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Article ; Online: Muscarinic acetylcholine activity modulates cortical silent period, but not motor evoked potentials, during muscle contractions.

Dempsey, Lisa M / Kavanagh, Justin J

2023 Volume 241, Issue 6, Page(s) 1543–1553

Abstract: This study used transcranial magnetic stimulation (TMS) to determine if muscarinic receptor blockade affects muscle responses during voluntary contractions. Motor evoked potentials (MEPs) were recorded from biceps brachii in 10 subjects (age: 23 ± 2) ... ...

Abstract	This study used transcranial magnetic stimulation (TMS) to determine if muscarinic receptor blockade affects muscle responses during voluntary contractions. Motor evoked potentials (MEPs) were recorded from biceps brachii in 10 subjects (age: 23 ± 2) during 10%, 25%, 50%, 75%, and 100% maximal voluntary contractions (MVCs). Each contraction intensity was examined under non-fatigued and fatigued conditions. All measurements were obtained post-ingestion of 25 mg promethazine or placebo. MEP area and the duration of the TMS-evoked silent period (SP) were calculated for all contractions. No drug-related differences were detected for MEP area during non-fatigued or fatigued contractions. A main effect of drug was detected for the SP (p = 0.019) where promethazine increased SP duration by an average of 0.023 [Formula: see text] 0.015 s. This drug effect was only identified for the unfatigued contractions and not following the sustained fatiguing contractions (p = 0.105). The cholinergic system does not influence corticospinal excitability during voluntary muscle contractions, but instead affects neural circuits associated with the TMS-evoked SP. Given the prevalence of cholinergic properties in prescription and over-the-counter medications, the current study enhances our understanding of mechanisms that may contribute to motor side-effects.
MeSH term(s)	Adult ; Humans ; Young Adult ; Acetylcholine ; Cholinergic Agents ; Electric Stimulation ; Electromyography ; Evoked Potentials, Motor/physiology ; Muscle Contraction/physiology ; Muscle Fatigue/physiology ; Muscle, Skeletal/physiology ; Promethazine ; Transcranial Magnetic Stimulation
Chemical Substances	Acetylcholine (N9YNS0M02X) ; Cholinergic Agents ; Promethazine (FF28EJQ494)
Language	English
Publishing date	2023-04-27
Publishing country	Germany
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	1201-4
ISSN	1432-1106 ; 0014-4819
ISSN (online)	1432-1106
ISSN	0014-4819
DOI	10.1007/s00221-023-06616-7
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Article ; Online: Voluntary activation of muscle in humans: does serotonergic neuromodulation matter?

Kavanagh, Justin J / Taylor, Janet L

The Journal of physiology

2022 Volume 600, Issue 16, Page(s) 3657–3670

Abstract: Ionotropic inputs to motoneurones have the capacity to depolarise and hyperpolarise the motoneurone, whereas neuromodulatory inputs control the state of excitability of the motoneurone. Intracellular recordings of motoneurones from in vitro and in situ ... ...

Abstract	Ionotropic inputs to motoneurones have the capacity to depolarise and hyperpolarise the motoneurone, whereas neuromodulatory inputs control the state of excitability of the motoneurone. Intracellular recordings of motoneurones from in vitro and in situ animal preparations have provided extraordinary insight into the mechanisms that underpin how neuromodulators regulate neuronal excitability. However, far fewer studies have attempted to translate the findings from cellular and molecular studies into a human model. In this review, we focus on the role that serotonin (5-HT) plays in muscle activation in humans. 5-HT is a potent regulator of neuronal firing rates, which can influence the force that can be generated by muscles during voluntary contractions. We firstly outline structural and functional characteristics of the serotonergic system, and then describe how motoneurone discharge can be facilitated and suppressed depending on the 5-HT receptor subtype that is activated. We then provide a narrative on how 5-HT effects can influence voluntary activation during muscle contractions in humans, and detail how 5-HT may be a mediator of exercise-induced fatigue that arises from the central nervous system.
MeSH term(s)	Animals ; Humans ; Motor Neurons/physiology ; Muscle Contraction/physiology ; Muscles/physiology ; Serotonin/pharmacology
Chemical Substances	Serotonin (333DO1RDJY)
Language	English
Publishing date	2022-08-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP282565
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Article ; Online: Short-latency afferent inhibition is reduced in people with multiple sclerosis during fatiguing muscle contractions.

Brotherton, Emily J / Sabapathy, Surendran / Dempsey, Lisa M / Kavanagh, Justin J

The European journal of neuroscience

2024 Volume 59, Issue 8, Page(s) 2087–2101

Abstract: Understanding how inhibitory pathways influence motor cortical activity during fatiguing contractions may provide valuable insight into mechanisms associated with multiple sclerosis (MS) muscle activation. Short-latency afferent inhibition (SAI) reflects ...

Abstract	Understanding how inhibitory pathways influence motor cortical activity during fatiguing contractions may provide valuable insight into mechanisms associated with multiple sclerosis (MS) muscle activation. Short-latency afferent inhibition (SAI) reflects inhibitory interactions between the somatosensory cortex and the motor cortex, and although SAI is typically reduced with MS, it is unknown how SAI is regulated during exercise-induced fatigue. The current study examined how SAI modulates motor evoked potentials (MEPs) during fatiguing contractions. Fourteen people with relapsing-remitting MS (39 ± 6 years, nine female) and 10 healthy individuals (36 ± 6 years, six female) participated. SAI was induced by stimulation of the median nerve that was paired with TMS over the motor representation of the abductor pollicis brevis. A contraction protocol was employed that depressed force generating capacity using a sustained 3-min 15% MVC, immediately followed by a low-intensity (15% MVC) intermittent contraction protocol so that MEP and SAI could be measured during the rest phases of each duty cycle. Similar force, electromyography and MEP responses were observed between groups. However, the MS group had significantly reduced SAI during the contraction protocol compared to the healthy control group (p < .001). Despite the MS group reporting greater scores on the Fatigue Severity Scale and Modified Fatigue Impact Scale, these scales did not correlate with inhibitory measures. As there were no between-group differences in SSEPs, MS-related SAI differences during the fatiguing contractions were most likely associated with disease-related changes in central integration.
MeSH term(s)	Humans ; Female ; Muscle Fatigue ; Multiple Sclerosis ; Neural Inhibition/physiology ; Transcranial Magnetic Stimulation/methods ; Evoked Potentials, Motor/physiology ; Muscle, Skeletal/physiology ; Electromyography ; Muscle Contraction/physiology ; Electric Stimulation ; Afferent Pathways/physiology
Language	English
Publishing date	2024-01-17
Publishing country	France
Document type	Journal Article
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/ejn.16253
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Article ; Online: Motor unit tracking using blind source separation filters and waveform cross-correlations: reliability under physiological and pharmacological conditions.

Goodlich, Benjamin I / Del Vecchio, Alessandro / Kavanagh, Justin J

Journal of applied physiology (Bethesda, Md. : 1985)

2023 Volume 135, Issue 2, Page(s) 362–374

Abstract: Recent advancements in the analysis of high-density surface electromyography (HDsEMG) have enabled the identification, and tracking, of motor units (MUs) to study muscle activation. This study aimed to evaluate the reliability of MU tracking using two ... ...

Abstract	Recent advancements in the analysis of high-density surface electromyography (HDsEMG) have enabled the identification, and tracking, of motor units (MUs) to study muscle activation. This study aimed to evaluate the reliability of MU tracking using two common methods: blind source separation filters and two-dimensional waveform cross-correlation. An experiment design was developed to assess physiological reliability and reliability for a drug intervention known to reduce the discharge rate of motoneurones (cyproheptadine). HDsEMG signals were recorded from tibialis anterior during isometric dorsiflexions to 10, 30, 50, and 70% of maximal voluntary contraction (MVC). MUs were matched within session (2.5 h) using the filter method, and between sessions (7 days) via the waveform method. Both tracking methods demonstrated similar reliability during physiological conditions [e.g., MU discharge: filter intraclass correlation coefficient (ICC): 10% of MVC = 0.76, to 70% of MVC = 0.86; waveform ICC: 10% of MVC = 0.78, to 70% of MVC = 0.91]. Although reliability slightly reduced after the pharmacological intervention, there were no discernible differences in tracking performance (e.g., MU discharge filter ICC: 10% of MVC = 0.73, to 70% of MVC = 0.75; waveform ICC: 10% of MVC = 0.84, to 70% of MVC = 0.85). The poorest reliability typically occurred at higher contraction intensities, which aligned with the greatest variability in MU characteristics. This study confirms that the tracking method may not impact the interpretation of MU data, provided that an appropriate experiment design is used. However, caution should be used when tracking MUs during higher-intensity isometric contractions.
MeSH term(s)	Reproducibility of Results ; Muscle, Skeletal/physiology ; Electromyography/methods ; Isometric Contraction/physiology ; Motor Neurons/physiology ; Muscle Contraction
Language	English
Publishing date	2023-07-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00271.2023
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Article ; Online: Serotonergic and noradrenergic contributions to motor cortical and spinal motoneuronal excitability in humans.

Thorstensen, Jacob R / Henderson, Tyler T / Kavanagh, Justin J

Neuropharmacology

2023 Volume 242, Page(s) 109761

Abstract: Animal models indicate that motor behaviour is shaped by monoamine neuromodulators released diffusely throughout the brain and spinal cord. As an alternative to conducting a single study to explore the effects of neuromodulators on the human motor system, ...

Abstract	Animal models indicate that motor behaviour is shaped by monoamine neuromodulators released diffusely throughout the brain and spinal cord. As an alternative to conducting a single study to explore the effects of neuromodulators on the human motor system, we have identified and collated human experiments investigating motor effects of well-characterised drugs that act on serotonergic and noradrenergic networks. In doing so, we present strong neuropharmacology evidence that human motor pathways are affected by neuromodulators across both healthy and clinical populations, insight that cannot be determined from a single reductionist experiment. We have focused our review on the effects that monoaminergic drugs have on muscle responses to non-invasive stimulation of the motor cortex and peripheral nerves, and other closely related tests of motoneuron excitability, and discuss how these measurement techniques elucidate the effects of neuromodulators at motor cortical and spinal motoneuronal levels. Although there is some heterogeneity in study methods, we find drugs acting to enhance extracellular concentrations of serotonin tend to reduce the excitability of the human motor cortex, and enhanced extracellular concentrations of noradrenaline increases motor cortical excitability by enhancing intracortical facilitation and reducing inhibition. Both monoamines tend to enhance the excitability of spinal motoneurons. Overall, this review details the importance of neuromodulators for the output of human motor pathways and suggests that commonly prescribed monoaminergic drugs target the motor system in addition to their typical psychiatric/neurological indications.
MeSH term(s)	Animals ; Humans ; Motor Cortex/physiology ; Evoked Potentials, Motor/physiology ; Motor Neurons ; Norepinephrine ; Neurotransmitter Agents/pharmacology ; Transcranial Magnetic Stimulation ; Muscle, Skeletal
Chemical Substances	Norepinephrine (X4W3ENH1CV) ; Neurotransmitter Agents
Language	English
Publishing date	2023-10-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2023.109761
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Article ; Online: Muscarinic receptor blockade causes postcontraction enhancement in corticospinal excitability following maximal contractions.

Dempsey, Lisa M / Kavanagh, Justin J

Journal of neurophysiology

2021 Volume 125, Issue 4, Page(s) 1269–1278

Abstract: ... ...

Abstract	Although
MeSH term(s)	Action Potentials/drug effects ; Adult ; Cross-Over Studies ; Double-Blind Method ; Electric Stimulation ; Electromyography ; Evoked Potentials, Motor/drug effects ; Female ; Humans ; Male ; Motor Cortex/drug effects ; Motor Neurons/drug effects ; Muscarinic Antagonists/administration & dosage ; Muscarinic Antagonists/pharmacology ; Muscle Contraction/drug effects ; Muscle Fatigue/drug effects ; Muscle, Skeletal/drug effects ; Promethazine/administration & dosage ; Promethazine/pharmacology ; Pyramidal Tracts/drug effects ; Spinal Cord/drug effects ; Transcranial Magnetic Stimulation ; Young Adult
Chemical Substances	Muscarinic Antagonists ; Promethazine (FF28EJQ494)
Language	English
Publishing date	2021-02-24
Publishing country	United States
Document type	Controlled Clinical Trial ; Journal Article
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00673.2020
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Article ; Online: Antagonism of 5-HT

Goodlich, Benjamin I / Pearcey, Gregory E P / Del Vecchio, Alessandro / Horan, Sean A / Kavanagh, Justin J

The Journal of physiology

2024 Volume 602, Issue 8, Page(s) 1759–1774

Abstract: ... 5- ... ...

Abstract	5-HT
MeSH term(s)	Adult ; Humans ; Serotonin/pharmacology ; Receptors, Serotonin, 5-HT2 ; Muscle, Skeletal/physiology ; Isometric Contraction/physiology ; Motor Neurons/physiology ; Electromyography/methods ; Muscle Contraction/physiology ; Recruitment, Neurophysiological/physiology
Chemical Substances	Serotonin (333DO1RDJY) ; Receptors, Serotonin, 5-HT2
Language	English
Publishing date	2024-03-19
Publishing country	England
Document type	Journal Article
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP285867
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Article ; Online: Voluntary muscle activation in people with multiple sclerosis is reduced across a wide range of forces following maximal effort-fatiguing contractions.

Brotherton, Emily J / Sabapathy, Surendran / Heshmat, Saman / Kavanagh, Justin J

Journal of neurophysiology

2023 Volume 130, Issue 5, Page(s) 1162–1173

Abstract: Although multiple sclerosis (MS) is frequently associated with motor impairment, little is known about how muscle activation is affected with MS. The aim of this study was to use transcranial magnetic stimulation (TMS) and motor nerve stimulation to ... ...

Abstract	Although multiple sclerosis (MS) is frequently associated with motor impairment, little is known about how muscle activation is affected with MS. The aim of this study was to use transcranial magnetic stimulation (TMS) and motor nerve stimulation to investigate voluntary muscle activation in people with MS across a range of contraction forces. Ten people with MS (39 ± 7 yr) and 10 healthy controls (40 ± 5 yr) performed elbow flexions at target contraction forces of 25%, 50%, 75%, 90%, and 100% maximal voluntary contraction (MVC) while electromyography (EMG) of the biceps brachii was recorded. Sustained elbow flexion MVCs were then performed until force declined to 60% of baseline MVC, where the target contraction forces were again examined but after the sustained MVC. Following the sustained MVC, there was a reduction in biceps EMG amplitude (
MeSH term(s)	Humans ; Muscle Fatigue/physiology ; Muscle Contraction/physiology ; Multiple Sclerosis ; Electric Stimulation ; Muscle, Skeletal/physiology ; Electromyography ; Fatigue ; Isometric Contraction/physiology
Language	English
Publishing date	2023-10-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00146.2023
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Article ; Online: The severity of acute hypoxaemia determines distinct changes in intracortical and spinal neural circuits.

McKeown, Daniel J / Stewart, Glenn M / Kavanagh, Justin J

Experimental physiology

2023 Volume 108, Issue 9, Page(s) 1203–1214

Abstract: The purpose of this study was to examine how two common methods of continuous hypoxaemia impact the activity of intracortical circuits responsible for inhibition and facilitation of motor output, and spinal excitability. Ten participants were exposed to ... ...

Abstract	The purpose of this study was to examine how two common methods of continuous hypoxaemia impact the activity of intracortical circuits responsible for inhibition and facilitation of motor output, and spinal excitability. Ten participants were exposed to 2 h of hypoxaemia at 0.13 fraction of inspired oxygen (
MeSH term(s)	Humans ; Transcranial Magnetic Stimulation/methods ; Evoked Potentials, Motor/physiology ; Transcutaneous Electric Nerve Stimulation ; Motor Cortex/physiology ; Hypoxia ; Electromyography ; Muscle, Skeletal/physiology
Language	English
Publishing date	2023-08-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1016295-1
ISSN	1469-445X ; 0958-0670
ISSN (online)	1469-445X
ISSN	0958-0670
DOI	10.1113/EP091224
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Article ; Online: Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT

Henderson, Tyler T / Taylor, Janet L / Thorstensen, Jacob R / Kavanagh, Justin J

The European journal of neuroscience

2023 Volume 59, Issue 1, Page(s) 17–35

Abstract: Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5- ... ...

Abstract	Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT
MeSH term(s)	Humans ; Cross-Over Studies ; Electric Stimulation ; Electromyography ; Evoked Potentials, Motor/physiology ; Motor Neurons/physiology ; Muscle, Skeletal/physiology ; Pyramidal Tracts/physiology ; Receptors, Serotonin, 5-HT2 ; Serotonin/pharmacology ; Transcranial Magnetic Stimulation ; Young Adult ; Adult ; Double-Blind Method
Chemical Substances	Receptors, Serotonin, 5-HT2 ; Serotonin (333DO1RDJY)
Language	English
Publishing date	2023-11-22
Publishing country	France
Document type	Journal Article
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/ejn.16190
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