Showing papers by "David Burke published in 2021"

Cortical inexcitability defines an adverse clinical profile in amyotrophic lateral sclerosis.

Abstract: BACKGROUND AND PURPOSE In amyotrophic lateral sclerosis, studies using threshold-tracking transcranial magnetic stimulation (TMS) have identified corticomotoneuronal dysfunction as a key pathogenic mechanism. Some patients, however, display no motor response at maximal TMS intensities, termed here an 'inexcitable' motor cortex. The extent to which this cortical difference impacts clinical outcomes remains unclear. The aim of this study was to determine the clinical profile of patients with inexcitability to TMS. METHODS Motor cortex excitability was evaluated using TMS. Patients in whom a motor evoked potential could not be recorded in one or more limbs at maximal TMS intensities were classified as four-limb or partially inexcitable. Demographic information, clinical variables and survival data were analysed. RESULTS From 133 patients, 40 were identified with inexcitability. Patients with four-limb inexcitability were younger (P = 0.03) and had lower-limb disease onset (64%), greater functional disability (P < 0.001) and faster disease progression (P = 0.02), particularly if inexcitability developed within 1 year of symptoms (P < 0.01). Patients with partial inexcitability had higher resting motor thresholds compared to the excitable cohort (P < 0.01), but averaged short-interval intracortical inhibition was similar (P = 0.5). Mean survival was reduced if inexcitability involved all limbs within 12 months of symptom onset (P = 0.04). CONCLUSION Amyotrophic lateral sclerosis patients with inexcitability of all four limbs to TMS have a distinct clinical profile of younger age and lower-limb onset. Importantly, these patients display a more malignant disease trajectory, with faster progression, greater functional disability and reduced survival when occurring in early disease. This measure may provide an important prognostic marker in amyotrophic lateral sclerosis.

Rebuttal from David Burke.

Abstract: Dr Dimitriou presents impressive and compelling data, and I congratulate him for ‘using newer technologies and pushing the envelope with human microneurography’ (Dimitriou 2021). He presents data indicating that, during movement, fusimotor drive can be modulated differently from α motoneuron activity, and on this point we agree completely. For example, Papaioannou and Dimitriou (2021) describe (i) a change in spindle discharge, presumably due to a change in fusimotor drive during movement [for which there is considerable evidence from other protocols, as summarized in my contribution (Burke 2021)], and they show (ii) changes that would effectively represent a withdrawal of the expected level of fusimotor drive [alluded to in my commentary (Burke 2021)]. These elegant experiments extend existing findings, and it is relevant to quote from an earlier paper: ‘the relationship between the skeletomotor and fusimotor drives to a muscle during a voluntary contraction is not rigidly fixed, but can be varied appropriately with the changing motor role demanded of the muscle by supraspinal drives and with the changes in sensory feed-back generated by the movement itself’ (Burke et al. 1980). Where our views depart is the extent to which the change in spindle activity is sufficient to drive changes in stretch reflex activity. Regardless of the spindle feedback, the supraspinal drives preceding and associated with movement will alter transmission through spinal reflex circuits. It is my view (and also that of Macefield & Knellwolf, 2018) that it is, as yet, unproven that the change in spindle feedback is sufficient to drive the change in reflex activity. Dr Dimitriou notes ‘additional experiments involving whole-arm perturbations during reach preparation demonstrate a modulation of stretch reflex gains’ (Dimitriou 2021). The question then arises whether any change in reflex gain is due to the change in spindle activity or merely accompanies it, i.e. whether the same supraspinal drives cause the change in gain and the change in fusimotor function without a causal relationship between the two. I argue that transmission through spinal reflex circuits is subject to powerful supraspinal controls, must change with movement, and may change differently in different movement paradigms. I acknowledge, however, that the situation cannot be ‘either/or’. An increase in spindle feedback entering circuits that have been primed will have effects greater than the same enhanced feedback entering un-primed circuitry. It should be acknowledged that my views are somewhat coloured by considerations of the pathophysiology of spasticity and other motor control disorders, which have, in the past, been attributed to disordered fusimotor function. I concede that many of the relevant studies have been directed at understanding the increase in muscle tone and tendon jerks that occur in subjects at rest [hence the initial section of my commentary on fusimotor activity at rest (Burke 2021)]. I therefore commend Dr Dimitriou for focusing on spindle feedback during movement. After all, the motor system exists in healthy people for movement, not rest. Nevertheless, as mentioned in the commentary, it is important not to neglect the other roles played by spindle feedback, for which selective or preferential activation/de-activation of fusimotor neurons may be important. In adults the fusimotor system may be important not for its effects on spinal reflexes but more because spindle feedback reaches cortex and is an important cue in conscious perception, kinaesthesia, for long-loop reflexes, and for the conscious, automatic and subconscious programming of movement and the automatic updating of movement during a task. It is relevant to highlight areas where textbooks convey a misleading impression. It is pleasing to note that Dr Dimitriou acknowledges but does not endorse one view of fusimotor function: ‘As often described in medical and neuroscience textbooks, “α–γ co-activation” acts to maintain spindle responsiveness to stretch despite skeletal muscle shortening’ and ‘the textbook version of α–γ co-activation essentially describes fusimotor function as ensuring that the stretch sensor remains operational despite skeletal muscle shortening’ (Dimitriou 2021). As mentioned in my commentary (Burke 2021), the evidence first from freely moving cats and then from human microneurography does not support this view. Fusimotor drive can maintain spindle activity only during slow movements (during which the unloading is more effectively neutralized by the increase in fusimotor drive), and preferably if the muscle is working against resistance (so that more effort is required for the movement, presumably with a greater fusimotor drive). In conclusion, I applaud Dr Dimitriou’s comment that ‘Future research shall determine whether independent fusimotor control plays a role in adjusting muscle stiffness across different motor tasks (e.g. object interception)’ (Dimitriou 2021). However I caution against automatically attributing changes in stiffness to the changes in spindle feedback even if they are correlated. The correlation need not be causal: the change in spindle feedback and the change in reflex activity (and stiffness) could both be consequences of changes in descending commands.

Electrophysiological investigation of motor axonal excitability in a mouse model of nerve constriction injury.

Abstract: Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours-1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength-duration properties, threshold electrotonus, current-threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre-injury baseline and sham-injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K+ conductances. The findings of this study demonstrate long-term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies.

James Waldo Lance 1926–2019

Abstract: James W. Lance was a clinical neurologist who created the first university-based department of neurology in Australia. He championed academic enquiry and the scientific basis of clinical practice, and his research had two major themes, motor control and headache. After his doctoral studies on the pyramidal tract of the cat, he became a pioneer of the new field of motor control studied in human subjects, making seminal contributions on the control of muscle tone, reflexes and movement in healthy subjects and the pathophysiology of movement disorders in patients. At the same time he developed a clinical research program into the mechanisms and management of headache, in particular migraine. These studies evolved into parallel experiments in human subjects, cats and monkeys, probing the control of the cerebral circulation and the mechanisms underlying craniofacial pain, for which he received international acclaim in both fields. He received international and Australian honours and was the first practising clinician to be elected a fellow of the Australian Academy of Science. He is rightfully credited with leading the development of academic neurology in Australia and overseas.