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• W3010535098 abstract "•Demonstration of a monosynaptic, prefrontal hyperdirect pathway in humans•Fastest fibers between the inferior frontal gyrus and ventral subthalamic nucleus•Stopping elicits co-activation of the origin and target of this pathway•Degree of co-activation predicts stopping speed The ability to dynamically change motor outputs, such as stopping an initiated response, is an important aspect of human behavior. A hyperdirect pathway between the inferior frontal gyrus and subthalamic nucleus is hypothesized to mediate movement inhibition, but there is limited evidence for this in humans. We recorded high spatial and temporal resolution field potentials from both the inferior frontal gyrus and subthalamic nucleus in 21 subjects. Cortical potentials evoked by subthalamic stimulation revealed short latency events indicative of monosynaptic connectivity between the inferior frontal gyrus and ventral subthalamic nucleus. During a stop signal task, stopping-related potentials in the cortex preceded stopping-related activity in the subthalamic nucleus, and synchronization between these task-evoked potentials predicted the stop signal reaction time. Thus, we show that a prefrontal-subthalamic hyperdirect pathway is present in humans and mediates rapid stopping. These findings may inform therapies to treat disorders featuring perturbed movement inhibition. The ability to dynamically change motor outputs, such as stopping an initiated response, is an important aspect of human behavior. A hyperdirect pathway between the inferior frontal gyrus and subthalamic nucleus is hypothesized to mediate movement inhibition, but there is limited evidence for this in humans. We recorded high spatial and temporal resolution field potentials from both the inferior frontal gyrus and subthalamic nucleus in 21 subjects. Cortical potentials evoked by subthalamic stimulation revealed short latency events indicative of monosynaptic connectivity between the inferior frontal gyrus and ventral subthalamic nucleus. During a stop signal task, stopping-related potentials in the cortex preceded stopping-related activity in the subthalamic nucleus, and synchronization between these task-evoked potentials predicted the stop signal reaction time. Thus, we show that a prefrontal-subthalamic hyperdirect pathway is present in humans and mediates rapid stopping. These findings may inform therapies to treat disorders featuring perturbed movement inhibition. Stopping a movement that has already been initiated is critical for motor control. Movement inhibition is thought to be mediated by a “hyperdirect” monosynaptic pathway between the inferior frontal gyrus (IFG) and the subthalamic nucleus (STN) (Aron et al., 2007Aron A.R. Behrens T.E. Smith S. Frank M.J. Poldrack R.A. Triangulating a cognitive control network using diffusion-weighted magnetic resonance imaging (MRI) and functional MRI.J. Neurosci. 2007; 27: 3743-3752Crossref PubMed Scopus (688) Google Scholar, Nambu et al., 2002Nambu A. Tokuno H. Takada M. Functional significance of the cortico-subthalamo-pallidal ‘hyperdirect’ pathway.Neurosci. Res. 2002; 43: 111-117Crossref PubMed Scopus (804) Google Scholar). In non-human primates, anterograde tracer studies demonstrate a lateral prefrontal projection to the ventral STN (Haynes and Haber, 2013Haynes W.I. Haber S.N. The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for basal ganglia models and deep brain stimulation.J. Neurosci. 2013; 33: 4804-4814Crossref PubMed Scopus (283) Google Scholar). Due to methodological constraints, however, there is limited evidence in humans that a monosynaptic IFG-STN pathway exists or that hyperdirect activation is involved in stopping. Tractography studies have identified white matter tracts between the IFG and STN (Aron et al., 2007Aron A.R. Behrens T.E. Smith S. Frank M.J. Poldrack R.A. Triangulating a cognitive control network using diffusion-weighted magnetic resonance imaging (MRI) and functional MRI.J. Neurosci. 2007; 27: 3743-3752Crossref PubMed Scopus (688) Google Scholar), although imaging lacks the ability to isolate pathways that are monosynaptic. Scalp electroencephalography (EEG) studies have identified short-latency evoked potentials (EPs) in the frontal-central cortex elicited from STN stimulation, indicating monosynaptic connectivity (Ashby et al., 2001Ashby P. Paradiso G. Saint-Cyr J.A. Chen R. Lang A.E. Lozano A.M. Potentials recorded at the scalp by stimulation near the human subthalamic nucleus.Clin. Neurophysiol. 2001; 112: 431-437Crossref PubMed Scopus (97) Google Scholar, Baker et al., 2002Baker K.B. Montgomery Jr., E.B. Rezai A.R. Burgess R. Lüders H.O. Subthalamic nucleus deep brain stimulus evoked potentials: physiological and therapeutic implications.Mov. Disord. 2002; 17: 969-983Crossref PubMed Scopus (115) Google Scholar, Walker et al., 2012Walker H.C. Huang H. Gonzalez C.L. Bryant J.E. Killen J. Cutter G.R. Knowlton R.C. Montgomery E.B. Guthrie B.L. Watts R.L. Short latency activation of cortex during clinically effective subthalamic deep brain stimulation for Parkinson’s disease.Mov. Disord. 2012; 27: 864-873Crossref PubMed Scopus (70) Google Scholar). However, EEG lacks the spatial resolution to discern whether the pathway originates in the IFG or if it is a distributed pathway across the frontal-central cortex. Functionally, the IFG and STN are thought to be involved in stopping (Aron et al., 2016Aron A.R. Herz D.M. Brown P. Forstmann B.U. Zaghloul K. Frontosubthalamic Circuits for Control of Action and Cognition.J. Neurosci. 2016; 36: 11489-11495Crossref PubMed Scopus (90) Google Scholar), but activity in this pathway has not yet been characterized with high spatiotemporal resolution. Initial functional imaging studies indicated that blood oxygenation in the STN region and IFG were modulated during a stop signal task. Single-site invasive electrophysiology studies showed that beta band (∼11–30 Hz) activity in the field potentials of the STN (Alegre et al., 2013Alegre M. Lopez-Azcarate J. Obeso I. Wilkinson L. Rodriguez-Oroz M.C. Valencia M. Garcia-Garcia D. Guridi J. Artieda J. Jahanshahi M. Obeso J.A. The subthalamic nucleus is involved in successful inhibition in the stop-signal task: a local field potential study in Parkinson’s disease.Exp. Neurol. 2013; 239: 1-12Crossref PubMed Scopus (98) Google Scholar, Kühn et al., 2004Kühn A.A. Williams D. Kupsch A. Limousin P. Hariz M. Schneider G.H. Yarrow K. Brown P. Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance.Brain. 2004; 127: 735-746Crossref PubMed Scopus (479) Google Scholar, Ray et al., 2012Ray N.J. Brittain J.S. Holland P. Joundi R.A. Stein J.F. Aziz T.Z. Jenkinson N. The role of the subthalamic nucleus in response inhibition: evidence from local field potential recordings in the human subthalamic nucleus.Neuroimage. 2012; 60: 271-278Crossref PubMed Scopus (96) Google Scholar) and IFG (Swann et al., 2009Swann N. Tandon N. Canolty R. Ellmore T.M. McEvoy L.K. Dreyer S. DiSano M. Aron A.R. Intracranial EEG reveals a time- and frequency-specific role for the right inferior frontal gyrus and primary motor cortex in stopping initiated responses.J. Neurosci. 2009; 29: 12675-12685Crossref PubMed Scopus (294) Google Scholar, Swann et al., 2012Swann N.C. Cai W. Conner C.R. Pieters T.A. Claffey M.P. George J.S. Aron A.R. Tandon N. Roles for the pre-supplementary motor area and the right inferior frontal gyrus in stopping action: electrophysiological responses and functional and structural connectivity.Neuroimage. 2012; 59: 2860-2870Crossref PubMed Scopus (270) Google Scholar), assessed independently, increased during successful stopping, prompting the hypothesis that synchronized oscillatory activity in these structures mediates movement inhibition. We used high-resolution, invasive electrophysiology in both the IFG and STN to characterize prefrontal hyperdirect topography and its functional relevance during stopping. In Parkinson’s disease (PD) patients undergoing awake neurosurgery for implantation of deep brain stimulation (DBS) electrodes, we used intraoperative electrocorticography (ECoG) targeted to the IFG and DBS electrodes targeted to the STN. We performed EP experiments to characterize monosynaptic connectivity, and we used the stop signal task to characterize stopping-related activity. Here, we provide physiological evidence for the existence of a prefrontal-subthalamic hyperdirect pathway in humans, show that the IFG and STN are tightly synchronized during stopping, and demonstrate that IFG-STN synchronization predicts stop signal reaction time (SSRT) across subjects. We enrolled 21 subjects with PD: 16 subjects participated in the EP experiments and 15 subjects performed the stop signal task (10 subjects participated in both) (Tables S1 and S2). EP data from 2 subjects were excluded due to technical failures. Stop signal task data from 5 subjects were excluded due to violation of the race model, in which unsuccessful STOP reactions times were greater than successful GO reaction times (Verbruggen et al., 2019Verbruggen F. Aron A.R. Band G.P. Beste C. Bissett P.G. Brockett A.T. Brown J.W. Chamberlain S.R. Chambers C.D. Colonius H. et al.A consensus guide to capturing the ability to inhibit actions and impulsive behaviors in the stop-signal task.eLife. 2019; 8: e46323Crossref PubMed Scopus (167) Google Scholar). Subjects were taken off dopaminergic medications for 12 h. The mean DBS electrode coordinates for the right STN, aligned to the anterior commissure-posterior commissure line, were 10.7 ± 0.6 (lateral), −3.5 ± 1.7 (anterior-posterior), and −6.2 ± 1.4 (vertical). The coordinates for the left STN were −11.5 ± 0.7, −3.4 ± 1.1, −7.4 ± 1.5. The mean age of the subjects was 67.5 ± 6.3 years and the mean disease duration was 8.6 ± 3.4 years. We found evidence for a prefrontal-subthalamic hyperdirect pathway in humans by stimulating in the STN and examining antidromic evoked activity in the prefrontal cortex. Short-latency potentials in the cortex support the existence of a fast-conducting monosynaptic connection. Figure 1 illustrates evoked cortical activity in a single-subject example. Contacts were localized both with imaging (Figures 1A and 1B) and electrophysiology (Figure 1C). Bipolar stimulation in the right STN in the 2 most ventral STN contacts evoked activity in the ipsilateral ECoG after ∼2 ms (Figure 1D). Because the short-latency EP was small in amplitude, we summed the EPs elicited from 2 stimulation settings with reversed anode and cathode configurations, similar to previous EEG studies (Walker et al., 2012Walker H.C. Huang H. Gonzalez C.L. Bryant J.E. Killen J. Cutter G.R. Knowlton R.C. Montgomery E.B. Guthrie B.L. Watts R.L. Short latency activation of cortex during clinically effective subthalamic deep brain stimulation for Parkinson’s disease.Mov. Disord. 2012; 27: 864-873Crossref PubMed Scopus (70) Google Scholar). We quantified the amplitude of the 2-ms EP to characterize the subthalamic and cortical topography of the hyperdirect pathway. We found that ventral STN stimulation elicited larger amplitude potentials than dorsal STN stimulation, suggesting stronger prefrontal-ventral STN connectivity (p = 4.0 × 10−6, Wilcoxon signed rank test; Figure 1E). Furthermore, greater EP amplitudes were found in channels covering the IFG regions compared to neighboring regions, suggesting stronger hyperdirect connectivity for the IFG than more distant cortical regions (Figure 1F). We ruled out artifactual contributions to this short-latency, low-amplitude event by manipulating stimulation and recording paradigms. Reversal of the stimulating anode and cathode reversed the stimulation artifact, but not the polarity of the EP (Figure 1G). We performed additional control experiments in 5 subjects. EPs scaled with stimulation current (Figure S1A) were invariant to the ECoG referencing scheme (Figure S1B), were not a cumulative effect of constant 10-Hz stimulation (Figure S1C), and did not arise from pallidal stimulation (Figure S1D). Across all of the subjects, we conducted matched analyses of EP latency, subthalamic topography, and cortical topography. The mean latency of the earliest cortical EP following STN stimulation was 2.2 ± 0.2 ms (Figure 2A). Ventral STN stimulation elicited larger-amplitude EPs than dorsal STN stimulation (p = 4.9 × 10−4, Wilcoxon signed rank test; Figure 2B). In the cortical regions that we covered, evoked responses were greatest in the IFG and the perisylvian region of the superior temporal lobe, with a tapering of amplitudes in peripheral regions (Figures 2C and S2). Hyperdirect EPs were elicited in the hemisphere ipsilateral to the stimulated STN in subjects with left or right ECoG coverage. To compare evoked activity in both hemispheres, we evaluated EPs in a single subject who received both left and right ECoG during 2 separate surgeries (Figure S3A). We found similar evoked responses ∼2 ms after left and right STN stimulation, indicating that lateral projections to the STN are not strongly lateralized (Figure S3B). The latency of the evoked response was earlier on the right hemisphere than on the left (p = 5.9 × 10−4, Wilcoxon rank-sum test; Figure S3C). Cortical topography was similar on both sides (Figure S3D), with the smallest evoked responses in contacts furthest from the IFG. Following the 2-ms potential, the next distinct cortical evoked event occurred 6.0 ± 0.35 ms after stimulation (Figure S4A). Even at this longer latency, conduction is still rapid enough to be mediated by retrograde activation of hyperdirect fibers, so we also assessed the topography of this longer latency potential. We found subjects in which the topography of the 6-ms potential clearly differed from that of the 2-ms potential, with larger amplitudes over dorsolateral prefrontal cortex than over the IFG, although in other subjects the topographies did not differ (see examples in Figure S4B). Across all of the subjects, the 6-ms potential was more broadly distributed across the prefrontal cortex (Figure S4C). This suggests that a more “diffuse” hyperdirect pathway from widespread prefrontal areas could use slightly smaller diameter axons, while the largest diameter, shortest latency fibers are relatively more restricted to the IFG-STN pathway (Figure 2C). To characterize the role of the prefrontal-subthalamic hyperdirect pathway in movement inhibition, subjects performed a visual stop signal task (Figure 3A). In 66% of trials, a left or right arrow cued a left or right button press, respectively (GO trials). In 33% of trials, a STOP cue followed the GO cue after a variable delay, signaling a halt in movement (STOP trials). Across all of the subjects, the mean GO trial accuracy was 86% ± 10% and the mean STOP accuracy was 66% ± 11% (Figure 3B). The mean GO reaction time was 779 ± 193 ms, the mean stop signal delay was 441 ± 209 ms, and the estimated SSRT was 384 ± 76 ms (Figure 3B). We generated event-related potentials (ERPs) of cortical- and STN-evoked activity during the task. After the STOP cue in successful STOP trials, ERP deflections appeared in both the cortex and STN after ∼200–300 ms (Figure 3C). To quantify the lag between cortical and subthalamic ERPs, we calculated the cross correlation (Figure 3D). Across subjects, the average cross-correlation lag between all of the cortical-STN channel pairs was −90 ± 131 ms, with the cortex leading the STN (p = 0.029, t test; Figure 3E). We validated our metric for prefrontal-STN lag by quantifying the temporal offset of cortical and STN ERPs with 1 alternative method. In ECoG and STN channels with distinct, matching ERP deflections, we calculated the difference in time between the deflection onset (maximum point in the upward deflection). Both calculations of cortico-STN ERP latency offset indicate that cortical activity precedes subthalamic activity during stopping (Figure 3E). Next, we asked whether the degree of circuit co-activation was linked to behavior. The mean prefrontal-subthalamic correlation across subjects was 0.46 ± 0.15 (Figure 3F). Across subjects, the degree of correlation was inversely related to the SSRT (p = 0.040, r = 0.65, Spearman correlation; Figure 3G), suggesting that greater hyperdirect circuit activity is linked to faster stopping. Although movement inhibition is impaired in PD (Gauggel et al., 2004Gauggel S. Rieger M. Feghoff T.A. Inhibition of ongoing responses in patients with Parkinson’s disease.J. Neurol. Neurosurg. Psychiatry. 2004; 75: 539-544Crossref PubMed Scopus (212) Google Scholar), we did not find physiology or stopping behaviors to be correlated with parkinsonian severity: subjects’ total scores on the Unified PD Rating Scale were not correlated with the SSRT (p = 0.82, r = 0.084, Pearson correlation) or with cortico-STN correlation during stopping (p = 0.72, r = 0.13, Pearson correlation). Within subjects, we looked for physiological predictors of behavior that would differentiate between successful and failed STOP trials. We hypothesized 3 different models that could produce success versus failure: (1) IFG-STN activity is more correlated during successful stopping, (2) IFG-STN lag is shorter during successful stopping, and (3) IFG-STN activity is initiated more quickly during successful stopping. Within subjects, we did not find differences in cortico-subthalamic correlation (p = 0.73, t test; Figure S5A) or IFG-STN lag (p = 0.93, t test; Figure S5B) during successful versus failed stopping. We found that cortical ERPs during successful stopping preceded activity during failed stopping within subjects, with a mean lag of −12 ± 21 ms (p = 0.050, 1 sample t test; Figure S5C), suggesting that faster initiation of IFG-STN activity is important for successful stopping. Previous studies characterizing single-site activity in either the IFG or the STN during stopping have linked modulations of beta power to successful stopping (Alegre et al., 2013Alegre M. Lopez-Azcarate J. Obeso I. Wilkinson L. Rodriguez-Oroz M.C. Valencia M. Garcia-Garcia D. Guridi J. Artieda J. Jahanshahi M. Obeso J.A. The subthalamic nucleus is involved in successful inhibition in the stop-signal task: a local field potential study in Parkinson’s disease.Exp. Neurol. 2013; 239: 1-12Crossref PubMed Scopus (98) Google Scholar, Kühn et al., 2004Kühn A.A. Williams D. Kupsch A. Limousin P. Hariz M. Schneider G.H. Yarrow K. Brown P. Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance.Brain. 2004; 127: 735-746Crossref PubMed Scopus (479) Google Scholar, Ray et al., 2012Ray N.J. Brittain J.S. Holland P. Joundi R.A. Stein J.F. Aziz T.Z. Jenkinson N. The role of the subthalamic nucleus in response inhibition: evidence from local field potential recordings in the human subthalamic nucleus.Neuroimage. 2012; 60: 271-278Crossref PubMed Scopus (96) Google Scholar, Swann et al., 2009Swann N. Tandon N. Canolty R. Ellmore T.M. McEvoy L.K. Dreyer S. DiSano M. Aron A.R. Intracranial EEG reveals a time- and frequency-specific role for the right inferior frontal gyrus and primary motor cortex in stopping initiated responses.J. Neurosci. 2009; 29: 12675-12685Crossref PubMed Scopus (294) Google Scholar, Swann et al., 2012Swann N.C. Cai W. Conner C.R. Pieters T.A. Claffey M.P. George J.S. Aron A.R. Tandon N. Roles for the pre-supplementary motor area and the right inferior frontal gyrus in stopping action: electrophysiological responses and functional and structural connectivity.Neuroimage. 2012; 59: 2860-2870Crossref PubMed Scopus (270) Google Scholar). We therefore conducted frequency domain analyses to characterize stopping-related oscillatory activity in the IFG and STN and stopping-related coherence between these structures. Figure 4A illustrates activity in a single cortical and a single STN channel for a sample patient. In single trials, delta activity in the IFG and STN increases immediately after the STOP cue. The onset of delta power modulation has a consistent temporal relationship with the onset of the STOP cue, and it does not appear after the GO cue (Figure S6A), suggesting that it is a modulation specific to the stopping process. Beta power decreases after the GO cue, and then increases after the STOP cue in the IFG and STN (Figures 4A and S6A). These delta and beta modulations were significant in the trial-averaged spectrograms (Figure S6). The increase in beta power occurred after the estimated time of stopping. Pooled activity across all of the subjects shows similar modulations in the grand average spectrograms (Figure 4B). We used the grand average spectrograms to characterize the cortical topography of stopping-related activity. In the regions covered, the IFG had the greatest task-related delta and beta power (p < 0.05 multifactorial ANOVA, with post hoc Tukey’s honestly significant difference (HSD) pairwise comparisons; Figure 4C). Since stopping-related delta activity in the frequency domain analyses is of short duration, it does not necessarily reflect an oscillatory phenomenon. This frequency domain modulation likely reflects the same ERP captured in the time domain. In support of this, task-evoked delta power was correlated with the amplitude of the ERP (p = 0.027, r = 0.17, Spearman correlation; Figure 4D). Finally, we asked whether beta modulations in IFG and STN, or coherent beta band interactions between IFG and STN, predicted stopping behaviors, either between or within subjects. Beta power at each site individually, quantified in the 13–30 Hz range and in 250-ms windows before and after the SSRT, was not predictive of SSRT (Bonferroni-corrected p > 0.05, Spearman correlation). Next, we analyzed beta in subject-specific narrow frequency bands, assessing beta amplitude and beta bursts in both the IFG and STN. Beta amplitude, burst rate, burst size, and burst duration (Hannah et al., 2019Hannah R. Muralidharan V. Sundby K.K. Aron A.R. Temporally-precise disruption of prefrontal cortex informed by the timing of beta bursts impairs human action-stopping.bioRxiv. 2019; https://doi.org/10.1101/843557Crossref Google Scholar) in both sites were not predictive of SSRT independently (Bonferroni-corrected p > 0.05, Spearman correlation) or in a combined multivariate regression model (p = 0.22, R2 = 0.35). Within subjects, these metrics also did not differentiate successful versus failed stopping (Bonferroni-corrected p > 0.05, Wilcoxon signed rank test). Furthermore, we did not find that beta amplitude or beta bursts were predictive of GO reaction times in either the IFG or STN (Bonferroni-corrected p > 0.05, Spearman correlation). Oscillatory coherence between the IFG and STN was also not predictive of SSRT in the beta band (p = 0.57, r = −0.21, Spearman correlation; Figure 4E) or in any other frequency range (Figure S7). We also looked for oscillatory interactions between IFG and STN by analyzing the power spectrum of the time-domain measure of synchronization discussed above, the cross correlation of the IFG and STN ERPs. These power spectra were calculated across all of the contact pairs and then averaged for each patient. We found some patients with a visible peak in the beta band, which is consistent with an oscillatory coherence between the prefrontal cortex and STN during stopping, although not all of the patients showed this peak (examples in Figure S8). However, there was no difference in SSRTs between patients with and without a beta peak (p = 0.062, Wilcoxon rank-sum test). Thus, in this population of PD patients taken off dopaminergic medication, we did not find evidence for a relationship between beta modulation and stopping or going in this circuit. We used invasive brain recordings in PD patients to characterize the IFG-STN circuit and its activity during stopping. By stimulating in the STN and recording in the prefrontal cortex, we identified a fast EP that provides the first physiological evidence of hyperdirect (monosynaptic) connectivity between the IFG and ventral STN in humans. During a stop signal task, we showed correlated stopping-related evoked activity in both the IFG and STN, and the degree of co-activation of these structures is predictive of stopping speed across subjects. Although we did find increases in IFG and STN beta at the estimated time of stopping, beta coherence was not correlated with stopping speed. Our study is the first to show that the hyperdirect circuit co-modulation is linked to stopping behaviors, which has broad implications for stimulation-based therapies to treat maladaptive movement inhibition. The hyperdirect pathway was initially proposed to be a rapid connection from the motor cortical regions to the STN, bypassing the striatum and providing rapid modulation of basal ganglia output (Nambu et al., 2002Nambu A. Tokuno H. Takada M. Functional significance of the cortico-subthalamo-pallidal ‘hyperdirect’ pathway.Neurosci. Res. 2002; 43: 111-117Crossref PubMed Scopus (804) Google Scholar). Subthalamic innervation from primary motor, supplementary motor, and premotor afferents was first identified in non-human primates using electrophysiological and histological techniques (Monakow et al., 1978Monakow K.H. Akert K. Künzle H. Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey.Exp. Brain Res. 1978; 33: 395-403Crossref PubMed Scopus (284) Google Scholar, Nambu et al., 1996Nambu A. Takada M. Inase M. Tokuno H. Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area.J. Neurosci. 1996; 16: 2671-2683Crossref PubMed Google Scholar, Nambu et al., 1997Nambu A. Tokuno H. Inase M. Takada M. Corticosubthalamic input zones from forelimb representations of the dorsal and ventral divisions of the premotor cortex in the macaque monkey: comparison with the input zones from the primary motor cortex and the supplementary motor area.Neurosci. Lett. 1997; 239: 13-16Crossref PubMed Scopus (130) Google Scholar). In humans, subthalamic stimulation elicits fast-latency EPs in motor cortical regions, recorded using EEG (Ashby et al., 2001Ashby P. Paradiso G. Saint-Cyr J.A. Chen R. Lang A.E. Lozano A.M. Potentials recorded at the scalp by stimulation near the human subthalamic nucleus.Clin. Neurophysiol. 2001; 112: 431-437Crossref PubMed Scopus (97) Google Scholar, Baker et al., 2002Baker K.B. Montgomery Jr., E.B. Rezai A.R. Burgess R. Lüders H.O. Subthalamic nucleus deep brain stimulus evoked potentials: physiological and therapeutic implications.Mov. Disord. 2002; 17: 969-983Crossref PubMed Scopus (115) Google Scholar, Walker et al., 2012Walker H.C. Huang H. Gonzalez C.L. Bryant J.E. Killen J. Cutter G.R. Knowlton R.C. Montgomery E.B. Guthrie B.L. Watts R.L. Short latency activation of cortex during clinically effective subthalamic deep brain stimulation for Parkinson’s disease.Mov. Disord. 2012; 27: 864-873Crossref PubMed Scopus (70) Google Scholar) and ECoG (Kelley et al., 2018Kelley R. Flouty O. Emmons E.B. Kim Y. Kingyon J. Wessel J.R. Oya H. Greenlee J.D. Narayanan N.S. A human prefrontal-subthalamic circuit for cognitive control.Brain. 2018; 141: 205-216Crossref PubMed Scopus (47) Google Scholar, Miocinovic et al., 2018Miocinovic S. de Hemptinne C. Chen W. Isbaine F. Willie J.T. Ostrem J.L. Starr P.A. Cortical Potentials Evoked by Subthalamic Stimulation Demonstrate a Short Latency Hyperdirect Pathway in Humans.J. Neurosci. 2018; 38: 9129-9141Crossref PubMed Scopus (41) Google Scholar), which is consistent with the retrograde activation of a hyperdirect pathway. More recently, attention has focused on a possible prefrontal-subthalamic pathway and its role in the cognitive control of inhibition. Histological tracing in non-human primates has identified prefrontal projections to the STN, with a topography favoring more ventral regions of the STN (Haynes and Haber, 2013Haynes W.I. Haber S.N. The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for basal ganglia models and deep brain stimulation.J. Neurosci. 2013; 33: 4804-4814Crossref PubMed Scopus (283) Google Scholar). However, there has been limited anatomic or physiological characterization of this pathway in humans. Our study is the first to use invasive electrodes at both the origin and the termination of the prefrontal-subthalamic hyperdirect pathway to show monosynaptic connectivity. Consistent with EP latencies reported in the EEG literature, we found an average latency of 2.2 ms for the earliest evoked event across all subjects. This EP likely reflects rapid axonal back-propagation, with a conduction time of ∼25 m/s, assuming a 5-cm distance between the prefrontal cortex and STN. These fibers are slower than the large axon fibers of the corticospinal tract, which have conduction velocities of 41 m/s (Ashby et al., 1998Ashby P. Strafella A. Dostrovsky J.O. Lozano A. Lang A.E. Immediate motor effects of stimulation through electrodes implanted in the human globus pallidus.Stereotact. Funct. Neurosurg. 1998; 70: 1-18Crossref PubMed Scopus (49) Google Scholar). This is consistent with rodent tract tracing studies, showing that corticospinal fibers that collateralize to the STN have smaller-diameter fibers than corticospinal axons that do not collateralize (Kita and Kita, 2012Kita T. Kita H. The subthalamic nucleus is one of multiple innervation sites for long-range corticofugal axons: a single-axon tracing study in the rat.J. Neurosci. 2012; 32: 5990-5999Crossref PubMed Scopus (143) Google Scholar). We also found a longer latency EP at 6 ms, suggesting hyperdi" @default.
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• W3010535098 title "Prefrontal-Subthalamic Hyperdirect Pathway Modulates Movement Inhibition in Humans" @default.
• W3010535098 cites W1550030659 @default.
• W3010535098 cites W1586994437 @default.
• W3010535098 cites W1940166213 @default.
• W3010535098 cites W1965680082 @default.
• W3010535098 cites W1973275321 @default.
• W3010535098 cites W1973275441 @default.
• W3010535098 cites W1973670737 @default.
• W3010535098 cites W1983297775 @default.
• W3010535098 cites W1983965289 @default.
• W3010535098 cites W1984652306 @default.
• W3010535098 cites W1989058665 @default.
• W3010535098 cites W2004293194 @default.
• W3010535098 cites W2008098183 @default.
• W3010535098 cites W2009772699 @default.
• W3010535098 cites W2015743230 @default.
• W3010535098 cites W2026851056 @default.
• W3010535098 cites W2032242647 @default.
• W3010535098 cites W2039729702 @default.
• W3010535098 cites W2047471489 @default.
• W3010535098 cites W2052214584 @default.
• W3010535098 cites W2059372579 @default.
• W3010535098 cites W2073690417 @default.
• W3010535098 cites W2078014777 @default.
• W3010535098 cites W2080316356 @default.
• W3010535098 cites W2082156070 @default.
• W3010535098 cites W2083932518 @default.
• W3010535098 cites W2090475450 @default.
• W3010535098 cites W2095401753 @default.
• W3010535098 cites W2101135654 @default.
• W3010535098 cites W2104822204 @default.
• W3010535098 cites W2110830643 @default.
• W3010535098 cites W2123820408 @default.
• W3010535098 cites W2134654421 @default.
• W3010535098 cites W2144344332 @default.
• W3010535098 cites W2147863265 @default.
• W3010535098 cites W2151721316 @default.
• W3010535098 cites W2161472384 @default.
• W3010535098 cites W2163910633 @default.
• W3010535098 cites W2168899895 @default.
• W3010535098 cites W2277882088 @default.
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• W3010535098 doi "https://doi.org/10.1016/j.neuron.2020.02.012" @default.
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