Biology subjects

Millard, S. K.

Publications and source records attributed to Millard, S. K..

10 recordsLinked to original sources

bioRxiv2026

Resilience to persistent pain is characterized by stable periodic and increased aperiodic cortical activity

Individual variability in pain perception raises fundamental questions about how biological and experiential factors shape pain processing. Cognitive-demanding motor training is a key driver of use-dependent brain plasticity and may contribute to differences in pain responses. Using musicians as a model of cognitive-motor expertise, we examined how such experience influences cortical dynamics and pain perception during experimentally induced prolonged musculoskeletal pain. Resting-state electroencephalography (EEG) was recorded in musicians and non-musicians before (Day 1) and during pain development (Days 3 and 8) following intramuscular nerve growth factor (NGF) administration. We parameterized periodic (alpha peak frequency, power, frontal asymmetry) and aperiodic (exponent, offset) components of the EEG signal to characterize intrinsic cortical activity. During pain development, non-musicians exhibited slowing of peak alpha frequency, a neural marker associated with ongoing pain. In contrast, musicians showed preserved alpha dynamics and greater left frontal asymmetry, reflecting resilient top-down pain regulation. Musicians also displayed higher aperiodic exponent across sessions, suggesting that musical training shapes the excitation-to-inhibition (E:I) balance potentially reflecting a shift toward greater inhibitory activity. Notably, across all participants, only aperiodic features improved the prediction of pain severity, with higher exponents and higher offsets associated with lower pain ratings. These findings demonstrate that cognitive-motor training shapes cortical dynamics during sustained pain, supporting more stable, resilient cortical responses to pain. Such training also contributes to inter-individual variability in pain processing. Moreover, this study identifies aperiodic EEG components as predictors of pain severity and resilience.

neuroscience↗

bioRxiv2024

Peak alpha frequency is not significantly altered by five days of experimental pain and repetitive transcranial stimulation of the left dorsolateral prefrontal cortex

Repetitive transcranial magnetic stimulation (rTMS) holds promise as a non-invasive pain treatment. Given the link between individual peak alpha frequency (PAF) of resting-state electroencephalographic recordings and pain sensitivity, and the potential for rTMS to modulate PAF, we investigated these relationships through a secondary analysis of established rTMS-induced analgesia in an experimental model of sustained muscle pain. In a randomised, single-blind, sham-controlled experiment, 30 healthy adults underwent either active (n=15) or sham (n=15) high-frequency rTMS (20 min) to the left dorsolateral prefrontal cortex for five consecutive days following induction of sustained experimental pain by nerve growth factor (NGF) injected into the right extensor carpi radialis brevis muscle. The pain intensity was assessed daily for 14 days on a numerical rating scale (NRS). PAF of the resting state electroencephalography (5 min) was assessed before and one day after the five rTMS treatment days. The pre-registered analysis revealed no significant changes in PAF following five consecutive days of active (from 9.90{+/-}0.39 Hz to 9.95{+/-}0.38 Hz) or sham (from 9.86{+/-}0.44 Hz to 9.81{+/-}0.35 Hz) rTMS, suggesting that the impact of rTMS on NGF-induced pain is independent of PAF modulation. However, exploratory analysis indicated an association between a larger absolute difference in baseline PAF to 10 Hz (i.e. the rTMS frequency) and higher NRS pain ratings at Day 5 in participants receiving active rTMS. This suggests rTMS is more efficient when delivered close to individual PAF or for those with PAF around 10 Hz, necessitating further exploration of PAFs role in rTMS-induced pain relief.

neuroscience↗

bioRxiv2024

A 5-day course of rTMS before pain onset ameliorates future pain and increases sensorimotor peak alpha frequency

Repetitive transcranial magnetic stimulation (rTMS) has shown promise as an intervention for pain. An unexplored research question is whether the delivery of rTMS prior to pain onset might protect against a future episode of prolonged pain. The present study aimed to determine i) whether 5 consecutive days of rTMS delivered prior to experimentally-induced prolonged jaw pain could reduce future pain intensity and ii) whether any effects of rTMS on pain were mediated by changes in corticomotor excitability (CME) and/or sensorimotor peak alpha frequency (PAF). On each day from Day 0-4, forty healthy individuals received a single session of active (n = 21) or sham (n = 19) rTMS over the left primary motor cortex. PAF and CME were assessed on Day 0 (before rTMS) and Day 4 (after rTMS). Prolonged pain was induced via intramuscular injection of nerve growth factor (NGF) in the right masseter muscle after the final rTMS session. From Days 5-25, participants completed twice-daily electronic dairies including pain on chewing and yawning (primary outcomes), as well as pain during other activities (e.g. talking), functional limitation in jaw function and muscle soreness (secondary outcomes). Compared to sham, individuals who received active rTMS subsequently experienced lower pain on chewing and yawning. Although active rTMS increased PAF, the effects of rTMS on pain were not mediated by changes in PAF or CME. This study is the first to show that rTMS delivered prior to pain onset can protect against future pain and associated functional impairment. Thus, rTMS may hold promise as a prophylactic intervention for persistent pain.

neuroscience↗

bioRxiv2024

POSTERIOR-SUPERIOR INSULA REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION REDUCES EXPERIMENTAL TONIC PAIN AND PAIN-RELATED CORTICAL INHIBITION IN HUMANS

High frequency repetitive transcranial magnetic stimulation (rTMS) to the posterosuperior insula (PSI) may produce analgesic effects. However, the neuroplastic changes behind PSI-rTMS analgesia remain poorly understood. The present study aimed to determine whether tonic capsaicin-induced pain and cortical inhibition (indexed using TMS-electroencephalography) are modulated by PSI-rTMS. Twenty healthy volunteers (10 females) attended two sessions randomized to active or sham rTMS. Experimental pain was induced by capsaicin administered to the forearm for 90 minutes, with pain ratings collected every 5 minutes. Left PSI-rTMS was delivered (10Hz, 100 pulses per train, 15 trains) [~]50 minutes post-capsaicin administration. TMS-evoked potentials (TEPs) and thermal sensitivity were assessed at baseline, during capsaicin pain prior to rTMS and after rTMS. Bayesian evidence of reduced pain scores and increased heat pain thresholds were found following active rTMS, with no changes occurring after sham rTMS. Pain (prior to active rTMS) led to an increase in the frontal negative peak [~]45 ms (N45) TEP relative to baseline. Following active rTMS, there was a decrease in the N45 peak back to baseline levels. In contrast, following sham rTMS, the N45 peak was increased relative to baseline. We also found that the reduction in pain NRS scores following active vs. sham rTMS was partially mediated by decreases in the N45 peak. These findings provide evidence of the analgesic effects of PSI-rTMS and suggest that the TEP N45 peak is a potential marker and mediator of both pain and analgesia.

neuroscience↗

bioRxiv2023

Can non-invasive brain stimulation modulate peak alpha frequency in the human brain? A systematic review and meta-analysis

Peak alpha frequency, the dominant oscillatory frequency within the alpha range (8-12 Hz), is associated with cognitive function and several neurological conditions, including chronic pain. Manipulating PAF could offer valuable insight into the relationship between PAF and various functions and conditions and provide new treatment avenues. This systematic review aimed to comprehensively synthesise effects of non-invasive brain stimulation (NIBS) on PAF speed. Relevant studies assessing PAF pre- and post-NIBS in healthy adults were identified through systematic searches of electronic databases (Embase, PubMed, PsychINFO, Scopus, The Cochrane Library) and trial registers. The Cochrane risk-of-bias tool was employed for assessing study quality. Quantitative analysis was conducted through pairwise meta-analysis when possible; otherwise, qualitative synthesis was performed. The review protocol was registered with PROSPERO (CRD42020190512) and the Open Science Framework (https://osf.io/2yaxz/). Eleven NIBS studies were included, all with a low risk-of-bias, comprising seven transcranial alternating current stimulation (tACS), three repetitive transcranial magnetic stimulation (rTMS), and one transcranial direct current stimulation (tDCS) study. Meta-analysis of active tACS conditions (eight conditions from five studies) revealed no significant effects on PAF (mean difference [MD] = -0.12, 95% CI = -0.32 to 0.08, p = 0.24). Qualitative synthesis provided no evidence that tDCS altered PAF and moderate evidence for transient increases in PAF with 10 Hz rTMS. There is limited evidence that NIBS can modulate PAF, and existing evidence does not demonstrate robust effects. Further studies employing standardised stimulation protocols are necessary to determine the potential of NIBS to modulate PAF.

neuroscience↗

bioRxiv2023

Effects of nicotine compared to placebo gum on sensitivity to pain and mediating effects of peak alpha frequency

Recent research has linked individual peak alpha frequency (PAF) to pain sensitivity, but whether PAF alterations can influence pain remains unclear. Our study investigated the effects of nicotine on pain sensitivity and whether pain changes are mediated by PAF changes. In a randomised, double-blind, placebo-controlled experiment, 62 healthy adults (18-44 years) received either 4 mg nicotine (n=29) or placebo gum (n=33). Resting state EEG and pain ratings during prolonged heat and pressure models were collected before and after nicotine intake. The nicotine group showed a small decrease in heat-pain ratings compared to placebo group when controlling confounders, and a small increase in PAF across the scalp from pre- to post-gum, both with and without confounder adjustment. These effects were most pronounced in the central-parietal and right-frontal electrodes. However, mediation analysis did not support the notion that PAF changes mediate nicotines effects on pain sensitivity. While a growing body of literature supports a link between PAF and both acute and chronic pain, further work is needed to understand the mechanisms of this link.

neuroscience↗

bioRxiv2023

Alterations in cortical excitability during pain: A combined TMS-EEG Study

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n = 29), multiple sustained thermal stimuli were administered to the forearm, with the first, second and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak [~]45ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n = 10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity.

neuroscience↗

bioRxiv2022

Intramuscular injection of nerve growth factor as a model of temporomandibular disorder: nature, time-course, and sex differences characterising the pain experience

BackgroundTemporomandibular disorder (TMD) is a common condition that frequently transitions to chronic symptoms. Experimental pain models that mimic the symptoms of clinical TMD may be useful in understanding the mechanisms, and sex differences, present in this disorder. Here we aimed to comprehensively characterise the nature and time-course of pain, functional impairment and hyperalgesia induced by repeated intramuscular injection of nerve growth factor (NGF) into the masseter muscle, and to investigate sex differences in the NGF-induced pain experience. Methods94 healthy individuals participated in a longitudinal observational study with 30-day follow-up. NGF was injected into the right masseter muscle on Day 0 and Day 2. Participants attended laboratory sessions to assess pain (Numerical Rating Scale; NRS), functional limitation (mouth opening distance, Jaw Functional Limitation Scale; JFLS) and mechanical sensitization (pressure pain thresholds; PPTs) on Days 0, 2 and 5 and completed twice daily electronic pain dairies from Day 0 to day 30. ResultsPeak pain averaged 2.0/10 (95 % CI: 1.6-2.4) at rest and 4.3/10 (95 % CI: 3.9-4.8) on chewing. Pain-free mouth opening distance reduced from 5.0 cm (95 % CI: 4.8-5.1 cm) on Day 0 to 3.7 cm (95 % CI: 3.5-3.9 cm) on Day 5. The greatest reduction in PPTs was observed over the masseter muscle. Females experienced higher pain, greater functional impairment, and greater sensitivity to mechanical stimuli than males. ConclusionIntramuscular injection of NGF is a useful model with which to explore the mechanisms, and sex differences, present in clinical TMD.

neuroscience↗

bioRxiv2021

The influence of somatosensory and auditory evoked potentials on concurrent transcranial-magnetic stimulation electroencephalography recordings

BackgroundTranscranial magnetic stimulation (TMS) evoked potentials (TEPs) can be used to index cortical excitability. However, it remains unclear to what extent TEPs reflect somatosensory and auditory-evoked potentials which arise from the scalp sensation and click of the TMS coil, as opposed to transcranial stimulation of cortical circuits. ObjectivesThe present study had two aims; a) to determine the extent to which sensory potentials contaminate TEPs using a spatially matched sham condition, and b) to determine whether sensory potentials reflect auditory or somatosensory potentials alone, or a combination of the two. MethodsTwenty healthy participants received active or sham stimulation, with the latter consisting of the click of a sham coil combined with scalp electrical stimulation. Earplugs/headphones were used to suppress the TMS click noise. Two additional control conditions i) electrical stimulation alone and ii) auditory stimulation alone were included in a subset of 13 participants. ResultsSignals from active and sham stimulation were correlated in spatial and temporal domains, especially >70ms post-stimulation. Relative to auditory or electrical stimulation alone, combined (sham) stimulation resulted in a) larger evoked responses b) stronger correlations with active stimulation and c) a signal that could not be explained by the linear sum of electrical and auditory stimulation alone. ConclusionsSensory potentials can confound data interpretations of TEPs at timepoints >70ms post-TMS, while earlier timepoints appear reflective of cortical excitability. Furthermore, contamination of TEPs cannot be explained by auditory or somatosensory potentials alone, but instead reflects a non-linear interaction between both sources. Future studies may benefit from controlling for sensory contamination using sham conditions that are spatially matched to active TMS, and which consist of combined auditory and somatosensory stimulation.

neuroscience↗

bioRxiv2020

A silent disco: Persistent entrainment of low-frequency neural oscillations underlies beat-based, but not memory-based temporal expectations

The brain uses temporal structure in the environment, like rhythm in music and speech, to predict the timing of events, thereby optimizing their processing and perception. Temporal expectations can be grounded in different aspects of the input structure, such as a regular beat or a predictable pattern. One influential account posits that a generic mechanism underlies beat-based and pattern-based expectations, namely entrainment of low frequency neural oscillations to rhythmic input, while other accounts assume different underlying neural mechanisms. Here, we addressed this outstanding issue by examining EEG activity and behavioral responses during silent periods following rhythmic auditory sequences. We measured responses outlasting the rhythms both to avoid confounding the EEG analyses with evoked responses, and to directly test whether beat-based and pattern-based expectations persist beyond stimulation, as predicted by entrainment theories. To properly disentangle beat-based and pattern-based expectations, which often occur simultaneously, we used non-isochronous rhythms with a beat, a predictable pattern, or random timing. In Experiment 1 (N = 32), beat-based expectations affected behavioral ratings of probe events for two beat-cycles after the end of the rhythm. The effects of pattern-based expectations reflected expectations for one interval. In Experiment 2 (N = 27), using EEG, we found enhanced spectral power at the beat frequency for beat-based sequences both during listening and silence. For pattern-based sequences, enhanced power at a pattern-specific frequency was present during listening, but not silence. Moreover, we found a difference in the evoked signal following pattern-based and beat-based sequences. Finally, we show how multivariate pattern decoding and multi scale entropy - measures sensitive to non-oscillatory components of the signal - can be used to probe temporal expectations. Together, our results suggest that the input structure used to form temporal expectations may affect the associated neural mechanisms. We suggest climbing activity and low-frequency oscillations may be differentially associated with pattern-based and beat-based expectations.

neuroscience↗