Modulation of cortical inhibition by rTMS - findings obtained from animal models

Abstract

Transcranial magnetic stimulation (TMS) has become a popular method to non-invasively stimulate the human brain. The opportunity to modify cortical excitability with repetitive stimulation (rTMS) has especially gained interest for its therapeutic potential. However, details of the cellular mechanisms of the effects of rTMS are scarce. Currently favoured are long-term changes in the efficiency of excitatory synaptic transmission, with low-frequency rTMS depressing it, but high-frequency rTMS augmenting. Only recently has modulation of cortical inhibition been considered as an alternative way to explain lasting changes in cortical excitability induced by rTMS. Adequate animal models help to highlight stimulation-induced changes in cellular processes which are not assessable in human rTMS studies. In this review article, we summarize findings obtained with our rat models which indicate that distinct inhibitory cell classes, like the fast-spiking cells characterized by parvalbumin expression, are most sensitive to certain stimulation protocols, e.g. intermittent theta burst stimulation. We discuss how our findings can support the recently suggested models of gating and homeostatic plasticity as possible mechanisms of rTMS-induced changes in cortical excitability.

Figure 1. rTMS-induced changes in the cortical expression of PV and CB

Theta-burst stimulation (TBS) of the rat brain affected the expression of the calcium-binding proteins parvalbumin (PV) and calbindin-D28k (CB). Intermittent TBS (iTBS, Huang et al. 2005) strongly reduced the number of cortical cells expressing PV both acutely (after about 2 h, Aa and b) and subchronically (1–7 days, Ac), while continuous TBS (cTBS, Huang et al. 2005) caused a transient (acute) reduction in the number of CB-expressing interneurons (Ba–c). Cortical slices in Aa and Ba were taken from rat frontal cortex. Scale bar corresponds to 100 μm. ROI: region of interest. *P < 0.05 compared to control (sham-treatment) condition (Tukey's post hoc test). Figures and diagrams partly taken and rearranged from Benali et al. (2011), with permission of the Society for Neuroscience.

Figure 2. iTBS and cTBS induced changes in EEG gamma power and spontaneous multi-unit spiking activity (MUA)

iTBS but not cTBS caused a lasting increase in the gamma power of the EEG recorded from frontal cortical areas in the anesthetized rat (Aa and b), which was accompanied by changes in spontaneous spiking activity recorded from layer IV of rat somatosensory cortex. B, increase in the rate of MUA following iTBS (not explicitly shown here, see Benali et al. 2011) was characterized by a stronger increase in short inter-spike intervals (1–10 and 11–25 ms), while longer intervals (>25 ms) were less changed. The left-most diagram shows a typical, Poisson-like, inter-spike interval distribution of cortical MUA. Results diagrams taken and rearranged from Benali et al. (2011), with permission of the Society for Neuroscience.

Figure 3. iTBS and cTBS induced changes in the amplitude of somatosensory evoked potentials (SEP)

SEPs were elicited with a triple-pulse protocol of electrical stimulation from the toe of a rat hindpaw with inter-pulse intervals of 35 ms corresponding to about 30 Hz (Aa). Typically, the second response shows strong suppression, which is quantified by the ratio of the second to the first SEP amplitude, named paired-pulse afferent inhibition (PPAI, Aa). iTBS increased the first and further reduced the second response, leading to stronger PPAI (Ba), while cTBS increased all response components, leaving PPAI unchanged (Ca). For the relationship of these effects to distinct inhibitory cortical systems (Ab, Bb and Cb), see discussion of main text. For results of A–C refer to Benali et al. 2011. Figures Ba and Ca modified from Benali et al. (2011), with permission of the Society for Neuroscience. D, results of paired-pulse TMS of rat brain showing reduced MEP size around 50 ms intervals supposed to be related to strong intracortical inhibition (modified with permission of the American Physiological Society from Vahabzadeh-Hagh et al. 2011).

Figure 4. iTBS but not cTBS improved rat learning performance in relation to changes in cortical protein expression

Rats were trained to distinguish rewarded from non-rewarded arms of a radial maze by tactile cues sensed via the whiskers of the rat (Aa). Other sensory cues, like visual, olfactory and spatial, were prevented (for details see Mix et al. 2010). Rats received iTBS, cTBS or sham-stimulation prior to each training block of 8 trials each. Intermittent TBS, but not cTBS, improved learning by reducing the number of trials needed by the rats to reach the threshold criterion of 75% correct choices (Ab and c). Subsequent to the learning experiments, rats were perfused either directly after the training when just reaching the threshold criterion (early effects, Ca) or 1 day after the last training block when reaching stable learning performance (late effects, Ca). Here, analysis of cortical protein expression is shown for the barrel cortex involved in learning task and for the visual cortex not involved (Ba). Eight groups of rats received different rTMS protocols and were either trained or not (learner, non-learner, Bb). Strong early (Cb) and late (Cc) changes in protein expression (c-Fos, GAD65, PV) were evident for iTBS treatment and learning but less for cTBS. For the relationship between changes in protein expression and learning performance, see discussion in the main text. Asterisks on top of bars indicate statistically significant differences from sham controls (yellow left-most bar) with *P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA + Fisher's LSD). Results according to and figures taken and modified from Mix et al. (2010), with permission of Wiley-Blackwell.

Figure 5. Modell of iTBS-related improvement of learning performance according to changes in the activity of PV+ FS interneurons

Aa, high-frequency activation of cortical axons by iTBS-rTMS will not only result in activation of excitatory neurons (pyramidal cells – green), but also of the excitatory synapses on inhibitory interneurons (here PV+ FS cells – red) and, secondary, their GABAergic synapses (yellow arrows indicate changes in electrical activity). Bb, as a consequence, these synapses are depressed (long-term depression, LTD) leading to hypoactivation of the interneurons and disinhibition of the pyramidal cell. As a gating process, this disinhibition may promote long-term potentiation (LTP) of active sensory inputs due to enhanced postsynaptic activity. Ab, the Bienenstock–Cooper–Munro model (BCM, Bienenstock et al. 1982) postulates that synaptic plasticity (LTD or LTP) is governed by a dynamic threshold (red dot) which adapts to the global mean rate of postsynaptic activation. In a balanced cell, this threshold is close to this activity level (vertical dotted line). Synaptic plasticity can be induced either if postsynaptic activity level at a particular synapse is significantly deviating from this threshold, as would be the case with gating by disinhibition (Bb), or if the plasticity threshold has been shifted by the history of postsynaptic activity (Cb). Postsynaptic hypoactivity induced via previous LTD at the excitatory synapses on PV+ cells would shift the plasticity threshold to a lower level of postsynaptic activity and would favour induction of LTP at sensory active synapses (Da and Cb/Db) while the inactive synapses remain depressed (Ca). For further explanations regarding the changes in PV expression and GABA release at either active or inactive circuits, see discussion in the main text.