Direct Cortical Response Research Articles

Shapes of direct cortical responses vs. short-range axono-cortical evoked potentials: The effects of direct electrical stimulation applied to the human brain

ObjectiveDirect cortical responses (DCR) and axono-cortical evoked potentials (ACEP) are generated by electrically stimulating the cortex either directly or indirectly through white matter pathways, potentially leading to different electrogenic processes. For ACEP, the slow conduction velocity of axons (median ≈ 4 m.s−1) is anticipated to induce a delay. For DCR, direct electrical stimulation (DES) of the cortex is expected to elicit additional cortical activity involving smaller and slower non-myelinated axons. We tried to validate these hypotheses. MethodsDES was administered either directly on the cortex or to white matter fascicles within the resection cavity, while recording DCR or ACEP at the cortical level in nine patients. ResultsShort but significant delays (≈ 2 ms) were measurable for ACEP immediately following the initial component (≈ 7 ms). Subsequent activities (≈ 40 ms) exhibited notable differences between DCR and ACEP, suggesting the presence of additional cortical activities for DCR. ConclusionDistinctions between ACEPs and DCRs can be made based on a delay at the onset of early components and the dissimilarity in the shape of the later components (>40 ms after the DES artifact). SignificanceThe comparison of different types of evoked potentials allows to better understand the effects of DES.

Evoked EEG Responses to TMS Targeting Regions Outside the Primary Motor Cortex and Their Test–Retest Reliability

Transcranial magnetic stimulation (TMS)–evoked electroencephalography (EEG) potentials (TEPs) provide unique insights into cortical excitability and connectivity. However, confounding EEG signals from auditory and somatosensory co-stimulation complicate TEP interpretation. Our optimized sham procedure established with TMS of primary motor cortex (Gordon in JAMA 245:118708, 2021) differentiates direct cortical EEG responses to TMS from those caused by peripheral sensory inputs. Using this approach, this study aimed to investigate TEPs and their test–retest reliability when targeting regions outside the primary motor cortex, specifically the left angular gyrus, supplementary motor area, and medial prefrontal cortex. We conducted three identical TMS–EEG sessions one week apart involving 24 healthy participants. In each session, we targeted the three areas separately using a figure-of-eight TMS coil for active TMS, while a second coil away from the head produced auditory input for sham TMS. Masking noise and electric scalp stimulation were applied in both conditions to achieve matched EEG responses to peripheral sensory inputs. High test–retest reliability was observed in both conditions. However, reliability declined for the ‘cleaned’ TEPs, resulting from the subtraction of evoked EEG response to the sham TMS from those to the active, particularly for latencies > 100 ms following the TMS pulse. Significant EEG differences were found between active and sham TMS at latencies < 90 ms for all targeted areas, exhibiting distinct spatiotemporal characteristics specific to each target. In conclusion, our optimized sham procedure effectively reveals EEG responses to direct cortical activation by TMS in brain areas outside primary motor cortex. Moreover, we demonstrate the impact of peripheral sensory inputs on test–retest reliability of TMS-EEG responses.

The Effect of Coil Orientation on the Stimulation of the Pre–Supplementary Motor Area: A Combined TMS and EEG Study

Studies using transcranial magnetic stimulation (TMS) have demonstrated the importance of direction and intensity of the applied current when the primary motor cortex (M1) is targeted. By varying these, it is possible to stimulate different subsets of neural elements, as demonstrated by modulation of motor evoked potentials (MEPs) and motor behaviour. The latter involves premotor areas as well, and among them, the presupplementary motor area (pre–SMA) has recently received significant attention in the study of motor inhibition. It is possible that, similar to M1, different neuronal populations can be activated by varying the direction and intensity of TMS; however, the absence of a direct electrophysiological outcome has limited this investigation. The problem can be solved by quantifying direct cortical responses by means of combined TMS and electroencephalography (TMS–EEG). We investigated the effect of variable coil orientations (0°, 90°, 180° and 270°) and stimulation intensities (100%, 120% and 140% of resting motor threshold) on local mean field potential (LMFP), transcranial evoked potential (TEP) peaks and TMS–related spectral perturbation (TRSP) from pre–SMA stimulation. As a result, early and late LMFP and peaks were larger, with the coil handle pointing posteriorly (0°) and laterally (90°). This was true also for TRSP in the β–γ range, but, surprisingly, θ–α TRSP was larger with the coil pointing at 180°. A 90° orientation activated the right M1, as shown by MEPs elicitation, thus limiting the spatial specificity of the stimulation. These results suggest that coil orientation and stimulation intensity are critical when stimulating the pre–SMA.

Recording brain responses to TMS of primary motor cortex by EEG – utility of an optimized sham procedure

IntroductionElectroencephalography (EEG) is increasingly used to investigate brain responses to transcranial magnetic stimulation (TMS). A relevant issue is that TMS is associated with considerable auditory and somatosensory stimulation, causing peripherally evoked potentials (PEPs) in the EEG, which contaminate the direct cortical responses to TMS (TEPs). All previous attempts to control for PEPs suffer from significant limitations. Objective/HypothesisTo design an optimized sham procedure to control all sensory input generated by subthreshold real TMS targeting the hand area of the primary motor cortex (M1), enabling reliable separation of TEPs from PEPs. MethodsIn 23 healthy (16 female) subjects, we recorded EEG activity evoked by an optimized sham TMS condition which masks and matches auditory and somatosensory co-stimulation during the real TMS condition: auditory control was achieved by noise masking and by using a second TMS coil that was placed on top of the real TMS coil and produced a calibrated sound pressure level. Somatosensory control was obtained by electric stimulation (ES) of the scalp with intensities sufficient to saturate somatosensory input. ES was applied in both the sham and real TMS conditions. Perception of auditory and somatosensory inputs in the sham and real TMS conditions were compared by psychophysical testing. Transcranially evoked EEG signal changes were identified by subtraction of EEG activity in the sham condition from EEG activity in the real TMS condition. ResultsPerception of auditory and somatosensory inputs in the sham vs. real TMS conditions was comparable. Both sham and real TMS evoked a series of similar EEG signal deflections and induced broadband power increase in oscillatory activity. Notably, the present procedure revealed EEG potentials and a transient increase in beta band power at the site of stimulation that were only present in the real TMS condition. DiscussionThe results validate the effectiveness of our optimized sham approach. Despite the presence of typical responses attributable to sensory input, the procedure provided evidence for direct cortical activation by subthreshold TMS of M1. The findings are relevant for future TMS-EEG experiments that aim at measuring regional brain target engagement controlled by an optimized sham procedure.

Characterizing Direct Cortical Responses to TMS

Characterizing Direct Cortical Responses to TMS

Impact of gyral geometry on cortical responses to surface electrical stimulation: insights from experimental and modeling studies

Objective. Invasive simultaneous stimulation and recording from intracranial electrodes and microwire arrays were used to investigate direct cortical responses to single pulses of electrical stimulation in humans. Approach. Microwire contacts measured surface potentials in cortical microdomains at a distance of 2–6 mm from the intracranial electrode. Direct cortical responses to stimulation (<20 ms) consisted of a larger surface negative potentials. Main results. The latencies of these responses were directly or inversely correlated with distances between the intracranial electrode and microwire contacts. We hypothesize that surface negative potentials reflected local synchronous depolarization of apical dendrites of pyramidal neurons in cortical microdomains in the superficial cortical layer and resulted from the activation of gray matter axons that delivered excitatory inputs to apical dendrites after cortical stimulation. We further hypothesized that the positive or inverse distance-latency correlations of the recorded negative responses were measured depending on whether activation of neurons originated at one (crown) or multiple (crown, lip, bank) sites throughout the gyrus simultaneously. The inverse distance-latency correlations then reflected the spatiotemporal superposition of different nearby sources of neuronal recruitment in the gyrus. To prove this hypothesis, we built an anatomically informed and biophysically realistic cortical network model and simulated early responses of cortical neurons to electrical stimulation in this cortical network model. The model simulations yielded negative potentials in simulated microdomains in the cortical model consistent with those recorded from humans. The model predicted sensitivity of cortical responses to the alignment of the stimulating electrode and microwire array with respect to the cortical gyrus and confirmed that gyral geometry has a major impact on direct neuronal recruitment, the timing, and the time course of neuronal activation in cortical microdomains. Significance. In this work, we demonstrated how the high-resolution forward network models can be used for better understanding and detailed prediction of cortical stimulation effects. Accurate predictive modeling tools are needed for the progress of brain stimulation therapies.

Reproducibility of cortical response modulation induced by intermittent and continuous theta-burst stimulation of the human motor cortex

BackgroundOver the past decade, the number of experimental and clinical studies using theta-burst-stimulation (TBS) protocols of transcranial magnetic stimulation (TMS) to modulate brain activity has risen substantially. The use of TBS is motivated by the assumption that these protocols can reliably and lastingly modulate cortical excitability despite their short duration and low number of stimuli. However, this assumption, and thus the experimental validity of studies using TBS, is challenged by recent work showing large inter- and intra-subject variability in response to TBS protocols. ObjectivesTo date, the reproducibility of TBS effects in humans has been exclusively assessed with motor evoked potentials (MEPs), which provide an indirect and limited measure of cortical excitability. Here we combined TMS with electroencephalography (TMS-EEG) and report the first comprehensive investigation of (1) direct TMS-evoked cortical responses to intermittent (iTBS) and continuous TBS (cTBS) of the human motor cortex, and (2) reproducibility of both iTBS- and cTBS-induced cortical response modulation against a robust sham control across repeat visits with commonly used cortical responsivity metrics. ResultsWe show that although single pulse TMS generates stable and reproducible cortical responses across visits, the modulatory effects of TBS vary substantially both between and within individuals. Overall, at the group level, most measures of the iTBS and cTBS-induced effects were not significantly different from sham-TBS. Most importantly, none of the significant TBS-induced effects observed in visit-1 were reproduced in visit-2. ConclusionsOur findings suggest that the generally accepted mechanisms of TBS-induced neuromodulation, i.e. through changes in cortical excitability, may not be accurate. Future research is needed to determine the mechanisms underlying the established therapeutic effects of TBS in neuropsychiatry and examine reproducibility of TBS-induced neuromodulation through oscillatory response dynamics.

Direct Activation of Cortical Neurons in the Primary Somatosensory Cortex of the Rat in Vivo Using Focused Ultrasound

We address the recent controversy over whether focused ultrasound (FUS) activates cortical neurons directly or indirectly by initially activating auditory pathways. We obtained two types of evidence that FUS can directly activate cortical neurons. The depth profile of the local field potential (LFP) in the barrel cortex of the rat in vivo indicated a generator was located within the cortical gray matter. The onset and peak latencies of the initial component p1 were 3.2 ± 0.25 ms (mean ± standard error of the mean) and 7.6 ± 0.12 ms, respectively, for the direct cortical response (DCR), 6.8 ± 0.40 and 14.3 ± 0.54 ms for the FUS-evoked LFP (4 MHz, 3.2 MPa, 50 or 300 µs/pulse, 1–20 pulses at 1 kHz) and 6.9 ± 0.51 and 15.8 ± 0.94 ms for the LFP evoked by 1-ms deflection of the C2 whisker projecting to the same area. The peak latency of the FUS p1 was statistically (t-test) longer than the DCR, but shorter than the whisker p1 at p < 0.005.

Comparison of cortical EEG responses to realistic sham versus real TMS of human motor cortex

BackgroundThe analysis of cortical responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) has been successfully applied to study human cortical physiology. However, in addition to the (desired) activation of cortical neurons and fibers, TMS also causes (undesired) indirect brain responses through auditory and somatosensory stimulation, which may contribute significantly to the overall EEG signal and mask the effects of intervention on direct cortical responses. ObjectivesTo test differences in EEG responses to real TMS at intensities above and below resting motor threshold (RMT) and a realistic sham stimulation. Methods12 healthy subjects participated in one session in which single-pulse TMS was applied to the left motor cortex in 3 different blocks, 150 pulses per block: 110%RMT, 90%RMT and realistic sham stimulation. Cortical responses were collected by a 64 electrode EEG system. TMS evoked potentials (TEPs) and TMS induced oscillations were analyzed. Methods12 healthy subjects participated in one session in which single-pulse TMS was applied to the left motor cortex in 3 different blocks, 150 pulses per block: 110%RMT, 90%RMT and realistic sham stimulation. Cortical responses were collected by a 64-channel EEG system. TMS evoked potentials (TEPs) and TMS induced oscillations were analyzed. ResultsTEPs from all conditions differed significantly, with TEPs from 110%RMT showing overall highest amplitudes and realistic sham lowest amplitudes. Sham stimulation had only minor effects on induced cortical oscillations compared to pre-stimulus baseline, TMS at 90%RMT resulted in a significant increase (50–200 m s) followed by a decrease (200–500 m s) in power of alpha and beta oscillations; TMS at 110% RMT led to an additional increase in beta power at late latencies (650–800 m s). ConclusionsReal TMS of motor cortex results in cortical responses significantly different from realistic sham. These differences very likely reflect to a significant extent direct activation of neurons, rather than sensory evoked activity.

Electrophysiological Activity Evoked by Direct Electrical Stimulation of the Human Brain: Interest of the P0 Component.

Direct electrical stimulation (DES) at 60 Hz is used clinically to perform real-time functional mapping of the brain and guide tumor resection during wide-awake neurosurgery. The electrophysiological effects of DES remain by far unknown, both locally and remotely. In this study, by lowering the DES frequency to 9 Hz and by using differential recording of electro-corticographic signals to improve the focality, we were able to observe that the amplitude of the initial P0 component of the direct cortical response increased when the inter-electrode distance was increased and the pulse width was decreased. This result strongly suggests that larger neural elements, including somas and axons of pyramidal neurons buried in deeper layers of the cortical column, are activated. Their activation produce the observed P0 component, which results from the synchronized summation of action potentials triggered by DES. Interestingly, the early P0 component was not observed during the usual 60 Hz DES. The study of the P0 component and subsequent evoked potentials may help decipher the effects of DES on the stimulated cortical column and identify the activation of underlying white matter fibers. This is crucial to better understand the electrophysiological diffusion of DES, especially at higher frequencies (e.g., 60 Hz).

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

The 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. A 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. The electrical artifact produced by the magnetic pulse lasted approximately 5 ms following TMS onset. Its length was invariant irrespective of different experimental conditions. These data suggest that it is possible to analyze the cortical evoked response induced by TMS 5 ms after TMS onset. The 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.

Early potentials of direct cortical responses: experimental study in dogs and pathophysiological and clinical implications.

The characteristics of the early component of the direct cortical response have not been well studied, although direct cortical response recording is a common method of brain function monitoring. In this experimental study, we sought conditions affording the clearest recording of the early potential, by varying the polarity and low-cutoff filter setting, and we confirmed that the early potential consists of two components, P1 and P2. When subcortical damage was induced by local cerebral compression or saline injection, transient changes in P1 and permanent disappearance of P2 were observed. P2 also disappeared when the fiber connections between the cortex and the basal ganglia, including the thalamus, were destroyed by wire insertion. With deep recording, both P1 and P2 exhibited potential reversal at a level histologically confirmed to be in Layer V of the cortex. These findings suggest that P1 is a spike reflecting the activity of pyramidal cells evoked by electrical stimulation of the brain surface and that P2 is a potential arising in Layer V of the cortex and is related to afferent fibers from the thalamus. Recording of P2 may be useful for monitoring for subcortical damage.

Early Potentials of Direct Cortical Responses: Experimental Study in Dogs and Pathophysiological and Clinical Implications

Early Potentials of Direct Cortical Responses: Experimental Study in Dogs and Pathophysiological and Clinical Implications

Early Potentials of Direct Cortical Responses: Experimental Study in Dogs and Pathophysiological and Clinical Implications

Early Potentials of Direct Cortical Responses: Experimental Study in Dogs and Pathophysiological and Clinical Implications

Early Potentials of Direct Cortical Responses: Experimental Study in Dogs and Pathophysiological and Clinical Implications

Early Potentials of Direct Cortical Responses: Experimental Study in Dogs and Pathophysiological and Clinical Implications

The effect of haemodilution and hypercapnia on the recovery of cerebral function from experimental focal ischaemia.

The direct cortical response (DCR) and associated local cerebral blood flow was recorded from the primate cerebral cortex during a period of focal ischaemia induced by middle cerebral artery occlusion (MCAO). The DCR was lost when local blood flow fell below 20 ml/100 g/min but began to recover as collateral flow increased. Hypercapnia demonstrated a loss of local vascular reactivity following MCAO, but isovolaemic haemodilution still proved effective in increasing blood flow to these areas. The reduction in blood oxygen content induced by haemodilution did not impair cerebral function but the reduction in whole blood viscosity did exacerbate cerebral susceptibility to hypercapnia-induced intra-cerebral steal.

Distinctive electrophysiological characteristics of functionally discrete brain areas: a tenable approach to functional localization.

The direct cortical response (DCR), an electrical potential recorded in the immediate vicinity of a surface cortical stimulus, shows a configuration in the primary sensory areas of animals that is different from the one observed in association cortex. This suggested the possibility that systematic study of the DCR in the human brain might reveal a profile of configurations in which the form of the response provides functional information about the gyri being tested. Studies were carried out in subhuman primates and in patients undergoing surgery for tumors, occult vascular malformations, and epilepsy. In the animals, DCR's from somatosensory, motor, and association cortex are distinguishable; however, there are no differences in configuration between motor and premotor responses, or between association responses from prefrontal and parietal cortex. In patients with epilepsy due to nonspace-occupying pathology, the responses did not show distinguishing features. In contrast, in the patients with tumors or occult vascular malformations, DCR's from somatosensory, motor, and premotor cortex could be readily distinguished from each other. Responses along the mid and posterior sylvian fissure of the dominant hemisphere also had distinctive features, but more data are needed before the significance of this finding with respect to language function can be assessed. The accumulating results suggest that analysis of DCR's may prove to be a useful method for functional localization in individuals with focal space-taking pathology.

The currents that flow in the somatosensory cortex during the direct cortical response

A current-flow and current-source-density analysis of the sensory evoked response (SER) and the direct cortical response (DCR) in the somatosensory cortex of rats was performed to determine the origin of these potentials. The SER was found to originate in layers II and III, as in cats, with a single excitatory neuronal circuit component. The DCR, on the other hand, has five components, three inhibitory and two excitatory. The activation and magnitude of these components vary with stimulus strength and frequency. During the second and fourth ms of the response, two inhibitory currents flow in layers V and VI; 2 ms later, excitatory current flows in layers II and III. This excitatory current appears to be the same one involved in the SER. Five ms later, the superficial excitatory current is replaced by an inhibitory one in the neighborhood of the DCR's negative peak. At strong stimulus strengths, this is followed by an excitatory current in layer V. The early inhibitory and excitatory components step up through layers upper-VI, V and III over time, implying that inhibition followed by excitation moves upward through cortex. The currents associated with the DCR in somatosensory cortex are compared with those for the DCR in motor and association cortex.

Laminar excitability cycles in neocortex

1. Laminar field potentials produced by paired electrocortical stimuli were recorded with a linear microelectrode array inserted perpendicular to the surface of rat somatosensory cortex. Current source-density (CSD) distributions of the direct cortical response (DCR) were computed from the potential profiles. Principal component analysis (PCA) was used to estimate the time course of evoked transmembrane currents of putative pyramidal cell populations in the supragranular and infragranular layers. 2. Both supra- and infragranular cells displayed an initial period after the conditioning stimulus in which test stimuli produced subnormal evoked response amplitudes. This was followed in both layers by a long period of supernormal then subnormal responses and a second period of supernormal responses. 3. The main laminar difference encountered was a general shortening of all phases of the excitability cycle in the supragranular cells. 4. Excitability cycles in the supra- and infragranular layers closely followed the morphology of average evoked responses to the conditioning stimulus alone. These results and physiological support to the validity of lamina-specific evoked response waveforms derived from combined CSD and PCA analysis of extracellular potential measurements. 5. The relationship between evoked potential amplitude changes and cortical excitability is discussed.

A method for eliminating the stimulus artifact from digital recordings of the direct cortical response

A computer algorithm which removes the electrical pulse stimulus artifact from digitized electrophysiological recordings is described. The technique has been applied to recordings of the direct cortical response (DCR). The process removes the stimulus artifact without removing the overlapping physiological signal. The results from recordings of the DCR in the rat before and after the artifact removal process are shown. The validity of the method is demonstrated from simultaneous recording of the same response with a minimal and maximal artifact. An examination of the residual artifact and degree of signal distortion after the algorithm has been applied is presented.