Repetitive Paired Associative Stimulation Research Articles

Effect of dorsolateral prefrontal cortex structural measures on neuroplasticity and response to paired-associative stimulation in Alzheimer's dementia.

Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Can we manipulate brain connectivity? A systematic review of cortico-cortical paired associative stimulation effects

ObjectiveCortico-cortical paired associative stimulation (ccPAS) is a form of dual-site transcranial magnetic stimulation (TMS) entailing a series of single-TMS pulses paired at specific interstimulus intervals (ISI) delivered to distant cortical areas. The goal of this article is to systematically review its efficacy in inducing plasticity in humans focusing on stimulation parameters and hypotheses of underlying neurophysiology. MethodsA systematic review of the literature from 2009–2023 was undertaken to identify all articles utilizing ccPAS to study brain plasticity and connectivity. Six electronic databases were searched and included. Results32 studies were identified. The studies targeted connections within the same hemisphere or between hemispheres. 28 ccPAS studies were in healthy participants, 1 study in schizophrenia, and 1 in Alzheimer’s disease (AD) patients. 2 additional studies used cortico-cortical repetitive paired associative stimulation (cc-rPAS) in generalized anxiety disorder (GAD) patients. Outcome measures include electromyography (EMG), behavioral measures, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). ccPAS seems to be able to modulate brain connectivity depending on the ISI. ConclusionsccPAS can be used to modulate corticospinal excitability, brain activity, and behavior. Although the stimulation parameters used across studies reviewed in this paper are varied, ccPAS is a promising approach for basic research and potential clinical applications. SignificanceRecent advances in neuroscience have caused a shift of interest from the study of single areas to a more complex approach focusing on networks of areas that orchestrate brain activity. Consequently, the TMS community is also witnessing a change, with a growing interest in targeting multiple brain areas rather than a single locus, as evidenced by an increasing number of papers using ccPAS. In light of this new enthusiasm for brain connectivity, this review summarizes existing literature and stimulation parameters that have proven effective in changing electrophysiological, behavioral, or neuroimaging-derived measures.

Low-intensity repetitive paired associative stimulation targeting the motor hand area at theta frequency causes a lasting reduction in corticospinal excitability

ObjectiveSub-motor threshold 5 Hz repetitive paired associative stimulation (5 Hz-rPAS25ms) produces a long-lasting increase in corticospinal excitability. Assuming a spike-timing dependent plasticity-like (STDP-like) mechanism, we hypothesized that 5 Hz-rPAS at a shorter inter-stimulus interval (ISI) of 15 ms (5 Hz-rPAS15ms) would exert a lasting inhibitory effect on corticospinal excitability. Methods20 healthy volunteers received two minutes of 5 Hz-rPAS15ms. Transcranial magnetic stimulation (TMS) was applied over the motor hotspot of the right abductor pollicis brevis muscle at 90% active motor threshold. Sub-motor threshold peripheral electrical stimulation was given to the left median nerve 15 ms before each TMS pulse. We assessed changes in mean amplitude of the unconditioned motor evoked potential (MEP), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and cortical silent period (CSP) before and for 60 minutes after 5-Hz rPAS15ms. ResultsSubthreshold 5-Hz rPAS15ms produced a 20–40% decrease in mean MEP amplitude along with an attenuation in SAI, lasting at least 60 minutes. A follow-up experiment revealed that MEP facilitation was spatially restricted to the target muscle. ConclusionsSubthreshold 5-Hz rPAS15ms effectively suppresses corticospinal excitability. Together with the facilitatory effects of subthreshold 5-Hz rPAS25ms (Quartarone et al., J Physiol 2006;575:657–670), the results show that sub-motor threshold 5-Hz rPAS induces STDP-like bidirectional plasticity in the motor cortex. SignificanceThe results of the present study provide a new short-time paradigm of long term depression (LTD) induction in human sensory-motor cortex.

P10 Efficacy of repetitive dual-site paired associative transcranial magnetic stimulation in the treatment of generalized anxiety disorder

P10 Efficacy of repetitive dual-site paired associative transcranial magnetic stimulation in the treatment of generalized anxiety disorder

Spatial Integration of Somatosensory Inputs during Sensory-Motor Plasticity Phenomena Is Normal in Focal Hand Dystonia.

Background Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements, and it seems to be lost in dystonia. Objectives. To explore if sensory information is abnormally processed and integrated in focal hand dystonia (FHD) and if surround inhibition phenomena are operating during sensory-motor plasticity and somatosensory integration in normal humans and in patients with FHD. Methods. We looked at the MEP facilitation obtained after 5 Hz repetitive paired associative stimulation of median (PAS M), ulnar (PAS U), and median + ulnar nerve (PAS MU) stimulation in 8 normal subjects and 8 FHD. We evaluated the ratio MU/(M + U) ∗ 100 and the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input. Results FHD had two main abnormalities: first, the amount of facilitation was larger than normal subjects; second, the spatial specificity was lost. The MU/(M + U) ∗ 100 ratio was similar in healthy subjects and in FHD patients, and the somatosensory integration was normal in this subset of patients. Conclusions. The inhibitory integration of somatosensory inputs and the somatosensory inhibition are normal in patients with focal dystonia as well as lateral surrounding inhibition phenomena during sensory-motor plasticity in FHD.

44. Surround inhibition abnormalities in focal hand dystonia may not depend by alterations in somatosensory integration

Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements and seems to be lost in dystonia. To explore if sensory information is abnormally processed and integrated in focal dystonia and if surround inhibition phenomena are operating during sensory-motor plasticity and sensory-motor integration in normal humans and in patients with focal hand dystonia. We looked at motor evoked potential (MEP) facilitation, in the APB and ADM muscles, obtained after 5 Hz repetitive paired associative stimulation, stimulating median (PAS M), ulnar (PAS U) and median + ulnar nerve (PAS MU) in 8 normal subjects and 8 dystonic patients. We evaluated the ratio MU/(M + U) × 100. Moreover, we tested the spatial and temporal somatosensory integration recording SEPs evoked by a dual nerve input. Our data confirmed that in dystonic patients the amount of facilitation was larger than normal subjects and the spatial specificity was lost. The MU/(M + U) × 100 ratio was similar in healthy subjects and in dystonic patients and the somatosensory integration was normal in this subset of patients. These data suggest that lateral surround inhibition phenomena during sensory-motor plasticity are normal in focal hand dystonia.

Who May Benefit From Armeo Power Treatment? A Neurophysiological Approach to Predict Neurorehabilitation Outcomes

BackgroundThe Armeo Power, a rehabilitation exoskeleton that allows early treatment of motor disabilities, provides intelligent arm support in a large 3-dimensional work space, thus enabling patients to perform intensive, repetitive, and goal-oriented exercises. This device could efficiently induce new connections and facilitate plasticity phenomena potentiation. Knowledge of the potential brain plasticity reservoir after brain damage constitutes a prerequisite for an optimal rehabilitation strategy. ObjectiveTo identify potential neurophysiologic markers predicting the responsiveness of stroke patients to upper limb robotic treatment. DesignProspective cohort study. SettingBehavioral and Robotic Neurorehabilitation Laboratory of IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy. PatientsWe enrolled 35 patients who had sustained a first-ever ischemic supratentorial stroke at least 2 months before enrollment and had unilateral hemiplegia. MethodsAll patients underwent 40 Armeo Power training sessions that lasted 1 hour each (ie, 5 times a week for 8 weeks). Main Outcome MeasurementsWe assessed the spasticity and motor function of the upper limb by means of the Modified Ashworth scale and Fugl-Meyer assessment, respectively. Moreover, we evaluated the cortical excitability and plasticity potential of the bilateral primary motor areas in response to the repetitive paired associative stimulation paradigm using transcranial magnetic stimulation and Armeo Power kinematic parameters. ResultsThe patients who showed significant repetitive paired associative stimulation aftereffects at baseline exhibited an evident increase of cortical plasticity in the affected hemisphere (motor evoked potential amplitude increase, P = .03), a decrease of interhemispheric inhibition (affected hemisphere cortical silent period duration decrease, P = .01; unaffected hemisphere cortical silent period duration increase, P = .004; repetitive paired associative stimulation aftereffect increase, P = .008). Such findings were paralleled by clinical improvements (Fugl-Meyer, P = .04) and Armeo Power kinematic improvements (elbow flexion/extension, P = .02; shoulder range of movement, P = .002). ConclusionsOur data suggest that use of Armeo Power may improve upper limb motor function recovery as predicted by reshaping of cortical and transcallosal plasticity, according to the baseline cortical excitability. Level of EvidenceIV

111. Impairment of synaptic plasticity in patients affected by brain tumors

Aim of the present study was to investigate motor cortex synaptic plasticity in both hemispheres of patients affected by brain tumors. We employed an electrophysiological protocol, named repetitive paired associative stimulation (rPAS), involving repetitive transcranial magnetic stimulation (rTMS) paired with electrical stimulation of the contralateral median nerve, that modifies cortico-spinal excitability. Ten right-handed patients (3 women), aged 49–70 years (mean age: 54.8 years), participated in the study. Motor evoked potentials (MEP) were measured at baseline before and for up to 30 min after 5 Hz-rPAS in abductor pollicis brevis (APB). rPAS consisted of 600 pairs of transcranial magnetic stimuli, at a rate of 5 Hz for 2 min, coupled with electrical median nerve stimulation preceding TMS over the contralateral M1 at an interstimulus interval of 25 ms. In both hemispheres of patient with brain tumors rPAS did not induce any significant changes in MEP amplitudes, compared with aged matched healthy controls. Synaptic plasticity is impaired in both hemispheres of patients affected by brain tumors.

A local signature of LTP-like plasticity induced by repetitive paired associative stimulation.

Repetitive paired associative stimulation (rPAS) repeatedly pairs electrical nerve stimulation (ENS) with transcranial magnetic stimulation (TMS) of the contralateral motor hand area (M1) at 5Hz frequency. So far, there are only few studies concerning the effects of PAS on the modulation of EEG power. Hence, aim of the present study was to investigate rPAS long term after-effects on cortical excitability looking at EEG power spectra. In four experimental sessions, separated by 2weeks interval, 12 awake subjects received rPAS of the right median nerve and left M1 at a fixed interval (ISI) of 25ms (real condition), 5Hz-TMS on left M1, 5Hz-ENS, of the right median nerve, and rPAS with changing ISI (sham condition). We measured peak-to-peak MEP amplitude, evoked from the target muscle (right abductor pollicis brevis muscle) at rest and the absolute power (POW) in four frequency bands: α (8-12Hz), β (13-30), θ (4-7) and δ (1-3), under rest conditions. All these parameters were evaluated in three detection blocks: baseline, immediately after and after 30' from the end of the conditioning protocol. Real rPAS induced a long-lasting homotopic cortical excitability modulation, as indexed by MEP amplitude increase, that was paralleled by a long-lasting reduction of α/β-POW and by a widespread θ-δ-POW modulation. rPAS applied over the sensory-motor cortex induced an LTP-like plasticity, as indexed by a robust reduction in the α/β POW positively correlated with the MEP amplitude increase. rPAS25ms may be a useful tool for motor neurorehabilitation promoting a sensory-motor coupling within β oscillations.

P 182. Normal lateral inhibition mechanism during sensory-motor plasticity in dystonia

Objective To explore if sensory information is processed and integrated during sensory-motor plasticity phenomena by using lateral inhibition mechanisms in normal humans and in patients with dystonia. Background Several evidence suggest that lateral inhibition is a system within sensory-motor cortex operating during the acquisition of new motor tasks in order to select the appropriate muscle sequence to be stored within the final motor engram. This mechanism is thought to be lost in dystonia and this should explain the development of redundant motor memories which could culminate in overflow phenomena and overt dystonia. Methods We have used transcranial magnetic stimulation to explore lateral inhibition during sensory-motor plasticity in 12 dystonic patients (7 focal hand dystonia, 5 cranial dystonia) and in 8 healthy subjects. In particular we looked at motor evoked potential (MEP) facilitation, in the abductor pollicis brevis (APB) and abductor digiti minimi (ADM), obtained after 5 Hz repetitive paired associative stimulation after median (PAS M), ulnar nerve stimulation (PAS U) and median + ulnar nerve (PAS MU) stimulation. In this way we evaluated the ratio MU/M + Ux100 (lateral inhibition index). Moreover, we evaluated the lateral inhibition index (Li index). This parameter is easily obtained by using the following formula: ratio MU/(M + U) x 100. MU is the MEP facilitation measured after PAS with simultaneous stimulation of median and ulnar and M + U is the amount of MEP facilitation, after PAS, induced from stimulation of the individual nerves. Results Our data confirmed that patients with dystonia had two main abnormalities: first the amount of facilitation was larger than normal subjects; second and more important the spatial specificity was lost. A three-factorial ANOVA demonstrated a significant time × group × conditioning interaction ( F = 7.9; p = 0.005). Lateral inhibition index was similar (about 50%) in healthy subjects and dystonic patients. Conclusions These data suggest that lateral inhibition is normal in dystonia during sensory-motor plasticity. Another mechanism could contribute to the formation of motor memories with redundant information, which could culminate in overt dystonia.

Rapid‐rate paired associative stimulation of the median nerve and motor cortex can produce long‐lasting changes in motor cortical excitability in humans

Repetitive transcranial magnetic stimulation (rTMS) or repetitive electrical peripheral nerve stimulation (rENS) can induce changes in the excitability of the human motor cortex (M1) that is often short-lasting and variable, and occurs only after prolonged periods of stimulation. In 10 healthy volunteers, we used a new repetitive paired associative stimulation (rPAS) protocol to facilitate and prolong the effects of rENS and rTMS on cortical excitability. Sub-motor threshold 5 Hz rENS of the right median nerve was synchronized with submotor threshold 5 Hz rTMS of the left M1 at a constant interval for 2 min. The interstimulus interval (ISI) between the peripheral stimulus and the transcranial stimulation was set at 10 ms (5 Hz rPAS10ms) or 25 ms (5 Hz rPAS25ms). TMS was given over the hot spot of the right abductor pollicis brevis (APB) muscle. Before and after rPAS, we measured the amplitude of the unconditioned motor evoked potential (MEP), intracortical inhibition (ICI) and facilitation (ICF), short- and long-latency afferent inhibition (SAI and LAI) in the conditioned M1. The 5 Hz rPAS25ms protocol but not the 5 Hz rPAS10ms protocol caused a somatotopically specific increase in mean MEP amplitudes in the relaxed APB muscle. The 5 Hz rPAS25ms protocol also led to a loss of SAI, but there was no correlation between individual changes in SAI and corticospinal excitability. These after-effects were still present 6 h after 5 Hz rPAS25ms. There was no consistent effect on ICI, ICF and LAI. The 5 Hz rENS and 5 Hz rTMS protocols failed to induce any change in corticospinal excitability when given alone. These findings show that 2 min of 5 Hz rPAS25ms produce a long-lasting and somatotopically specific increase in corticospinal excitability, presumably by sensorimotor disinhibition.