Stoney vs. Histed: Quantifying the spatial effects of intracortical microstimulation

BackgroundIntracortical microstimulation (ICMS) is used to map neural circuits and restore lost sensory modalities such as vision, hearing, and somatosensation. The spatial effects of ICMS remain controversial: Stoney and colleagues proposed that the volume of somatic activation increased with stimulation intensity, while Histed et al., suggested activation density, but not somatic activation volume, increases with stimulation intensity.ObjectiveWe used computational modeling to quantify the spatial effects of ICMS intensity and unify the apparently paradoxical findings of Histed and Stoney.MethodsWe implemented a biophysically-based computational model of a cortical column comprising neurons with realistic morphology and representative synapses. We quantified the spatial effects of single pulses and short trains of ICMS, including the volume of activated neurons and the density of activated neurons as a function of stimulation intensity.ResultsAt all amplitudes, the dominant mode of somatic activation was by antidromic propagation to the soma following axonal activation, rather than via transsynaptic activation. There were no occurrences of direct activation of somata or dendrites. The volume over which antidromic action potentials were initiated grew with stimulation amplitude, while the volume of somatic activation increased marginally. However, the density of somatic activation within the activated volume increased with stimulation amplitude.ConclusionsThe results resolve the apparent paradox between Stoney and Histed's results by demonstrating that the volume over which action potentials are initiated grows with ICMS amplitude, consistent with Stoney. However, the volume occupied by the activated somata remains approximately constant, while the density of activated neurons within that volume increase, consistent with Histed.     

Microstimulation-evoked neural responses in visual cortex are depth dependent

BackgroundCortical visual prostheses often use penetrating electrode arrays to deliver microstimulation to the visual cortex. To optimize electrode placement within the cortex, the neural responses to microstimulation at different cortical depths must first be understood.ObjectiveWe investigated how the neural responses evoked by microstimulation in cortex varied with cortical depth, of both stimulation and response.MethodsA 32-channel single shank electrode array was inserted into the primary visual cortex of anaesthetized rats, such that it spanned all cortical layers. Microstimulation with currents up to 14 μA (single biphasic pulse, 200 μs per phase) was applied at depths spanning 1600 μm, while simultaneously recording neural activity on all channels within a response window 2.25–11 ms.ResultsStimulation elicited elevated neuronal firing rates at all depths of cortex. Compared to deep sites, superficial stimulation sites responded with higher firing rates at a given current and had lower thresholds. The laminar spread of evoked activity across cortical depth depended on stimulation depth, in line with anatomical models.ConclusionStimulation in the superficial layers of visual cortex evokes local neural activity with the lowest thresholds, and stimulation in the deep layers evoked the most activity across the cortical column. In conjunction with perceptual reports, these data suggest that the optimal electrode placement for cortical microstimulation prostheses has electrodes positioned in layers 2/3, and at the top of layer 5.     

PET-Based Confirmation of Orientation Sensitivity of TMS-Induced Cortical Activation in Humans

BackgroundCurrently, it is difficult to predict precise regions of cortical activation in response to transcranial magnetic stimulation (TMS). Most analytical approaches focus on applied magnetic field strength in the target region as the primary factor, placing activation on the gyral crowns. However, imaging studies support M1 targets being typically located in the sulcal banks.Objective/hypothesisTo more thoroughly investigate this inconsistency, we sought to determine whether neocortical surface orientation was a critical determinant of regional activation.MethodsMR images were used to construct cortical and scalp surfaces for 18 subjects. The angle (θ) between the cortical surface normal and its nearest scalp normal for ～50,000 cortical points per subject was used to quantify cortical location (i.e., gyral vs. sulcal). TMS-induced activations of primary motor cortex (M1) were compared to brain activations recorded during a finger-tapping task using concurrent positron emission tomographic (PET) imaging.ResultsBrain activations were primarily sulcal for both the TMS and task activations (P < 0.001 for both) compared to the overall cortical surface orientation. Also, the location of maximal blood flow in response to either TMS or finger-tapping correlated well using the cortical surface orientation angle or distance to scalp (P < 0.001 for both) as criteria for comparison between different neocortical activation modalities.ConclusionThis study provides further evidence that a major factor in cortical activation using TMS is the orientation of the cortical surface with respect to the induced electric field. The results show that, despite the gyral crown of the cortex being subjected to a larger magnetic field magnitude, the sulcal bank of M1 had larger cerebral blood flow (CBF) responses during TMS.     

Triad-conditioning Transcranial Magnetic Stimulation in Parkinson's Disease

BackgroundTranscranial magnetic stimulation (TMS) has been used to reveal excitability changes of the primary motor cortex (M1) in Parkinson's disease (PD). Abnormal rhythmic neural activities are considered to play pathophysiological roles in the motor symptoms of PD. The cortical responses to external rhythmic stimulation have not been studied in PD. We recently reported a new method of triad-conditioning TMS to detect the excitability changes after rhythmic conditioning stimuli, which induce facilitation by 40-Hz stimulation in healthy volunteers.ObjectiveWe applied a triad-conditioning TMS to PD patients to reveal the motor cortical response characteristics to rhythmic TMS.MethodsThe subjects included 13 PD patients and 14 healthy volunteers. Three conditioning stimuli over M1 at an intensity of 110% active motor threshold preceded the test TMS at various inter-stimulus intervals corresponding to 10–200 Hz.ResultsThe triad-conditioning TMS at 40 Hz induced no MEP enhancement in PD patients in either the On or Off state, in contrast to the facilitation observed in the normal subjects. Triad-conditioning TMS at 20–33 Hz in the beta frequency elicited significant MEP suppression in PD patients. The amount of suppression at 20 Hz positively correlated with the UPDRS III score.ConclusionWe observed abnormal M1 responses to rhythmic TMS in PD. The suppression induced by beta frequency stimulation and no facilitation by 40-Hz stimulation may be related to abnormal beta and gamma band activities within the cortical-basal ganglia network in PD patients. The motor cortical response to rhythmic TMS may be an additional method to detect physiological changes in humans.     

A Model of TMS-induced I-waves in Motor Cortex

BackgroundTranscranial magnetic stimulation (TMS) allows to manipulate neural activity non-invasively, and much research is trying to exploit this ability in clinical and basic research settings. In a standard TMS paradigm, single-pulse stimulation over motor cortex produces repetitive responses in descending motor pathways called I-waves. However, the details of how TMS induces neural activity patterns in cortical circuits to produce these responses remain poorly understood. According to a traditional view, I-waves are due to repetitive synaptic inputs to pyramidal neurons in layer 5 (L5) of motor cortex, but the potential origin of such repetitive inputs is unclear.Objective/hypothesisHere we aim to test the plausibility of an alternative mechanism behind D- and I-wave generation through computational modeling. This mechanism relies on the broad distribution of conduction delays of synaptic inputs arriving at different parts of L5 cells' dendritic trees and their spike generation mechanism.MethodsOur model consists of a detailed L5 pyramidal cell and a population of layer 2 and 3 (L2/3) neurons projecting onto it with synapses exhibiting short-term depression. I-waves are simulated as superpositions of spike trains from a large population of L5 cells.ResultsOur model successfully reproduces all basic characteristics of I-waves observed in epidural responses during in vivo recordings of conscious humans. In addition, it shows how the complex morphology of L5 neurons might play an important role in the generation of I-waves. In the model, later I-waves are formed due to inputs to distal synapses, while earlier ones are driven by synapses closer to the soma. Finally, the model offers an explanation for the inhibition and facilitation effects in paired-pulse stimulation protocols.ConclusionsIn contrast to previous models, which required either neural oscillators or chains of inhibitory interneurons acting upon L5 cells, our model is fully feed-forward without lateral connections or loops. It parsimoniously explains findings from a range of experiments and should be considered as a viable alternative explanation of the generating mechanism of I-waves.     

Targeting of White Matter Tracts with Transcranial Magnetic Stimulation

BackgroundTMS activations of white matter depend not only on the distance from the coil, but also on the orientation of the axons relative to the TMS-induced electric field, and especially on axonal bends that create strong local field gradient maxima. Therefore, tractography contains potentially useful information for TMS targeting.Objective/methodsHere, we utilized 1-mm resolution diffusion and structural T1-weighted MRI to construct large-scale tractography models, and localized TMS white matter activations in motor cortex using electromagnetic forward modeling in a boundary element model (BEM).ResultsAs expected, in sulcal walls, pyramidal cell axonal bends created preferred sites of activation that were not found in gyral crowns. The model agreed with the well-known coil orientation sensitivity of motor cortex, and also suggested unexpected activation distributions emerging from the E-field and tract configurations. We further propose a novel method for computing the optimal coil location and orientation to maximally stimulate a pre-determined axonal bundle.ConclusionsDiffusion MRI tractography with electromagnetic modeling may improve spatial specificity and efficacy of TMS.     

Activation of single cells in cat visual cortex by electrical stimulation of the cortical surface

Extracellular recordings were made from the striate cortex of the cat to determine the latency and threshold characteristics of physiologically identified neurons activated by electrical stimuli delivered to the cortical surface. Using parameters of stimulation analogous to those used on conscious man for eliciting visual phosphenes, we made the following observations: (i) 62.5% of a sample population of striate neurons (N = 192) were successfully activated by cortical surface stimulation. The range of distances between the stimulation site and the population of cells studied was 1 to 2 mm. Whereas more than two-thirds of the cortical neurons with simple or complex receptive fields responded to surface stimulation, less than one-half the neuronal population identified as geniculocortical fibers could be successfully activated by analogous surface stimulation. (ii) When single, brief pulses of constant current were delivered to the stimulating electrode, the mean latency of the neuronal response tended to be shortest for geniculate fibers, and simple cells tended to fire earlier on the average than complex cells. (iii) When the mean threshold current required for neuronal activation was measured, thresholds tended to be lowest for geniculocortical fibers and simple cells often required lower activation currents than complex cells. (iv) Evidence that electrical stimulation of the pia-arachnoid surface of the visual cortex can activate cortical neurons via intervening synaptic pathways was obtained. Supporting data were derived from measured latency characteristics and intracellular observations.     

Lateralization of forelimb motor evoked potentials by transcranial magnetic stimulation in rats

ObjectivesTo approximate methods for human transcranial magnetic stimulation (TMS) in rats, we tested whether lateralized cortical stimulation resulting in selective activation of one forelimb contralateral to the site of stimulation could be achieved by TMS in the rat.MethodsMotor evoked potentials (MEP) were recorded from the brachioradialis muscle bilaterally in adult male anesthetized rats (n = 13). A figure-of-eight TMS coil was positioned lateral to midline. TMS intensity was increased stepwise from subthreshold intensities to maximal machine output in order to generate input–output curves and to determine the motor threshold (MT) for brachioradialis activation.ResultsIn 100% of the animals, selective activation of the contralateral brachioradialis, in the absence of ipsilateral brachioradialis activation was achieved, and the ipsilateral brachioradialis was activated only at TMS intensities exceeding contralateral forelimb MT. With increasing TMS intensity, the amplitudes of both the ipsilateral and contralateral signals increased in proportion to TMS strength. However, the input–output curves for the contralateral and ipsilateral brachioradialis were significantly different (p < 0.001) such that amplitude of the ipsilateral MEP was reliably lower than the contralateral signal.ConclusionsWe demonstrate that lateralized TMS leading to asymmetric brachioradialis activation is feasible with conventional TMS equipment in anesthetized rats.SignificanceThese data show that TMS can be used to assess the unilateral excitability of the forelimb descending motor pathway in the rat, and suggest that rat TMS protocols analogous to human TMS may be applied in future translational research.     

Cell type-specific excitability probed by optogenetic stimulation depends on the phase of the alpha oscillation

BackgroundAlpha oscillations have been proposed to provide phasic inhibition in the brain. Yet, pinging alpha oscillations with transcranial magnetic stimulation (TMS) to examine phase-dependent network excitability has resulted in conflicting findings. At the cellular level, such gating by the alpha oscillation remains poorly understood.ObjectiveWe examine how the excitability of pyramidal cells and presumed fast-spiking inhibitory interneurons depends on the phase of the alpha oscillation.MethodsOptogenetic stimulation pulses were administered at random phases of the alpha oscillation in the posterior parietal cortex (PPC) of two adult ferrets that expressed channelrhodopsin in pyramidal cells. Post-stimulation firing probability was calculated as a function of the stimulation phase of the alpha oscillation for both verum and sham stimulation.ResultsThe excitability of pyramidal cells depended on the alpha phase, in anticorrelation with their intrinsic phase preference; pyramidal cells were more responsive to optogenetic stimulation at the alpha phase with intrinsically low firing rates. In contrast, presumed fast-spiking inhibitory interneurons did not show such a phase dependency despite their stronger intrinsic phase preference.ConclusionsAlpha oscillations gate input to PPC in a phase-dependent manner such that low intrinsic activity was associated with higher responsiveness to input. This finding supports a model of cortical oscillation, in which internal processing and communication are limited to the depolarized half-cycle, whereas the other half-cycle serves as a signal detector for unexpected input. The functional role of different parts of the alpha cycle may vary across the cortex depending on local neuronal firing properties.     

Associative plasticity in intracortical inhibitory circuits in human motor cortex

ObjectivePaired associative stimulation (PAS) is a transcranial magnetic stimulation technique inducing Hebbian-like synaptic plasticity in the human motor cortex (M1). PAS is produced by repetitive pairing of a peripheral nerve shock and a transcranial magnetic stimulus (TMS). Its effect is assessed by a change in size of a motor evoked response (MEP). MEP size results from excitatory and inhibitory influences exerted on cortical pyramidal cells, but no robust effects on inhibitory networks have been demonstrated so far.MethodIn 38 healthy volunteers, we assessed whether a PAS intervention influences three intracortical inhibitory circuits: short (SICI) and long (LICI) intracortical inhibitions reflecting activity of GABA_A and GABA_B interneurons, respectively, and long afferent inhibition (LAI) reflecting activity of somatosensory inputs.ResultsAfter PAS, MEP sizes, LICI and LAI levels were significantly changed while changes of SICI were inconsistent. The changes in LICI and LAI lasted 45 min after PAS. Their direction depended on the delay between the arrival time of the afferent volley at the cortex and the TMS-induced cortical activation during the PAS.ConclusionsPAS influences inhibitory circuits in M1.SignificancePAS paradigms can demonstrate Hebbian-like plasticity at selected inhibitory networks as well as excitatory networks.     

Preferential Activation of Unique Motor Cortical Networks With Transcranial Magnetic Stimulation: A Review of the Physiological,Functional, and Clinical Evidence

ObjectivesThe corticospinal volley produced by application of transcranial magnetic stimulation (TMS) over primary motor cortex consists of a number of waves generated by trans-synaptic input from interneuronal circuits. These indirect (I)-waves mediate the sensitivity of TMS to cortical plasticity and intracortical excitability and can be assessed by altering the direction of cortical current induced by TMS. While this methodological approach has been conventionally viewed as preferentially recruiting early or late I-wave inputs from a given populations of neurons, growing evidence suggests recruitment of different neuronal populations, and this would strongly influence interpretation and application of these measures. The aim of this review is therefore to consider the physiological, functional, and clinical evidence for the independence of the neuronal circuits activated by different current directions.Materials and MethodsTo provide the relevant context, we begin with an overview of TMS methodology, focusing on the different techniques used to quantify I-waves. We then comprehensively review the literature that has used variations in coil orientation to investigate the I-wave circuits, grouping studies based on the neurophysiological, functional, and clinical relevance of their outcomes.ResultsReview of the existing literature reveals significant evidence supporting the idea that varying current direction can recruit different neuronal populations having unique functionally and clinically relevant characteristics.ConclusionsFurther research providing greater characterization of the I-wave circuits activated with different current directions is required. This will facilitate the development of interventions that are able to modulate specific intracortical circuits, which will be an important application of TMS.     

Biophysical reconstruction of the signal conduction underlying short-latency cortical evoked potentials generated by subthalamic deep brain stimulation

ObjectiveDirect activation of the hyperdirect (HD) pathway has been linked to therapeutic benefit from subthalamic deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD). We sought to quantify the axonal conduction biophysics of corticofugal axons directly stimulated by subthalamic DBS and reconcile those findings with short-latency cortical evoked potential (EP) results.MethodsWe used a detailed computational model of human subthalamic DBS to quantify axonal activation and conduction. Signal propagation to cortex was evaluated for medium (5.7 µm), large (10.0 µm), and exceptionally large (15.0 µm) diameter corticofugal axons associated with either internal capsule (IC) fibers of passage or the HD pathway. We then compared the modeling results to human cortical EP measurements that have described an exceptionally fast component (EP0) occurring ~1 ms after the stimulus pulse, a fast component (EP1) at ~3 ms, and a slower component (EP2) at ~5 ms.ResultsSubthalamic stimulation of the HD pathway with large and medium diameter axons propagated action potentials to cortex with timings that coincide with the EP1 and EP2 signals, respectively. Only direct activation of exceptionally large diameter fibers in the IC generated signals that could approach the EP0 timing. However, the action potential biophysics do not generally support the existence of a cortical EP less than 1.5 ms after DBS onset.ConclusionsThe EP1 and EP2 signals can be biophysically linked to antidromic activation of the HD pathway.SignificanceTheoretical reconstruction of cortical EPs from subthalamic DBS demonstrate a convergence of anatomical, biophysical, and electrophysiological results.     

Alpha-band cortico-cortical phase synchronization is associated with effective connectivity in the motor network

ObjectiveCommunication-through-coherence proposes that the phase synchronization (PS) of neural oscillations between cortical areas supports neural communication. In this study, we exploited transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) to test this hypothesis at the macroscale level, i.e., whether PS between cortical areas supports interarea communication. TEPs are electroencephalographic (EEG) responses time-locked to TMS pulses reflecting interarea communication, as they are generated by the transmission of neural activity from the stimulated area to connected regions. If interarea PS is important for communication, it should be associated with the TEP amplitude in the connected areas.MethodsTMS was delivered over the left primary motor cortex (M1) of fourteen healthy volunteers, and 70-channel EEG was recorded. Early TEP components were source-localized to identify their generators, i.e., distant brain regions activated by M1 through effective connections. Next, linear regressions were used to test the relationship between the TEP amplitude and the pre-stimulus PS between the M1 and the connected regions in four frequency bands (range 4–45 Hz).ResultsPre-stimulus interarea PS in the alpha-band was positively associated with the amplitude of early TEP components, namely, the N15 (ipsilateral supplementary motor area), P25 (contralateral M1) and P60 (ipsilateral parietal cortex).ConclusionsAlpha-band PS predicts the response amplitude of the distant brain regions effectively connected to M1.SignificanceOur study supports the role of EEG-PS in interarea communication, as theorized by communication-through-coherence.     

Deep brain stimulation of terminating axons

BackgroundDeep brain stimulation (DBS) of the subthalamic region is an established treatment for the motor symptoms of Parkinson's disease. Several types of neural elements reside in the subthalamic region, including subthalamic nucleus (STN) neurons, fibers of passage, and terminating afferents. Recent studies suggest that direct activation of a specific population of subthalamic afferents, known as the hyperdirect pathway, may be responsible for some of the therapeutic effects of subthalamic DBS.ObjectiveThe goal of this study was to quantify how axon termination affects neural excitability from DBS. We evaluated how adjusting different stimulation parameters influenced the relative excitability of terminating axons (TAs) compared to fibers of passage (FOPs).MethodsWe used finite element electric field models of DBS, coupled to multi-compartment cable models of axons, to calculate activation thresholds for populations of TAs and FOPs. These generalized models were used to evaluate the response to anodic vs. cathodic stimulation, with short vs. long stimulus pulses.Results: Terminating axons generally exhibited lower thresholds than fibers of passage across all tested parameters. Short pulse widths accentuated the relative excitability of TAs over FOPs.Conclusion(s): Our computational results demonstrate a hyperexcitability of terminating axons to DBS that is robust to variation in the stimulation parameters, as well as the axon model parameters.     

High-Frequency Transcranial Magnetic Stimulation Combined With Functional Magnetic Resonance Imaging Reveals Distinct Activation Patterns Associated With Different Dorsolateral Prefrontal Cortex Stimulation Sites

ObjectivesTranscranial magnetic stimulation (TMS) has been extensively used for the treatment of depression, obsessive-compulsive disorder, and certain neurologic disorders. Despite having promising treatment efficacy, the fundamental neural mechanisms of TMS remain understudied.Materials and MethodsIn this study, 15 healthy adult participants received simultaneous TMS and functional magnetic resonance imaging to map the modulatory effect of TMS when it was applied over three different sites in the dorsolateral prefrontal cortex. Independent component analysis (ICA) was used to identify the networks affected by TMS when applied over the different sites. The standard general linear model (GLM) analysis was used for comparison.ResultsICA showed that TMS affected the stimulation sites as well as remote brain areas, some areas/networks common across all TMS sites, and other areas/networks specific to each TMS site. In particular, TMS site and laterality differences were observed at the left executive control network. In addition, laterality differences also were observed at the dorsal anterior cingulate cortex and dorsolateral/dorsomedial prefrontal cortex. In contrast with the ICA findings, the GLM-based results mainly showed activation of auditory cortices regardless of the TMS sites.ConclusionsOur findings support the notion that TMS could act through a top-down mechanism, indirectly modulating deep subcortical nodes by directly stimulating cortical regions.Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT03394066.     

Rotational field TMS: Comparison with conventional TMS based on motor evoked potentials and thresholds in the hand and leg motor cortices

BackgroundTranscranial magnetic stimulation (TMS) is a rapidly expanding technology utilized in research and neuropsychiatric treatments. Yet, conventional TMS configurations affect primarily neurons that are aligned parallel to the induced electric field by a fixed coil, making the activation orientation-specific. A novel method termed rotational field TMS (rfTMS), where two orthogonal coils are operated with a 90° phase shift, produces rotation of the electric field vector over almost a complete cycle, and may stimulate larger portion of the neuronal population within a given brain area.ObjectiveTo compare the physiological effects of rfTMS and conventional unidirectional TMS (udTMS) in the motor cortex.MethodsHand and leg resting motor thresholds (rMT), and motor evoked potential (MEP) amplitudes and latencies (at 120% of rMT), were measured using a dual-coil array based on the H7-coil, in 8 healthy volunteers following stimulation at different orientations of either udTMS or rfTMS.ResultsFor both target areas rfTMS produced significantly lower rMTs and much higher MEPs than those induced by udTMS, for comparable induced electric field amplitude. Both hand and leg rMTs were orientation-dependent.ConclusionsrfTMS induces stronger physiologic effects in targeted brain regions at significantly lower intensities. Importantly, given the activation of a much larger population of neurons within a certain brain area, repeated application of rfTMS may induce different neuroplastic effects in neural networks, opening novel research and clinical opportunities.     

TMS-EEG co-registration: On TMS-induced artifact

ObjectiveThe combination of brain stimulation by transcranial magnetic stimulation (TMS) and simultaneous electroencephalographic (EEG) recording has the potential to be of great value for understanding human brain functions. Recording EEG during TMS can be technically challenging because TMS induces a very strong electrical field that can saturate recording amplifiers for a long duration. Advances in amplifier technology, however, have led to the development of TMS-compatible EEG equipment that can work in very high, time-varying magnetic fields without saturation. The aim of the present study was to identify stimulus-related artifacts, and to provide experimental data containing the length of the artifact induced by the magnetic field and its variations with respect to the experimental setting.MethodsA phantom head was stimulated to record the artifact while excluding cortical responses. We tested different types of electrodes, coils, models of stimulator, and frequencies and intensities of stimulation to see how these parameters influence the duration of the artifact.ResultsThe electrical artifact produced by the magnetic pulse lasted approximately 5 ms following TMS onset. Its length was invariant irrespective of different experimental conditions.ConclusionsThese data suggest that it is possible to analyze the cortical evoked response induced by TMS 5 ms after TMS onset.SignificanceThe possibility to study the early physiological responses to TMS stimulation may have valuable implications for both clinical and experimental purposes, providing information about the early direct cortical response of the stimulated areas.     

Transcranial alternating current stimulation (tACS) modulates cortical excitability as assessed by TMS-induced phosphene thresholds

ObjectiveRecent developments in transcranial alternating current stimulation (tACS) provide a powerful approach to establish the functional roles of neuronal oscillatory activities in the human brain. Here, we investigated whether tACS can reach and modulate the excitability of the visual cortex in a frequency-dependent manner.MethodsWe measured the cortical excitability of the visual cortex using single pulse transcranial magnetic stimulation (TMS) while delivering tACS to the occipital region at different frequencies (5, 10, 20 and 40 Hz).ResultsWe found that tACS at 20 Hz decreased TMS–phosphene threshold (i.e., increased the excitability of the visual cortex) during the stimulation, whereas other frequencies did not affect TMS–phosphene thresholds.ConclusionsOur findings demonstrate direct interactions of tACS with the visual cortex in a frequency-dependent manner.SignificanceOur present work provides further demonstration of the potential of tACS as a method to selectively modulate the excitability of the visual cortex.     

Blood Oxygenation Changes Modulated by Coil Orientation During Prefrontal Transcranial Magnetic Stimulation

BackgroundPrefrontal transcranial magnetic stimulation (TMS) is being investigated as a treatment for several neurological and psychiatric disorders. The direction of the cortical current induced by TMS can be modulated by the coil orientation and this influences the extent of neural depolarization. Although the optimal coil orientation has previously been established for motor cortex, identifying an optimal coil orientation for prefrontal areas is more challenging due to the absence of a motor response. The current study used near infra-red spectroscopy (NIRS) to investigate the impact of coil orientation on TMS induced changes in prefrontal blood oxygenation (HbO). It was hypothesized that a greater change in HbO would be observed when current was induced in a posterior to anterior direction.MethodsSingle pulse and trains of 1 Hz repetitive TMS (rTMS) were administered to the left prefrontal cortex while simultaneously recording HbO response bilaterally. The effect of coil orientation was examined at 45°, 135°, and 225° counterclockwise from midline.ResultsGreatest changes in HbO were observed at a 45° orientation when both single and rTMS were applied, and only minor changes were observed at 135° and 225°. Application of short trains of rTMS at 45° resulted in transient increases in HbO that were significantly greater in magnitude than when the coil orientation was reversed.ConclusionsThe utility of NIRS for examining the TMS evoked physiological response at non-motor areas is highlighted in this study. Prefrontal HbO response evoked by TMS is sensitive to the direction of induced cortical current and it appears that the de facto 45° angle utilized in most clinical studies may prove to be optimal.     

Modeling motor-evoked potentials from neural field simulations of transcranial magnetic stimulation

ObjectiveTo develop a population-based biophysical model of motor-evoked potentials (MEPs) following transcranial magnetic stimulation (TMS).MethodsWe combined an existing MEP model with population-based cortical modeling. Layer 2/3 excitatory and inhibitory neural populations, modeled with neural-field theory, are stimulated with TMS and feed layer 5 corticospinal neurons, which also couple directly but weakly to the TMS pulse. The layer 5 output controls mean motoneuron responses, which generate a series of single motor-unit action potentials that are summed to estimate a MEP.ResultsA MEP waveform was generated comparable to those observed experimentally. The model captured TMS phenomena including a sigmoidal input–output curve, common paired pulse effects (short interval intracortical inhibition, intracortical facilitation, long interval intracortical inhibition) including responses to pharmacological interventions, and a cortical silent period. Changes in MEP amplitude following theta burst paradigms were observed including variability in outcome direction.ConclusionsThe model reproduces effects seen in common TMS paradigms.SignificanceThe model allows population-based modeling of changes in cortical dynamics due to TMS protocols to be assessed in terms of changes in MEPs, thus allowing a clear comparison between population-based modeling predictions and typical experimental outcome measures.