A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy Controls
<b>Background/Objectives</b>: Plasticity deficits play a key role in the pathophysiology of various psychiatric and neurological disorders. Paired associative stimulation (PAS) leverages Hebbian principles to induce synaptic plasticity in the human brain. By repeatedly pairing (1) the pe...
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2025-04-01
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| author | Kenan Hodzic Magnus Thordstein Joakim Strandberg Elisabet Jerlhag Caroline E. Wass |
| author_facet | Kenan Hodzic Magnus Thordstein Joakim Strandberg Elisabet Jerlhag Caroline E. Wass |
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| description | <b>Background/Objectives</b>: Plasticity deficits play a key role in the pathophysiology of various psychiatric and neurological disorders. Paired associative stimulation (PAS) leverages Hebbian principles to induce synaptic plasticity in the human brain. By repeatedly pairing (1) the peripheral nerve stimulation of the median nerve with (2) transcranial magnetic stimulation over the primary motor cortex (M1) at different inter-stimulus intervals (25 ms; PAS-25, or 10 ms; PAS-10), corticospinal excitability can be increased (PAS-25, mimicking long-term potentiation (LTP)) or decreased (PAS-10, mimicking long-term depression (LTD)). However, variations in the number of pairings and inter-pair intervals lack consensus. The aim of the study was to evaluate four different PAS paradigms, i.e., PAS-10 and PAS-25 with both 180 versus 225 pairings each, to establish the most reliable PAS protocols for LTP- and LTD-like cortical changes. <b>Methods</b>: In a randomized, double-blind, crossover study, 14 healthy participants underwent PAS-10 and PAS-25 with 180 and 225 pairings. Excitability was assessed by quantifying the EMG response amplitude of a hand muscle to a single stimulus. <b>Results</b>: PAS-25 with 225 pairings produced a robust enhancement of corticospinal excitability, while PAS-25 with 180 pairings was less effective. Surprisingly, PAS-10 with both 180 and 225 pairings also increased excitability. <b>Conclusions</b>: While all four PAS paradigms enhanced M1 excitability, PAS-25 with 225 pairings induced the strongest group-level effects and was most time-efficient. Significant individual variability of PAS responses suggests that optimizing PAS parameters, including pairing number and interstimulus intervals, may be necessary for personalized approaches. |
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| spelling | doaj-art-1ebe3547bf43435cba1d3249acc7e7ee2025-08-20T02:33:40ZengMDPI AGBrain Sciences2076-34252025-04-0115546110.3390/brainsci15050461A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy ControlsKenan Hodzic0Magnus Thordstein1Joakim Strandberg2Elisabet Jerlhag3Caroline E. Wass4Division of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, SwedenDepartment of Biomedicine and Clinical Sciences, Linköping University, 581 83 Linköping, SwedenDepartment for Clinical Neurophysiology, Sahlgrenska University Hospital, 413 45 Gothenburg, SwedenDivision of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, SwedenDivision of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden<b>Background/Objectives</b>: Plasticity deficits play a key role in the pathophysiology of various psychiatric and neurological disorders. Paired associative stimulation (PAS) leverages Hebbian principles to induce synaptic plasticity in the human brain. By repeatedly pairing (1) the peripheral nerve stimulation of the median nerve with (2) transcranial magnetic stimulation over the primary motor cortex (M1) at different inter-stimulus intervals (25 ms; PAS-25, or 10 ms; PAS-10), corticospinal excitability can be increased (PAS-25, mimicking long-term potentiation (LTP)) or decreased (PAS-10, mimicking long-term depression (LTD)). However, variations in the number of pairings and inter-pair intervals lack consensus. The aim of the study was to evaluate four different PAS paradigms, i.e., PAS-10 and PAS-25 with both 180 versus 225 pairings each, to establish the most reliable PAS protocols for LTP- and LTD-like cortical changes. <b>Methods</b>: In a randomized, double-blind, crossover study, 14 healthy participants underwent PAS-10 and PAS-25 with 180 and 225 pairings. Excitability was assessed by quantifying the EMG response amplitude of a hand muscle to a single stimulus. <b>Results</b>: PAS-25 with 225 pairings produced a robust enhancement of corticospinal excitability, while PAS-25 with 180 pairings was less effective. Surprisingly, PAS-10 with both 180 and 225 pairings also increased excitability. <b>Conclusions</b>: While all four PAS paradigms enhanced M1 excitability, PAS-25 with 225 pairings induced the strongest group-level effects and was most time-efficient. Significant individual variability of PAS responses suggests that optimizing PAS parameters, including pairing number and interstimulus intervals, may be necessary for personalized approaches.https://www.mdpi.com/2076-3425/15/5/461transcranial magnetic stimulationpaired associative stimulationplasticityperipheral nerve stimulationneurophysiologypsychiatry |
| spellingShingle | Kenan Hodzic Magnus Thordstein Joakim Strandberg Elisabet Jerlhag Caroline E. Wass A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy Controls Brain Sciences transcranial magnetic stimulation paired associative stimulation plasticity peripheral nerve stimulation neurophysiology psychiatry |
| title | A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy Controls |
| title_full | A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy Controls |
| title_fullStr | A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy Controls |
| title_full_unstemmed | A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy Controls |
| title_short | A Methodological Evaluation of Four Different Paired Associative Stimulation Paradigms in Healthy Controls |
| title_sort | methodological evaluation of four different paired associative stimulation paradigms in healthy controls |
| topic | transcranial magnetic stimulation paired associative stimulation plasticity peripheral nerve stimulation neurophysiology psychiatry |
| url | https://www.mdpi.com/2076-3425/15/5/461 |
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