Biology subjects

Siebner, H. R.

Publications and source records attributed to Siebner, H. R..

At least 19 recordsLinked to original sources

bioRxiv2026

Immediate cortical responses to transcranial magnetic stimulation of the human motor leg area

Background: Immediate transcranial evoked potentials (iTEPs) are ultra-early electroencephalographic responses elicited by single-pulse transcranial magnetic stimulation (TMS) of the primary motor cortical hand area (M1-HAND). Their characteristic latency, waveform, and sensitivity to short-interval intracortical inhibition suggest a close relationship to the cortical generators of indirect corticospinal volleys (I-waves). Here, we tested the hypothesis that iTEPs constitute a fundamental physiological response of human motor cortex and therefore generalize across motor representations, including the leg representation (M1-LEG). Methods: Single-pulse TMS was delivered over the motor cortical representation of the right tibialis anterior (TA) in 16 healthy volunteers. In a subset of participants (n=10), stimulus-response curves and paired-pulse short-interval intracortical inhibition (SICI) measures were obtained. Results: TMS of M1-LEG elicited reproducible iTEPs consisting of a slow positive deflection with superimposed high-frequency peaks with topographic maxima in electrodes adjacent to the stimulation site. M1-LEG iTEPs emerged close to active motor threshold and increased in prevalence and amplitude with increasing stimulation intensity. Paired-pulse stimulation produced consistent SICI of the second and third iTEP peaks. M1-LEG stimulation also evoked conventional later TEPs with latencies and polarities closely resembling those recorded after M1-HAND stimulation. Conclusions: TMS of the human M1-LEG elicits robust iTEPs that closely resemble those recorded from M1-HAND in their timing, intensity dependence, and sensitivity to intracortical inhibition. These findings indicate that iTEPs are not specific to M1-HAND but reflect a general physiological response of human motor cortex closely linked to corticospinal I-wave generation. This broadens their utility as a non-invasive probe of excitatory and inhibitory circuit dynamics throughout the human motor system.

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bioRxiv2026

Striatal Dopaminergic Dysfunction Constrains Motor Invigoration in Parkinson's Disease

Bradykinesia is a cardinal motor feature of Parkinson's disease and is characterised by a reduced ability to generate movements with normal speed and force. Although nigrostriatal dopamine loss is regarded as the primary cause, direct human evidence linking dopaminergic degeneration to striatal dysfunction and impaired motor output and vigour remains limited. To investigate this relationship, we developed a grip-force paradigm that quantified movement vigour as the ability to rapidly generate force. Fifty-three individuals with Parkinson's disease, 30 with levodopa-induced dyskinesia and 23 without, and 25 age-matched healthy controls performed the task during 3T functional MRI. Thirty-five patients additionally underwent dopamine transporter PET imaging to assess associations among nigrostriatal dopaminergic integrity, striatal activity and motor performance. Patients with Parkinson's disease showed marked reductions in initial movement vigour accompanied by reduced bilateral putaminal activation during force generation. Lower putaminal dopamine transporter binding was associated with both poorer movement vigour and weaker grip-related putaminal activation during functional MRI, establishing a direct link between nigrostriatal degeneration, impaired striatal recruitment and motor slowing. Functional MRI further revealed reduced reward-related responses in the nucleus accumbens. Across participants, stronger reward-related ventral striatal activity was associated with greater movement vigour, suggesting that motivational processes contribute independently to motor performance. Patients with levodopa-induced dyskinesia exhibited more severe putaminal dopaminergic denervation than patients without dyskinesia but showed no additional impairment of movement vigour or striatal task responses. These findings provide direct in vivo evidence that dorsal nigrostriatal dopaminergic degeneration constrains movement vigour in Parkinson's disease through reduced striatal recruitment during action generation. Impaired reward-related signalling in ventral striatum emerges as an additional, partly independent mechanism influencing motor performance, highlighting distinct motor and motivational contributions to bradykinesia.

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bioRxiv2026

Opposing modulation of cortical and corticospinal excitability across movement-related beta stages

Discrete voluntary movement depends on rapid changes in neural excitability across cortical and corticospinal circuits, yet how intrinsic movement-related neural states shape multi-level excitability remains unclear. Here, we combined individualized, state-targeted transcranial magnetic stimulation (TMS) with electroencephalography and electromyography recordings during visually cued finger movements to probe excitability across movement-related beta-band dynamics during two complementary experiments. Immediate transsynaptic cortical excitability closely tracked intrinsic beta dynamics, with attenuation of the second immediate TMS-evoked potential during beta desynchronization and recovery during the post-movement beta rebound. In contrast, corticospinal excitability showed the opposite pattern, with larger motor-evoked potentials during beta desynchronization and reduced responses during beta rebound. Together, these findings identify endogenous beta-state dynamics as a key regulator of movement-related cortical excitability and reveal a fundamental dissociation between how intrinsic brain activity tunes local cortical excitability and corticospinal output in humans.

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bioRxiv2026

Age-Related Differences in Bimanual Coordination Are Associated with Increased Cerebellar Activity and Reduced Frontal Recruitment

Bimanual coordination declines in late adulthood, but the neural mechanisms underlying these changes remain unclear. Age-related differences in brain activity have been interpreted either as compensatory recruitment of frontal cognitive control regions or as a shift toward feedback-based control, supported by sensory and cerebellar processing systems. To investigate these hypotheses, we examined brain activity, using fMRI in twenty-three younger and twenty-three older adults performing a bimanual visuomotor pinch-force task with different task complexities. Behaviourally, older adults showed lower accuracy than younger adults, particularly when task demands increased. Neuroimaging results revealed general age-dependent increases in activity within posterior cerebellar lobules VI-VII, regions overlapping with the classical oculomotor vermis and implicated in visuomotor adaptation, movement calibration, and error-based motor learning. In addition, during the more demanding task condition, older adults showed a greater increase in activation of anterior cerebellar lobules IV-V and a decrease in activation of the medial frontal pole (BA10). No consistent age-related increases or decreases in task related activation was observed in parieto-frontal regions. Moreover, better task performance across age groups was associated with lower activation in frontal cognitive control regions, including the superior medial frontal gyrus and right inferior frontal gyrus. Together, these results suggest increased feedback- and error-related sensorimotor processing in older adults involving the cerebellum and frontal cortex.

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bioRxiv2026

Direct Assessment of Short-Latency Intracortical Inhibition via Immediate TMS-Evoked Potentials

Short-interval intracortical inhibition (SICI) is the most widely used neurophysiological index of GABAergic inhibition in the human cortex. However, it is an indirect measure, inferring synaptic inhibition from suppression of peripherally recorded motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In the standard protocol, a subthreshold conditioning pulse suppresses the MEP evoked by a suprathreshold test pulse delivered 1-5 ms later. Interpretation is further complicated by temporal overlap with short-interval intracortical facilitation (SICF), reflecting excitatory interactions at interstimulus intervals of [~]1.5 and 2.7 ms. To overcome these limitations, we recorded immediate TMS-evoked EEG potentials (iTEPs; 1-10 ms post-stimulus) as a more direct measure of motor cortical activity in 16 healthy volunteers (20-35 years; 7 male). The conventional SICI protocol suppressed only later components of the iTEP, likely corresponding to late corticospinal volleys previously identified in epidural spinal recordings after suprathreshold TMS, while the earliest iTEP component was unaffected. Importantly, later iTEPs were suppressed to a similar extent whether conditioning-test intervals coincided with SICF peaks or troughs, and the magnitude of iTEP suppression correlated with concurrently recorded paired-pulse MEP suppression. SICI also reduced an early TEP component (N15; 10-20 ms), but paired-pulse N15 suppression showed a different dependence on stimulus intensity and did not correlate with MEP suppression. These findings demonstrate that SICI measured via MEPs does not reflect a global index of cortical GABAergic motor cortical inhibition but instead reflects inhibition within specific cortical circuits that can be investigated directly with iTEPs.

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bioRxiv2026

Network reconfiguration preserves prediction error signallingin the aging brain

Cognitive aging is widely associated with a progressive weakening of predictive brain mechanisms. This view is supported by decades of electrophysiological studies reporting attenuated mismatch responses in older adults. Yet the literature remains inconsistent, suggesting that aging may not uniformly attenuate predictive processing. One possibility is that multiple predictive subsystems operate concurrently but have rarely been disentangled. Here we address this question by separating whole-brain networks underlying predictive processing in source-reconstructed magnetoencephalography (MEG) data from 77 younger and older adults performing the auditory local-global paradigm. Network decomposition revealed three temporally overlapping predictive subsystems with distinct functional profiles. Aging exerted selective effects across these networks. Sensory prediction error responses were enhanced within a network linking auditory cortices with medial cingulate regions, whereas responses associated with reorientation of attention and contextual pattern processing were attenuated in older adults. The level of multivariate recurrency across these networks was preserved with aging, while the processing of sensory violations induced more recurrency and less divergence relative to contextual violations in both groups. These findings challenge the prevailing view that predictive processing simply declines with age. Instead, aging redistributes predictive resources across distinct neural systems, amplifying sensory-based processes while weakening more cognitively demanding predictive mechanisms.

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bioRxiv2025

No Evidence for Stronger Brain-Behavior Associations in the Bimanual Motor Network of Older Adults

Bimanual motor performance declines with age, is accompanied by cortical thinning and alterations in white matter microstructure within motor control networks. Aging is also associated with increased interindividual variability in behavioural and structural markers, and some studies report stronger brain-behaviour associations in older compared to younger adults. However, evidence for this remains mixed, and it is unclear whether young adults express similar relationships under comparable task demands. We tested whether bimanual performance is related differently to structural brain properties in younger and older adults. Twenty-three younger (22-27 years) and twenty-three older adults (65-70 years) performed a visually guided bimanual pinch-force task and underwent whole-brain structural magnetic resonance imaging (MRI). Fractional anisotropy (FA) and cortical thickness (CTh) were extracted from a pre-defined bilateral visuo-motor network and compared between groups. In regions showing significant age-related differences, we tested whether and how FA and CTh values correlates with bimanual performance within each age group. Older adults showed lower FA in the anterior portions of the bilateral superior longitudinal fasciculus (SLF) III and right inferior fronto-occipital fasciculus (IFOF), and lower CTh across most visuomotor regions, along with lower bimanual performance compared to young adults. Structure-function analyses in these areas revealed that bimanual performance correlated positively with FA in the anterior segment of the right SLF III in younger but not older adults. Furthermore, larger hemispheric asymmetries in cortical thickness between the dominant and non-dominant SMA correlated positively with larger intermanual performance differences between the dominant and non-dominant hand in younger but not older adults. These findings suggest that intrahemispheric white-matter integrity and interhemispheric cortical balance support efficient bimanual control in early adulthood, but they provide no evidence that structure-function relationships increase with age.

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bioRxiv2025

Target engagement in human motor cortex induced by constant sinusoidal and amplitude-modulated transcranial AC stimulation

Transcranial alternating current stimulation (tACS) is a noninvasive technique for modulating brain oscillations. While sinusoidal tACS (sin-tACS) delivers current at a constant amplitude, amplitude-modulated tACS (AM-tACS) uses a high-frequency carrier modulated by a low-frequency envelope. We systematically compared the acute effects of sin-tACS at theta (5 Hz), alpha (10 Hz), beta (20 Hz), and gamma (140 Hz) frequencies, and AM-tACS (140 Hz carrier frequency modulated at theta, alpha, or beta) on corticospinal excitability. Healthy participants received 2 mA peak-to-peak tACS to the primary motor hand area (M1HAND) via a bipolar montage (M1HAND-Pz). Each tACS block consisted of ten 30-second stimulation periods interleaved with 6-second pauses, followed by 11 minutes without stimulation. Corticospinal excitability was assessed during each block using single-pulse transcranial magnetic stimulation (TMS), delivered at the peak and trough of tACS. MEP amplitudes were generally larger at the trough. Only beta sin-tACS and theta AM-tACS significantly modulated corticospinal excitability. Beta sin-tACS increased MEP amplitudes in early stimulation epochs, while theta AM-tACS facilitated MEPs in later stimulation epochs and this facilitation persisted briefly after stimulation ended. Participants with stronger early responses to beta sin-tACS also tended to show greater delayed effects with theta AM-tACS. These excitability changes during tACS were not predicted by simulated electric field strength. A follow-up EEG experiment revealed that beta sin-tACS increased beta power over left sensorimotor cortex, while theta AM-tACS decreased beta power over midline parietal cortex. These EEG changes were restricted to tACS pauses. The results show that sin-tACS and AM-tACS can both modulate corticospinal excitability, but functional changes differ in temporal dynamics, frequency specificity, and cortical region engagement.

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bioRxiv2025

Blunted response of caudal locus coeruleus to arousing stimuli in Parkinson's Disease

Parkinsons disease (PD) causes progressive degeneration of noradrenergic neurons in the locus coeruleus (LC), contributing to non-motor symptoms. Using neuromelanin-sensitive ultra-high field (7T) MRI, we previously identified a reduction in neuromelanin signal in the caudal LC, indicating a rostro-caudal gradient of noradrenergic cell loss. Caudal LC degeneration was associated with greater severity of non-motor symptoms such as orthostatic hypotension and apathy. In the current study, we expanded the PD cohort to further validate the structure-symptom relationships within the LC and investigate how degeneration along the rostro-caudal LC axis affects arousal-related functional responsivity. To this end, 71 people with PD in the ON-medication state and 40 age- and sex-matched healthy controls underwent clinical assessments and 7T magnetization transfer-weighted (MTw) MRI to quantify structural changes along the rostro-caudal LC axis. A subgroup of 30 people with PD and 27 controls underwent 7T fMRI to assess LC responsivity to arousing auditory and visual stimuli in two fMRI sessions on separate days. Healthy controls were scanned twice without medication, while people with PD were studied on and off dopaminergic medication in counterbalanced order. In the PD group, MTw MRI confirmed a significant reduction of the regional neuromelanin signal in caudal LC relative to the control group (P = 0.0099). This structural disintegration correlated with orthostatic hypotension (P = 0.0087) and cognitive impairment (P = 0.036), corroborating its clinical relevance. Functional MRI revealed reduced activation of the caudal LC to arousing visual and auditory stimuli in people with PD relative to controls (P = 0.012). This difference reached statistical significance only in the ON-medication state, with a similar but non-significant trend in the OFF-medication state (P = 0.10). In an exploratory analysis of a smaller sub-sample, structural and functional caudal LC signals were significantly correlated in both people with PD and healthy controls (P = 0.0069). Together, the findings provide evidence for a rostro-caudal gradient of LC pathology in PD at both structural and functional levels. While structural MRI provides fine-grained insights into spatial gradients of disease-related pathology, functional MRI captures impaired functional responsivity of caudal LC. The presence of arousal-induced hypoactivation of caudal LC in the ON-medication state indicates that LC dysfunction extends beyond dopamine deficits in PD, highlighting complex interactions between dopaminergic and noradrenergic systems.

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bioRxiv2025

Quantifying state-dependent control properties of brain dynamics from perturbation responses

The brain can be conceptualized as a control system facilitating transitions between states, such as from rest to motor activity. Applying network control theory to measurements of brain signals enables characterization of brain dynamics through control properties. However, most prior studies that have applied network control theory have evaluated brain dynamics under unperturbed conditions, neglecting the critical role of external perturbations in accurate system identification. In this study, we combine a perturbation input paradigm with a network control theory framework and propose a novel method for estimating the controllability Gramian matrix in a simple, theoretically grounded manner. This method provides insights into brain dynamics, including overall controllability (quantified by the Gramians eigenvalues) and specific controllable directions (represented by its eigenvectors). As a proof of concept, we applied our method to transcranial magnetic stimulationinduced electroencephalographic responses across four motor-related states and two resting states. We found that states such as open-eye rest, closed-eye rest, and motor-related states were more effectively differentiated using controllable directions than overall controllability. However, certain states, like motor execution and motor imagery, remained indistinguishable using these measures. These findings indicate that some brain states differ in their intrinsic control properties as dynamical systems, while others share similarities that make them less distinguishable. This study underscores the value of control theory-based analyses in quantitatively how intrinsic brain states shape the brains responses to stimulation, providing deeper insights into the dynamic properties of these states. This methodology holds promise for diverse applications, including characterizing individual response variability and identifying conditions for optimal stimulation efficacy. Significant statementThe brain can be viewed as a control system transitioning between states, such as from rest to motor activity. Previous studies using network control theory mostly evaluated brain dynamics without external perturbations, neglecting their role in accurate system identification. This study integrates perturbation inputs with network control theory to propose a method for estimating the controllability Gramian, thereby providing insights into brain dynamics. We applied this approach to TMS-induced EEG responses in motor-related and resting states. Our findings show that controllable directions (eigenvectors) allow better discrimination between states than overall controllability. Our method can quantitatively assess brain state differences, and has potential applications in characterizing individual response variability and optimizing stimulation efficacy.

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bioRxiv2025

Rostro-caudal TMS mapping of immediate transcranial evoked potentials reveals a pericentral crescendo-decrescendo pattern

BackgroundWe recently demonstrated that single-pulse TMS of the primary sensorimotor hand area (SM1HAND) elicits an immediate transcranial evoked potential (iTEP). This iTEP response appears within 2-7 ms post-TMS, featuring high-frequency peaks superimposed on a slow positive wave. Here, we used a linear TMS-EEG mapping approach to characterize the rostro-caudal iTEP expression and compared it to that of motor-evoked potentials (MEPs). MethodsIn 15 healthy young volunteers (9 females), we identified the iTEP hotspot in left SM1HAND. We applied single biphasic TMS pulses at an intensity of 110% of resting motor threshold over six cortical sites along a rostro-caudal axis (2 cm rostral to 3 cm caudal to the SM1HAND hotspot). We analyzed site-specific iTEP and MEP responses. ResultsiTEP magnitude decreased rostrally and caudally from the SM1HAND hotspot. MEPs exhibited a similar rostro-caudal crescendo-decrescendo pattern. While iTEP and MEP response profiles were similar, normalized iTEP amplitudes decayed less rapidly at the first postcentral site. DiscussionThese findings support the idea that pericentral iTEPs reflect a direct response signature of the pericentral cortex, possibly involving a synchronized TMS-induced excitation of cortical pyramidal tract neurons. Similar but non-identical rostro-caudal patterns suggest that iTEPs and MEPs may arise from overlapping but distinct neuronal populations.

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bioRxiv2024

Fast FEM-based Electric Field Calculations for Transcranial Magnetic Stimulation

ObjectiveTo provide a Finite-Element Method (FEM) for rapid, repeated evaluations of the electric field induced by transcranial magnetic stimulation (TMS) in the brain for changing coil positions. ApproachPreviously, we introduced a first-order tetrahedral FEM enhanced by super- convergent patch recovery (SPR), striking a good balance between computational efficiency and accuracy (Saturnino et al 2019 J. Neural Eng. 16 066032). In this study, we refined the method to accommodate repeated simulations with varying TMS coil position. Starting from a fast direct solver, streamlining the pre- and SPR-based post-calculation steps using weight matrices computed during initialization strongly improved the computational efficiency. Additional speedups were achieved through efficient multi-core and GPU acceleration, alongside the optimization of the volume conductor model of the head for TMS. Main ResultsFor an anatomically detailed head model with [~]4.4 million tetrahedra, the optimized implementation achieves update rates above 1 Hz for electric field calculations in bilateral gray matter, resulting in a 60-fold speedup over the previous method with identical accuracy. An optimized model without neck and with adaptive spatial resolution scaled in dependence to the distance to brain grey matter, resulting in [~]1.9 million tetrahedra, increased update rates up to 10 Hz, with [~]3% numerical error and [~]4% deviation from the standard model. Region-of-interest (ROI) optimized models focused on the left motor, premotor and dorsolateral prefrontal cortices reached update rates over 20 Hz, maintaining a difference of <4% from standard results. Our approach allows efficient switching between coil types and ROI during runtime which greatly enhances the flexibility. SignificanceThe optimized FEM enhances speed, accuracy and flexibility and benefits various applications. This includes the planning and optimization of coil positions, pre-calculation and training procedures for real-time electric field simulations based on surrogate models as well as targeting and dose control during neuronavigated TMS.

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bioRxiv2024

Single and paired TMS pulses engage spatially distinct corticomotor representations in human pericentral cortex

Single-pulse transcranial magnetic stimulation (TMS) of the primary motor hand area (M1-HAND) can assess corticomotor function in humans by evoking motor evoked potentials (MEP). Paired-pulse TMS at peri-threshold intensity elicits short-latency intracortical facilitation (SICF) with early peaks at inter-pulse intervals of 1.0-1.8ms (SICF1) and 2.4-3ms (SICF2). The similarity between the periodicity of SICF and indirect (I-)waves in the corticospinal volleys evoked by single-pulse TMS suggests that SICF originates from I-wave generating circuits. This study aimed to explore the mechanisms of MEP generation by mapping the corticomotor representations of single-pulse and paired-pulse TMS targeting SICF1 and SICF2 peaks in 14 participants (7 female). MEPs were recorded from two hand muscles and the spatial properties of each corticomotor map were analyzed. For both hand muscles, we found a consistent posterior shift of the center-of-gravity (CoG) for SICF maps compared to single-pulse maps, with a larger shift for SICF1. CoG displacement in the SICF1 map correlated with individual SICF1 latencies. Further, ADM maps consistently peaked more medially than FDI maps and paired-pulse TMS resulted in larger corticomotor maps than single-pulse TMS. This is the first study to show that circuits responsible for SICF have a more posterior representation in the precentral crown than those generating MEPs via single-pulse TMS. These findings indicate that paired-pulse TMS probing SICF1, SICF2, and single-pulse TMS engage overlapping but spatially distinct cortical circuits, adding further insights into the intricate organization of the human motor hand area. New & NoteworthySingle- and paired-pulse transcranial magnetic stimulation (TMS) is widely used to study corticomotor physiology in humans, but do they engage the same intracortical circuits? We compared the spatial properties of corticomotor maps elicited by single-pulse TMS to those elicited by paired-pulse short-latency intracortical facilitation (SICF). SICF maps consistently showed a posterior shift in center of gravity compared to single-pulse maps, suggesting that paired-pulse TMS engages cortical circuits that are spatially distinct from single-pulse TMS.

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bioRxiv2024

Methodological choices matter: A systematic comparison of TMS-EEG studies targeting the primary motor cortex

BackgroundTranscranial magnetic stimulation (TMS) triggers time-locked cortical activity that can be recorded with electroencephalography (EEG). Transcranial evoked potentials (TEPs) are widely used to probe brain responses to TMS. MethodsHere, we systematically reviewed 137 published experiments that studied TEPs elicited from TMS to the human primary motor cortex (M1) in healthy individuals to investigate the impact of methodological choices. We scrutinized prevalent methodological choices and assessed how consistently they were reported in published papers. We extracted amplitudes and latencies from reported TEPs and compared total cortical activation and specific TEP peaks and components. ResultsReporting of methodological details was overall sufficient, but some relevant information regarding the TMS settings and the recording and pre-processing of EEG data were missing in more than 25% of the included experiments. The published TEP latencies and amplitudes confirm the prototypical TEP waveform of M1, comprising distinct N15, P30, N45, P60, N100, and P180 peaks. However, variations in amplitude and latencies were evident across studies. Higher stimulation intensities were associated with overall larger TEP amplitudes. Active noise masking during TMS generally resulted in lower TEP amplitudes compared to no or passive masking but did not specifically impact those TEP peaks linked to long-latency sensory processing. Studies implementing independent component analysis (ICA) for artifact removal generally reported lower TEP amplitudes. ConclusionSome aspects of reporting practices could be improved in TEP studies to enable replication. Methodological choices, including TMS intensity and the use of noise masking or ICA, introduce systematic differences in reported TEP amplitudes. Further investigation into the significance of these and other methodological factors and their interactions is warranted.

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bioRxiv2023

Mapping axon diameters and conduction velocity in the rat brain - different methods tell different stories of the structure-function relationship

The structure-function relationship of nerve fibers describes an empirically determined linear relationship between axon diameter, myelin thickness (i.e., g-ratio), and conduction velocity. We investigated the structure-function relationship with different modalities in axons projecting through the corpus callosum of the rodent brain. We measured transcallosal conduction times using optogenetically evoked local field potentials (LFP) and estimated conduction velocity after measuring the callosal length with diffusion magnetic resonance imaging (dMRI) based tractography. Tractography followed the same projection as the fluorescently labeled axons in the corpus callosum. In the same animal, axon diameters were quantified using transmission electron microscopy (TEM) and dMRI. Axon distributions of TEM indicated a bimodal population, where the larger axons shrink more than the smaller ones, when comparing the modes with cryo-TEM. When applying shrinkage-correction to axon diameters from TEM of dehydrated tissue, they were better aligned with estimates from dMRI obtained in the same animal. Measured LFPs predicted axon diameters that agree with the primary mode of the axon distribution, whereas the large axons estimated by dMRI predicted latencies too short to be measured by LFPs. Different modalities show different degrees of variations, being low between animals, suggesting that the variation is methodologically dominated - not anatomically. Our results show that modalities have different sensitivity profiles to the whole axon diameter distribution. Therefore, caution must be taken when interpreting a methods prediction of a metric, as it may not represent the full but only a sub-part of the structure-function relationship of an axonal projection. Significance StatementWe acquire both functional and structural metrics, namely conduction velocity, pathway length, axon diameter, and g-ratio in the same cohort of animals. The transcallosal conduction time was obtained from electrophysiological measurements after contralateral optogenetic stimulation in the rat motor cortex. Cryo-fixation of the tissue reveals different shrinkages for different sub-populations in the diameter distribution. Measured latencies correspond to the small axonal subpopulation with diameters extending up to the mode of the distribution obtained with electron microscopy. Diffusion-MRI primarily appears sensitive to the larger axons, obtained with histology, after correcting for diameter weighting and shrinkage. Different modalities can have very different sensitivities to the structure-function relationship of an axonal projection which must be accounted for in the interpretation.

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bioRxiv2023

Exploring an EM-algorithm for banded regression in computational neuroscience

Regression is a principal tool for relating brain responses to stimuli or tasks in computational neuroscience. This often involves fitting linear models with predictors that can be divided into groups, such as distinct stimulus feature subsets in encoding models or features of different neural response channels in decoding models. When fitting such models, it can be relevant to allow differential shrinkage of the different groups of regression weights. Here, we explore a framework that allow for straightforward definition and estimation of such models. We present an expectation-maximization algorithm for tuning hyperparameters that control shrinkage of groups of weights. We highlight properties, limitations, and potential use-cases of the model using simulated data. Next, we explore the model in the context of a BOLD fMRI encoding analysis and an EEG decoding analysis. Finally, we discuss cases where the model can be useful and scenarios where regularization procedures complicate model interpretation.

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bioRxiv2023

Transcranial magnetic stimulation of primary motor cortex elicits a site-specific immediate transcranial evoked potential

BackgroundTranscranial evoked potentials (TEPs) measured via electroencephalography (EEG) are widely used to study the cortical responses to transcranial magnetic stimulation (TMS). Immediate transcranial evoked potentials (i-TEPs) have been obscured by pulse and muscular artifacts. Thus, the TEP peaks that are commonly reported have latencies that are too long to be caused by direct excitation of cortical neurons. MethodsIn 14 healthy individuals, we recorded i-TEPs evoked by a single biphasic TMS pulse targeting the primary motor hand area (M1HAND) or parietal or midline control sites. Sampling EEG at 50 kHz enabled us to reduce the duration of the TMS pulse artifact to a few milliseconds, while minor adjustments of the TMS coil tilt or position enabled us to avoid cranial muscular twitches during the experiment. ResultsWe observed an early positive EEG deflection starting after approx. 2 ms combined with a series of peaks with an inter-peak interval of [~]1.1-1.4 ms in electrodes overlying the stimulated sensorimotor region. This multi-peak i-TEP response was only evoked by TMS of the M1HAND region and was modified by changes in stimulation intensity and current direction. DiscussionSingle-pulse TMS of the M1HAND evokes an immediate local multi-peak response at the cortical site of stimulation. Our results suggest that the observed i-TEP patterns are genuine cortical responses evoked by TMS caused by synchronized excitation of pyramidal neurons in the targeted precentral cortex. This notion needs to be corroborated in future studies, including further investigations into the potential contribution of instrumental or physiological artifacts.

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bioRxiv2022

Dynamic involvement of premotor and supplementary motor areas in bimanual pinch force control

Many bimanual activities of daily living require quick shifts between symmetric and asymmetric motor output generated by the right and left hand. Bimanual motor control has been mostly studied during continuous repetitive tasks, while little research has been carried out in experimental settings requiring dynamic changes in motor output generated by both hands. Here, we performed functional magnetic resonance imaging (MRI) while healthy volunteers performed a visually guided, bimanual pinch force task. This enabled us to map functional activity and connectivity of premotor and motor areas during bimanual pinch force control in different task contexts, requiring mirror-symmetric or inverse-asymmetric changes in discrete pinch force exerted with the right and left hand. The bilateral dorsal premotor cortex showed increased activity and effective coupling to the ipsilateral supplementary motor area (SMA) in the inverse-asymmetric context compared to the mirror-symmetric context of bimanual pitch force control. Compared to unilateral pinches, all bimanual pinch force conditions were characterized by an increased level of activation in the bilateral primary motor hand area (M1-HAND) and stronger coupling from SMA to the ipsilateral M1-HAND. Task-related activity of a cluster in the left caudal SMA scaled positively with the degree of synchronous initiation of bilateral pinch force adjustments, irrespectively of the task context. The results suggest that the dorsal premotor cortex mediates increasing complexity of bimanual coordination by increasing coupling to the SMA-M1 network.

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