The brain’s billions of neurons communicate with one another using electrical signals. Applying a magnetic field to a small area of the scalp can temporarily disrupt these signals by inducing small electrical currents in the brain tissue underneath. The currents interfere with the brain’s own electrical signals and temporarily disrupt the activity of the stimulated brain region.

This technique, which is known as transcranial magnetic stimulation, is often used to investigate the roles of specific brain regions. By examining what happens when a region is briefly taken ‘offline’, it is possible to deduce what that area normally does. Transcranial magnetic stimulation is also used to treat brain disorders ranging from epilepsy to schizophrenia without the need for surgery or drugs. But despite its widespread usage, little is known about how transcranial magnetic stimulation affects individual neurons.

Neurons are made up of a cell body, which has numerous short branches called dendrites, and a cable-like structure called the axon. Neurons signal to each other by releasing chemical messengers across junctions called synapses. The chemical signals are generally released from the axon of one neuron and bind to receptor proteins on a dendrite on another neuron to stimulate electrical activity in the receiving neuron.

Murphy et al. have now investigated how transcranial magnetic stimulation affects the activity of dendrites from neurons within the cortex of the rat brain. This revealed that the magnetic fields stimulate other neurons that inhibit the activity of dendrites from neurons within the deeper layers of the cortex. The inhibition process depends on a type of receptor protein in the dendrites called GABA_B receptors; blocking these receptors prevents transcranial magnetic stimulation from altering the activity of stimulated brain regions.

The processes occurring in these dendrites have been linked to cognitive function. The next challenge will be to integrate the non-invasive transcranial magnetic stimulation approach with cognitive tests in humans that can now manipulate dendritic activity to test their importance under various circumstances.

Transcranial magnetic stimulation (TMS) holds great promise as a non-invasive method that can be used to both enhance and impair cognitive abilities (Eldaief et al., 2013). As such, it has proved to be an important tool for addressing basic questions about brain function as well as for diagnostic and therapeutic purposes (Fregni and Pascual-Leone, 2007). Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief electric current through a magnetic coil. As a general rule, TMS affects the action of feedback projections (Juan and Walsh, 2003; Hung et al., 2005; Camprodon et al., 2010; Zanto et al., 2011) leading to a disruption in perception (Shimojo et al., 2001; Kammer et al., 2005). Due to this influence on higher order cognitive processing, TMS is not only useful for examining the interactions of different brain areas (Pascual-Leone and Walsh, 2001; Silvanto et al., 2005; Murd et al., 2012), but it has also been used as a therapeutic method to alleviate some of the symptoms of hemispatial neglect (Nyffeler et al., 2009), schizophrenia including auditory hallucinations (Giesel et al., 2012), pain, depression and epilepsy. Despite great interest (Mueller et al., 2014), the cellular influence of TMS has yet to be ascertained since the precise effects of TMS at the level of a single neuron are very difficult to gauge, particularly in humans.

The neural architecture of the brain means the neural processes which receive and transform most synaptic inputs, the dendrites, extend into the upper layers where TMS would be most effective. Since dendrites can shape synaptic input to be greater or less than their linear sum (Polsky et al., 2004; Losonczy and Magee, 2006; Larkum et al., 2009) thereby altering the firing properties of the neuron (Larkum et al., 1999), the active properties of dendrites have attracted attention and have been linked to cognitive processes and feature selectivity (Lavzin et al., 2012; Xu et al., 2012; Smith et al., 2013; Cichon and Gan, 2015). Furthermore, it has been suggested that active dendritic processing underlies a more general principle of cortical operation that facilitates parallel associations between different cortical regions and the thalamus (Larkum, 2013) which is controlled by dendritic inhibition (Palmer et al., 2012; Lovett-Barron and Losonczy, 2014). Establishing the validity of this hypothesis will have important ramifications for understanding brain function as a whole. TMS presents a most promising way to study the causal relationship between active dendritic properties and cognition but only if its effect on dendrites can be understood and ultimately controlled.

Using an optical fiber imaging approach, here we present a study examining the effect of TMS on sensory-evoked dendritic activity in layer 5 pyramidal neurons of the somatosensory cortex. We find that TMS suppresses dendritic Ca²⁺ activity evoked by tactile stimulation and that this suppression can be abolished by blocking GABA_B receptors and excitatory transmission in the upper layers of the cortex. We uncover the cellular mechanisms underlying TMS-evoked inhibition, demonstrating that TMS of the rat brain activates long-range fibers that leads to the activation of dendrite-targeting inhibitory neurons in the upper cortical layers which in-turn suppress dendritic Ca²⁺ activity. Since indirect brain stimulation shows immense promise in treating many neurological disorders, such as epilepsy (Berenyi et al., 2012), this study not only illustrates the cellular mechanisms underlying TMS but also highlights dendrites as potential targets for therapeutic approaches.

We recorded the Ca²⁺ activity in populations of layer 5 (L5) pyramidal neuron dendrites in the hindlimb somatosensory cortex of urethane anesthetized rats using a custom-made fiber optic 'periscope' in vivo (Murayama et al., 2007) oriented horizontally for use in tandem with a TMS coil (Figure 1A, Figure 1—figure supplement 1A). Pyramidal neurons located approximately 800 μm below the cortical surface were loaded with the Ca²⁺ indicator Oregon Green BAPTA1 AM (OGB1 AM; Figure 1A inset and see 'Materials and methods'). Using this approach, large dendritic Ca²⁺ responses to brief hindpaw stimulation (100 V, 1 ms) were reliably evoked after 70 min loading with OGB1 AM (Figure 1—figure supplement 1B). To investigate the effects of TMS on evoked cortical network activity, the TMS coil was positioned just above the craniotomy (Figure 1A) and a single brief TMS pulse was evoked together with the stimulation of the hindpaw (Figure 1B) greater than 70 min post loading with OGB1 AM. TMS caused a significant decrease in the hindpaw-evoked dendritic Ca²⁺ response when triggered 50 ms before hindpaw stimulation (Figure 1C and Figure 1—figure supplement 2A), both in the maximum amplitude (control, 7.3 ± 1.5 △F/F versus TMS, 5.0 ± 1.1 △F/F, n = 17, p<0.05) and integral (control, 4.3 ± 0.9 △F/F•s versus TMS, 2.4 ± 0.6 △F/F•s; n = 17; p<0.001, Figure 1D). Further, the size of the coil (Figure 1—figure supplement 2B) and the type of hindpaw stimulation (Figure 1—figure supplement 2C) did not influence the results, whereas the distance of the coil from the cortical region of interest influenced the effectiveness of the TMS inhibition on the dendritic sensory responses (Figure 1—figure supplement 3).

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Integral and amplitude of evoked calcium transient.

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What is the cause of this TMS-induced decrease in dendritic calcium activity? L5 pyramidal neuron dendrites have been previously shown to be strongly inhibited by the activation of post-synaptic GABA_B (Pérez-Garci et al., 2006; Chalifoux and Carter, 2011; Palmer et al., 2012) receptors. To test whether GABA_B receptors are predominantly causing the TMS-induced dendritic inhibition, the GABA_B antagonist CGP52432 was locally perfused into the recording region (Figure 2A) affecting up to 300 μm of the surrounding tissue (Figure 2—figure supplement 1). Blocking GABA_B receptors prevented the TMS-evoked decrease in the Ca²⁺ response to hindpaw stimulation in both the integral (control_cgp, 2.3 ± 0.5 △F/F•s versus TMS_cgp, 2.1 ± 0.5 △F/F•s; p=0.62) and maximum amplitude (control_cgp, 7.7 ± 2.8 △F/F versus TMS_cgp, 7.2 ± 1.9 △F/F; n = 7; p=0.66, Figure 2B). L5 dendrites have been shown to also be inhibited by the activation of GABA_A (Kim et al., 1995; Murayama et al., 2009) receptors. Although cortical application of Gabazine causes a six-fold increase in the sensory evoked dendritic response (Figure 2—figure supplement 2), block of GABA_A receptors also prevented the TMS-evoked decrease in Ca²⁺ response to hindpaw stimulation (HS amplitude, 130 ± 30% of control; n = 6; Figure 2—figure supplement 2). Taken together, the fact that blocking both GABA_A and GABA_B receptors abolished the dendritic effect of TMS s.

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To investigate the laminar profile of the influence of TMS on neuronal activity, the Ca²⁺ indicator OGB1-AM was injected at different cortical depths (L5, 800 μm; Layer 2/3, 300 μm; Layer 1, 100 μm) and the Ca²⁺ response to TMS alone was recorded. TMS itself did not directly activate L5 pyramidal neuron dendrites (Figure 3A; n = 4), contrasting greatly to the large TMS-evoked Ca²⁺ response in cells within layer 2/3 (L2/3; 3.0 ± 1.1 △F/F; n = 3; Figure 3B) and layer 1 (L1; 5.5 ± 2.1 △F/F; n = 12; Figure 3B). Importantly, the TMS-evoked Ca²⁺ response in these upper cortical layers was similar to the response evoked by physiological stimulation via hindpaw stimulation (L2/3, 3.5 ± 1.2 △F/F•s and L1, 6.4 ± 2 △F/F•s). The lack of a direct response to TMS in L5 pyramidal neuron dendrites implies that the inhibition of sensory evoked dendritic transients was mediated by the action of inhibitory neurons. Furthermore, the response to TMS in upper-layer neurons leaves open the possibility that local inhibitory neurons might be recruited by TMS either directly, via TMS-induced membrane activation or indirectly, via synaptic transmission.

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To test these possibilities, the Ca²⁺ response to hindpaw stimulation was recorded before (5.5 ± 3.3 △F/F•s) and after (3.2 ± 3.6 △F/F•s) blocking synaptic transmission by locally applying the AMPA antagonist CNQX to the upper cortical layers at the site of the recording (Figure 4). Under these conditions, CNQX prevented the inhibitory effect of TMS in L5 pyramidal neuron dendrites (n = 10; Figure 4A–C and Figure 4—figure supplement 1). Therefore, since blocking excitatory AMPA-mediated transmission prevented the TMS inhibitory effect, TMS-evoked inhibition in L5 pyramidal neuron dendrites must be of polysynaptic (indirect) origin. We next tested whether the TMS-evoked Ca²⁺ transient in L1 was also of synaptic origin as TMS influenced cell activity in the upper cortical layers (Figure 4) and therefore possibly provides the TMS-evoked inhibition of L5 dendrites. Indeed, TMS-evoked activity in L1 neurons was suppressed by CNQX application, significantly reducing the Ca²⁺ response amplitude by 53 ± 7% (n = 8; p<0.05; Figure 4D–F). Therefore, the TMS-evoked Ca²⁺ response in L1 neurons is of synaptic origin. Taken together, this data suggests that the inhibition of sensory-evoked L5 dendritic Ca²⁺ responses was primarily mediated by upper-layer inhibitory neurons driven to fire synaptically from neurons or axons recruited by TMS.

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Figure 5

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The results from this study demonstrate the subcellular effect of TMS on dendritic Ca²⁺ activity for the first time. TMS alone did not directly activate L5 pyramidal dendrites but instead activated axonal processes coursing through the upper layers and synapsing onto GABA_B-mediating interneurons in L1. A similar form of synaptic activation of interneurons leading to inhibition in L5 pyramidal neuron dendrites has been shown previously with activation of callosal input to the cortex (Palmer et al., 2012). This form of 'silent' inhibition involves the activation of inhibitory conductances which are not detectable at the soma except through their eventual influence on the generation of action potential output. These results therefore highlight an effect of single-pulse TMS on the cortical network, which involves the activation of a specific cortical microcircuit.

The action of TMS at the cellular and network levels is extremely complex and likely constitutes the activation of a range of different cell types leading to multiple effects (Rossi et al., 2009; Siebner et al., 2009). A recent combined experimental and theoretical investigation of the biophysical underpinnings of TMS suggested that the generation of a magnetic field is most likely to evoke firing in cell bodies as opposed to dendrites or axons (Pashut et al., 2014). This is consistent with our finding that no dendritic activity was observed with TMS stimulation alone indicating there was no direct activation of the pyramidal cell dendrites and contrasted with the signals found in both L1 and L2/3 neurons following a TMS pulse. It is also consistent with the activation of neurogliaform interneurons in L1 that target the dendrites of L5 pyramidal neurons and suppress Ca²⁺ activity (Ziemann, 2010; Terao and Ugawa, 2002; Pashut et al., 2011; Tamás et al., 2003; Oláh et al., 2007; Oláh et al., 2009). This form of dendritic inhibition arises from the metabotropic inactivation of L-type (Ca_v1) channels in the apical dendrite that underlie the dendritic Ca²⁺ activity (Wozny and Williams, 2011) and can last several hundred milliseconds (Pérez-Garci et al., 2006). The suppression of Ca²⁺ channels can significantly reduce the action potential firing of the pyramidal neuron even when the driving input to the pyramidal neuron is not predominantly dendritic (Palmer et al., 2012). The long time-scale of this form of inhibition (~500 ms) raises interesting consequences for the participation of pyramidal neurons in the cortical network. The similarity of some of the effects of TMS to interhemispheric inhibition has been noted previously in human studies (Jiang et al., 2013; Lee, 2014; Pérez-Garci et al., 2013; Ferbert et al., 1992) including its mediation via GABA_B receptor-activation (Ferbert et al., 1992; Kobayashi et al., 2003), although these investigations could not examine the cellular mechanisms.

For this study, we used a large coil typically used in humans and a smaller (25 mm) coil designed for use in rodents. The effect on dendritic Ca²⁺ was the same in both cases. Clearly, the use of TMS coils with rats where the magnetic field generated is comparable to the size of the rat brain itself raises the possibility that the effects in humans may differ. However, the cortical feedback fibers which synapse onto the tuft dendrites of pyramidal neurons are located in the part of the cortex closest to the magnetic coil (i.e. L1) in both rats and humans (Larkum et al., 1999; Larkum, 2013), suggesting there would be overlap with respect to the influence of TMS.

The aim of this study was to examine the effect of TMS on dendritic activity in L5 neocortical neurons rather than a general study on the overall effects of TMS at the cellular level. We were interested in this, in particular, because we have previously hypothesized that cell assemblies over different cortical regions might be associated through the activation of dendritic Ca²⁺ spikes in these neurons (Larkum, 2013). According to this hypothesis, dendritic activity in these neurons is a marker of important cognitive processes. The finding that TMS targets this mechanism is therefore highly relevant to the rationale of the study and may be instructive in understanding current applications of TMS. For instance, TMS has been used to alleviate some of the symptoms of hemispatial neglect (Nyffeler et al., 2009) and auditory hallucinations (Giesel et al., 2012) via unknown inhibitory processes.

In conclusion, the results presented here indicate that the inhibitory actions of TMS is due to the recruitment of upper cortical layer interneurons mediating both GABA_A and GABA_B-receptor-activated inhibition in the dendrites of pyramidal neurons. This may have implications for the interpretation of results in humans using TMS as a form of 'virtual lesion' (Lee et al., 2007).

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Author details

1. Sean C Murphy

   1. Neurocure Cluster of Excellence, Humboldt University, Berlin, Germany
   2. Physiologisches Institut, Universität Bern, Bern, Switzerland
   3. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia

   Contribution

   SCM, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   sean.murphy@florey.edu.au

   Competing interests

   The authors declare that no competing interests exist.

2. Lucy M Palmer

   Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia

   Contribution

   LMP, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Thomas Nyffeler

   1. Neurology and Neurorehabilitation Centre, Luzerner Kantonsspital, Luzern, Switzerland
   2. Departments of Neurology, University Hospital, Inselspital, University of Bern, Bern, Switzerland
   3. Department of Clinical Research, University Hospital, Inselspital, University of Bern, Bern, Switzerland

   Contribution

   TN, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

4. René M Müri

   1. Departments of Neurology, University Hospital, Inselspital, University of Bern, Bern, Switzerland
   2. Department of Clinical Research, University Hospital, Inselspital, University of Bern, Bern, Switzerland

   Contribution

   RMM, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

5. Matthew E Larkum

   1. Neurocure Cluster of Excellence, Humboldt University, Berlin, Germany
   2. Physiologisches Institut, Universität Bern, Bern, Switzerland

   Contribution

   MEL, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   matthew.larkum@gmail.com

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-9799-2656

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