Continuous and intermittent transcranial magnetic theta burst stimulation modify tactile learning performance and cortical protein expression in the rat differently

Abstract

Repetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability in a stimulus-frequency-dependent manner. Two kinds of theta burst stimulation (TBS) [intermittent TBS (iTBS) and continuous TBS (cTBS)] modulate human cortical excitability differently, with iTBS increasing it and cTBS decreasing it. In rats, we recently showed that this is accompanied by changes in the cortical expression of proteins related to the activity of inhibitory neurons. Expression levels of the calcium-binding protein parvalbumin (PV) and of the 67-kDa isoform of glutamic acid decarboxylase (GAD67) were strongly reduced following iTBS, but not cTBS, whereas both increased expression of the 65-kDa isoform of glutamic acid decarboxylase. In the present study, to investigate possible functional consequences, we applied iTBS and cTBS to rats learning a tactile discrimination task. Conscious rats received either verum or sham rTMS prior to the task. Finally, to investigate how rTMS and learning effects interact, protein expression was determined for cortical areas directly involved in the task and for those either not, or indirectly, involved. We found that iTBS, but not cTBS, improved learning and strongly reduced cortical PV and GAD67 expression. However, the combination of learning and iTBS prevented this effect in those cortical areas involved in the task, but not in unrelated areas. We conclude that the improved learning found following iTBS is a result of the interaction of two effects, possibly in a homeostatic manner: a general weakening of inhibition mediated by the fast-spiking interneurons, and re-established activity in those neurons specifically involved in the learning task, leading to enhanced contrast between learning-induced and background activity.

Assessment and modulation of cortical inhibition using transcranial magnetic stimulation

“…Indeed, using organotypic brain slice cultures, it was shown that repetitive magnetic stimulation induces structural, functional and molecular changes of excitatory synapses, corresponding long-term potentiation and thus associative excitatory synaptic plasticity (Vlachos et al, 2012). Consistent with these findings it was shown that rTMS promotes learning in animal experiments (Mix et al, 2010) and motor rehabilitation following ischemic stroke in humans (Brodie et al, 2014;Volz et al, 2016). However, it remains unclear how complex brain function in healthy subjects and in patients is improved by activity-dependent modifications of neuronal networks, caused by several hundred of exogenous magnetic pulses.…”

“…Another electrophysiological study in the primary somatosensory cortex of rats further demonstrates that a decrease of PV expression, induced by iTBSrTMS, is accompanied by an increase of sensory responses (Thimm and Funke, 2015). This observation supports the notion that rTMS-induced disinhibition could underlie the previously described improvement in learning behaviour (Mix et al, 2010). Albeit, studies of interneuronal activity-and plasticity-markers are not directly demonstrating rTMS-induced functional changes of inhibitory synapses.…”

Theta-Burst Transcranial Magnetic Stimulation Alters Cortical Inhibition

“…However, a contribution of FS cell activity to enhanced MUA cannot be excluded. Although reduced PV expression following iTBS indicates reduced activation of FS cells in general (see Discussion), repeated somesthetic stimulation may increase activity in a subset of FS cells according to the afferent drive, similarly as we propose for the combination of learning with rTMS (Mix et al, 2010). SEPs were elicited by electrically stimulating one toe of the rat's hindpaw by a triple-pulse protocol of 35 ms interpulse interval.…”

Untersuchung und Modulation kortikaler Inhibition mittels transkranieller Magnetstimulation

“…Tatsächlich gelang es in organotypischen Hirnschnittkulturen nachzuweisen, dass repetitive Magnetstimulation strukturelle, funktionelle und molekulare Veränderungen an erregenden Synapsen induziert, die einer Langzeitpotenzierung und somit assoziativer synaptischer Plastizität entsprechen (Vlachos et al 2012). Scheinbar konsistent mit diesen Befunden zeigte sich, dass rTMS das Lernverhalten im Tierexperiment verbessert (Mix et al 2010) und Bewegungslernen nach einem Schlaganfall beim Menschen fördern kann (Brodie et al 2014;Volz et al, 2016 …”

“…Ähnliche Zusammenhänge zwischen PV-Expression und der Balance erregender zu hemmenden synaptischen Eingängen wurden auch im Hippokampus von Mäusen beschrieben (Donato et al 2013). Eine elektrophysiologische Studie im primären somatosensorischen Kortex der Ratte zeigte dann auch, dass eine durch iTBS-rTMS-induzierte Abnahme der PV-Expression von einer Steigerung sensorischer Antworten begleitet ist (Thimm und Funke 2015), die ursächlich für die zuvor beschriebene Steigerung der Lernleistung sein könnte (Mix et al 2010), sodass diese Studien das Model der rTMS-induzierten Disinhibition stützen. Allerdings lassen Untersuchungen inhibitorischer Aktivitäts-und Plastizitätsmarker nur indirekte Aussagen über rTMS-induzierte funktionelle Veränderungen inhibitorischer Synapsen zu.…”