Modulation of corticospinal excitability by paired associative stimulation following stroke.

Modulation of human corticospinal excitability by paired associative stimulation in patients with amyotrophic lateral sclerosis and effects of Riluzole

Modulation of corticospinal excitability by paired associative stimulation: Reproducibility of effects and intraindividual reliability

FV 1 Cholinergic brain structure and sensory-afferent modulation of motor cortex excitability

Depression affects millions of Americans and is a leading contributor to disability and mortality in the United States. Evidence indicates that neuroplasticity is impaired in those with depression and successful treatment for depression appears to reestablish neuroplastic potential. Aerobic exercise (AE) has well-established antidepressant effects and has been shown to modulate neuroplasticity in non-depressed subjects. To date, the acute influence of exercise intensity on indices of neuroplastic adaptation have yet to be described. PURPOSE: To examine the efficacy of acute AE as a neuro-modulatory intervention in non-depressed control subjects. METHODS: Thirteen non-depressed subjects (8 female; 34.5 ± 8.7 years old) completed three experimental sessions that included assessment of corticospinal excitability (CE), AE (15 minutes) and paired associative stimulation (PAS) to determine neuroplastic potential. CE was assessed via transcranial magnetic stimulation and surface electromyography of the abductor pollicis brevis muscle before and after exercise, and for one hour after PAS. AE was performed on a stationary cycle ergometer at low intensity (LO), 35% heart rate reserve (HRR); high intensity (HI), 70% HRR; or a non-exercise control condition (CON). The primary outcome was change in peak-to-peak motor evoked potential amplitude relative to baseline assessment. RESULTS: Mean post-exercise CE across all time points was increased 26.2% in the LO condition, and 2.9% in the CON condition while the HI condition reduced CE 6.3%. Immediately following exercise, the LO condition produced a rapid 27.1% increase in CE while the HI condition produced a rapid 16.3% decrease in CE. Both the LO and HI conditions demonstrated a homeostatic response immediately post-PAS with a 15.0% reduction and 27.8% increase in CE, respectively. CONCLUSION: Lower exercise intensity appears to have a greater influence on increasing CE. Interestingly, the rapid effects of exercise appeared to be reversed by PAS suggesting the presence of homeostatic metaplasticity during these conditions. Modulation of CE via exercise in depression has yet to be established but may underlie the anti-depressant effects of AE. Work examining the influence of AE on CE in depression is currently in progress.

P 29. BDNF val66met polymorphism influences the time course of changes in corticospinal excitability induced by paired associative and transcranial direct current stimulation

Most candidate genes and genetic abnormalities linked to autism spectrum disorders (ASD) are thought to play a role in developmental and experience-dependent plasticity. As a possible index of plasticity, we assessed the modulation of motor corticospinal excitability in individuals with Asperger's syndrome (AS) using transcranial magnetic stimulation (TMS). We measured the modulatory effects of theta-burst stimulation (TBS) on motor evoked potentials (MEPs) induced by single-pulse TMS in individuals with AS as compared with age-, gender- and IQ-matched neurotypical controls. The effect of TBS lasted significantly longer in the AS group. The duration of the TBS-induced modulation alone enabled the reliable classification of a second study cohort of subjects as AS or neurotypical. The alteration in the modulation of corticospinal excitability in AS is thought to reflect aberrant mechanisms of plasticity, and might provide a valuable future diagnostic biomarker for the disease and ultimately offer a target for novel therapeutic interventions.

Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation.

Inter-individual variability is a common issue of noninvasive brain stimulation. This study aimed to augment neuroplasticity induced by paired associative stimulation (PAS) through leveraging interlimb neural interactions. Specifically, we assessed lower-limb corticospinal excitability when voluntary ipsilateral upper-limb muscle contraction (UMC) was integrated into lower-limb PAS in 19 able-bodied young adults. PAS targeted the right soleus muscle (i.e., a lower-limb muscle), pairing peripheral nerve stimulation (PNS) with transcranial magnetic stimulation (TMS) to modulate cortical excitability. Experiment 1 evaluated motor-evoked potentials (MEPs) and Hoffmann reflex (H-reflex) after PAS + UMC, PAS, and UMC interventions. Experiment 2 investigated the modulation of MEP and short-interval intracortical inhibition (SICI) following PAS + UMC and PAS interventions, with focused attention on PNS. During PAS + UMC intervention, participants performed right wrist flexion at 30% maximum voluntary contraction coinciding with stimulation. Results showed a significant increase in MEPs 30 min after PAS + UMC intervention, with enhanced increase under controlled attention. The H-reflex slightly increased 15 and 30 min after PAS + UMC intervention. SICI increased 30 min after PAS + UMC intervention, though the correlation between MEP and SICI observed in PAS intervention was absent in PAS + UMC intervention. Our findings suggest that combining lower-limb PAS with UMC can facilitate lower-limb corticospinal excitability more effectively than conventional PAS, despite the complex neural mechanism underlying PAS.

Timing of Modulation of Corticospinal Excitability by Heartbeat Differs with Interoceptive Accuracy

Paired associative stimulation (PAS) has been shown to increase corticospinal excitability (CSE) providing a promising adjuvant therapeutic approach for stroke. Combining PAS with movement of the stimulated limb may further increase enhancement of CSE, however, individuals with moderate to severe stroke may not be able to engage in the necessary repetitive voluntary movements of the paretic limb. The objective of this study was to investigate the feasibility of contralaterally coordinated PAS (ccPAS) applied to the resting hand extensors during fast extension of the contralateral hand. A potential dependency of CSE modulation on the phase of the movement of the opposite hand was evaluated. Eleven participants each completed three session: PAS applied to the resting right hand during the preparation phase of the extension of the contralateral (left) hand; PAS applied during the execution phase of the left hand extension; and PAS applied with both hands at rest. Motor evoked potentials (MEPs) were evoked from the right extensor digitorum communis (EDC) and flexor digitorum superficialis (FDS) muscles prior and immediately after each session. PAS delivered during the muscle contraction of the left hand and PAS delivered at rest both increased the MEP amplitude in the right EDC. PAS delivered before the left hand movement onset led to a decrease in the MEP amplitude measured in the right EDC muscle. We conclude that PAS induced bidirectional changes in the amplitude of MEPs that were dependent on the phase of the movement of the opposite hand.

#40: Direction of PAS-Induced Modulation of Corticospinal Excitability Depends on Timing Between Stimulation and Movement Onset

Brain plasticity refers to changes in the organization of the brain as a result of different environmental stimuli. The aim of this study was to assess the genetic variation of brain plasticity, by comparing intrapair differences between monozygotic (MZ) and dizygotic (DZ) twins. Plasticity was examined by a paired associative stimulation (PAS) in 32 healthy female twins (9 MZ and 7 DZ pairs, aged 22.6±2.7 and 23.8±3.6 years, respectively). Stimulation consisted of low frequency repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with a single pulse transcranial magnetic stimulation (TMS) for activation of the abductor pollicis brevis muscle (APB). Corticospinal excitability was monitored for 30 min following the intervention. PAS induced an increase in the amplitudes of the motor evoked potentials (MEP) in the resting APB, compared to baseline. Intrapair differences, after baseline normalization, in the MEP amplitudes measured at 25-30 min post-intervention, were almost double for DZ (1.25) in comparison to MZ (0.64) twins (P =0.036). The heritability estimate for brain plasticity was found to be 0.68. This finding implicates that genetic factors may contribute significantly to interindividual variability in plasticity paradigms. Genetic factors may be important in adaptive brain reorganization involved in motor learning and rehabilitation from brain injury.

The ability to induce plasticity in human primary motor cortex (M1) may be diminished with advancing age. Intracortical inhibition is critical for M1 plasticity and regular participation in physical activity can promote M1 plasticity. This study assessed modulation of M1 excitability and inhibition after paired associative stimulation (PAS) and motor skill acquisition in young and older adults, which also considered the cardiorespiratory fitness of each participant. Thirty-one older (60–88 years) and 20 young (20–33 years) adults were recruited. Electromyographic recordings were obtained from the dominant hand first dorsal interosseous muscle. A sequential visual isometric force task that required index finger abduction was used to investigate motor skill acquisition. Transcranial magnetic stimulation protocols were used to examine corticomotor excitability and short- and long-interval intracortical inhibition (SICI and LICI) before and after each intervention. Corticomotor excitability, normalized to baseline, increased after PAS in young but not older adults, while no age-related differences were observed after skill acquisition. Facilitation of corticomotor excitability after PAS, but not skill acquisition, was positively correlated with cardiorespiratory fitness. SICI decreased after PAS and increased after skill acquisition, with no differences between age groups. LICI increased for young adults and decreased for older adults after PAS, but did not change after skill acquisition. Overall, there was intervention-specific modulation of inhibition, an age-related difference in LICI after PAS, and higher cardiorespiratory fitness was associated with greater corticomotor excitability facilitation after PAS. These findings may help inform future endeavors focused on attenuating age-related declines in brain and motor-cognitive function.

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique combining transcranial magnetic stimulation and peripheral nerve stimulation. PAS allows connections between cortical areas and peripheral nerves (C/P PAS) or between cortical regions (C/C PAS) to be strengthened or weakened by spike-timing-dependent neural plasticity mechanisms. Since PAS modulates both neurophysiological features and motor performance, there is growing interest in its application in neurorehabilitation. We aimed to synthesize evidence on the motor rehabilitation role of PAS in stroke patients. We performed a literature search following the PRISMA Extension for Scoping Reviews Framework. Eight studies were included: one investigated C/C PAS between the cerebellum and the affected primary motor area (M1), seven applied C/P PAS over the lesional, contralesional, or both M1. Seven studies evaluated the outcome on upper limb and one on lower limb motor recovery. Although several studies omit crucial methodological details, PAS highlighted effects mainly on corticospinal excitability, and, more rarely, an improvement in motor performance. However, most studies failed to prove a correlation between neurophysiological changes and motor improvement. Although current studies seem to suggest a role of PAS in post-stroke rehabilitation, their heterogeneity and limited number do not yet allow definitive conclusions to be drawn.

Background: Short-latency afferent inhibition (SAI) is a method used to assess sensorimotor integration. Inhibition typically occurs at an interstimulus interval (ISI) of 20–22 ms or N20 + 2 ms. Paired associative stimulation (PAS) applied at certain ISIs consecutively can induce changes in corticospinal excitability. Usually, ISIs of 10 and 25 ms are applied in PAS. In this study, we aimed to investigate the relationship between ISIs of SAI and PAS, a neuromodulation paradigm. To achieve this, we first identified the optimal ISIs that produced maximum inhibition and facilitation during SAI by evaluating multiple ISIs. Subsequently, we applied the PAS paradigm with these ISIs. Materials and Methods: Twelve healthy participants were recruited for the study conducted over three sessions. During the first session, we examined the ISI of maximum inhibitory and ISI of facilitatory or minimum inhibitory (if facilitation was absent) in each participant at multiple ISIs. In the other two sessions, we applied PAS at the ISI of maximum inhibitory and the ISI of facilitatory or minimum inhibitory. We compared the motor-evoked potential (MEP) amplitudes before PAS, immediately after PAS, and 30 min after PAS. Results: The highest inhibition in SAI was observed at an ISI of 22 ms. In 60% of the participants, inhibition was most prominent at this ISI. Facilitation was not observed in 50% of the participants. During the PAS paradigm, which used the ISI of maximum inhibitory, significant facilitation was observed 30 min after the procedure compared with baseline (P = 0.011) and immediately post-PAS (P = 0.026). The mean MEP amplitude decreased significantly 30 min after the procedure compared with the baseline in ISI of only detected facilitation (P = 0.041). Conclusion: Our findings suggest that the ISI of maximum inhibition can vary among individuals, and that facilitation may not be observed in everyone within the ISI range of 22 ms to 40 ms. The results indicate that paired stimuli at ISI of maximum inhibitory in SAI increase corticospinal excitability. In addition, PAS at ISI of only facilitation decreases excitability. These changes in excitability may be explained by spike-timing-dependent plasticity.