to a mechanically superior response to the perturbation, we know that in response to perturbations, muscle activation is tailored to the initial biomechanical conditions [59]. By examining whether perturbation neural excitability in different initial conditions pre-dicts reactive muscle activation patterns, we can determine whether task difficulty related subliminal excitability modulation reflects preparation for future muscle activation. On a different note, animal studies show that a reduction of cortical GABAergic activity leads to simultaneous activation of multiple muscles [60]. Therefore, though we measured GABAa excitability of single muscles (chapters 2 and 3), a general task difficulty related decrease in cortical GABA activity may be the mechanism underlying the increase in common cortical inputs (chapter 4).
Second, as discussed in section 6.2, cortical inputs favor reciprocal (AG-AG) control over stiffness (AG-ANT) control, especially in more difficult tasks. Reciprocal control is particularly
favorable in more difficult tasks since it allows for a large repertoire of flexible responses to perturbations. And since reciprocal control during sway requires greater planning and preparation [14], it is not surprising that greater cortical involvement is required for such fine control. Indeed, during reciprocal control, inhibition of muscles whose activation is counter-productive or detrimental to the task [61,62], is as important as co-activation of the required muscles. In fact, it is possible that the task difficulty related increase in cortical GABAb inhibition (chapter 3) plays a role in the selective muscle activation required for reciprocal control. From a clinical perspective, these findings urge us to consider the role of descending inputs in the age related increase in the reliance on stiffness control [63], especially since it is already known that the relative contribution of cortical and subcortical inputs to balance control changes with aging [64].
Third, this thesis provides preliminary evidence that higher cognitive attributes like con-fidence influence motor performance through modulation of cortical excitability. We measured excitability of M1 neurons but M1 receives inputs from several other brain areas including the pre-frontal cortex and basal ganglia [47], which are plausible candidates for mediating effects of confidence. Finally, individual differences in intrinsic neural excitability may be driven by genetic [49] or other unknown factors. It would also be worthwhile to examine whether such differences reflect the neuroplasticity [65,66] driven by the diverse experiences of the study population. Indeed, GABA modulation is especially important for practice-dependent plasticity [67] and we specifically found that individual differences in GABA are associated with differences in the neural control of increasingly difficult standing tasks.
In summary, the findings of this thesis provide a more nuanced understanding of the role of the cortex in standing balance control. The cortex is likely involved in higher order planning and processing, which includes context-specific preparation for potential per-turbations and supporting the appropriate activation (and deactivation) of muscles for reciprocal control. Also, the cortex likely mediates cognitive or possible experience depen-dent effects on standing balance control. What are the clinical and practical implications of these findings? I suspect that in individuals without neural pathology and even in athletes, sub-optimal cortical processing may account for minor balance issues and consequent limitations on achievable performance. Furthermore, the cortex is one the first brain areas affected by aging [68,69] and deficits in cortical planning and processing may compound the well-known effects of musculoskeletal and sensory changes on balance. Armed with this information, it may be possible to identify individuals in whom balance deficits are driven by sub-optimal cortical processing. For instance, further research may identify pre-perturbation neural excitability patterns associated with biomechanically inadequate or inefficient responses to perturbations. Subsequently, athletic training and/ or clinical
interventions could be specifically tailored to target cortical processes. There may also be a role for neuromodulation techniques that target the cortex and complement exercise programs for improving balance [70,71].
6. CoNClusioNs
This thesis examined the role of cortical inputs to lower extremity muscles in the control of standing balance. With increasing task difficulty, there is an increase in the neural in-puts that drive muscle activations and support sway. Cortical contributions to this neural input, at least for muscle groups comprising synergies, increase with increasing difficulty. Though the contributing cortical neurophysiological processes could not be identified, our data show that cortical inputs favor reciprocal control which is inherently more complex than stiffness control. Additionally, there are task difficulty related subliminal changes in cortical excitability which may be important for meeting complex postural goals, besides sway control, like responding to perturbations. Finally, the effects of cognitive attributes like confidence on motor performance are likely mediated by cortical neurophysiological processes. The main conclusion is that the cortex plays a role in the higher order planning and processing required for determining muscle activation patterns in increasingly difficult standing tasks.
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