Linking cortical and behavioural inhibition: Testing the parameter specificity of a transcranial magnetic stimulation protocol

Across a series of studies, our laboratory has shown that the efficiency of action stopping is associated with the strength of GABA_A-mediated short-intracortical inhibition (SICI) as measured using transcranial magnetic stimulation (TMS). However, these studies used fixed TMS parameters, which may not optimally probe GABA_A receptor activity for each individual. In the present study, we measured the relationship between stopping efficiency and SICI using a range of TMS parameters. Participants completed a right-hand unimanual stop signal task to obtain a measure of stopping efficiency. Resting-state SICI was measured from the left primary motor cortex using six combinations of interstimulus intervals and conditioning pulse intensities. We also established the parameters which generated the strongest SICI (SICI_max) and weakest SICI (SICI_min) for each individual. We found that stopping efficiency was significantly predicted by SICI using various TMS parameters, including SICI_max. Interestingly, SICI_min accounted for a similar proportion of variance in stopping efficiency as SICI measured using other TMS parameters. The findings suggest that the relationship between stopping efficiency and SICI is robust, reliable, and not influenced by the extent to which SICI is optimally probed.     

Effects of Medications and Subthalamic Nucleus-Deep Brain Stimulation on the Cutaneous Silent Period in Patients With Parkinson's Disease

ObjectivesWe sought to evaluate whether the cutaneous silent period (CSP) could be an electrophysiological indicator reflective of the effects of therapy for Parkinson's disease (PD), including anti-PD medications or deep brain stimulation (DBS).Material and MethodsWe recorded the CSP in 43 patients with PD prior to and following the administration of medication during a pre-DBS evaluation (30 cases) and the “on” and “off” states of subthalamic nucleus DBS (13 cases). The CSP was elicited from the abductor pollicis brevis muscle by an electrical stimulation of the index finger that was 2, 4, and 15 times stronger than the sensory threshold (ST). We measured changes in latencies, including the onset, duration, and end of CSP, and waveform scores from 0 to 3. The correlation between the CSP score and unified PD rating score part III (UPDRS-III) also was assessed.ResultsThe onset latency and duration of CSP were significantly different between high- (15ST) and low-strength stimulations (2ST and 4ST). However, there were no significant latency changes (onset, duration, end of CSP) before and after receiving medication, or during the on and off state of the DBS. Anti-PD medications substantially increased the CSP waveform score only in the 4ST state. However, the waveform score significantly increased in all stimuli states during the DBS-on state. Both medication and the DBS-on state decreased the UPDRS-III. Nevertheless, there was no statistically significant correlation between the UPDRS-III and CSP waveform scores.ConclusionDifferent onset latencies and the duration of CSP between low- and high-strength stimuli support the hypotheses proposing two different reflex pathways. Despite being independent from the UPDRS-III, the CSP may be an electrophysiological indicator reflective of the changes in inhibitory activity to the spinal α-motoneuron in response to anti-PD medications and DBS.     

Simulation of transcranial magnetic stimulation in head model with morphologically-realistic cortical neurons

BackgroundTranscranial magnetic stimulation (TMS) enables non-invasive modulation of brain activity with both clinical and research applications, but fundamental questions remain about the neural types and elements TMS activates and how stimulation parameters affect the neural response.ObjectiveTo develop a multi-scale computational model to quantify the effect of TMS parameters on the direct response of individual neurons.MethodsWe integrated morphologically-realistic neuronal models with TMS-induced electric fields computed in a finite element model of a human head to quantify the cortical response to TMS with several combinations of pulse waveforms and current directions.ResultsTMS activated with lowest intensity intracortical axonal terminations in the superficial gyral crown and lip regions. Layer 5 pyramidal cells had the lowest thresholds, but layer 2/3 pyramidal cells and inhibitory basket cells were also activated at most intensities. Direct activation of layers 1 and 6 was unlikely. Neural activation was largely driven by the field magnitude, rather than the field component normal to the cortical surface. Varying the induced current direction caused a waveform-dependent shift in the activation site and provided a potential mechanism for experimentally observed differences in thresholds and latencies of muscle responses.ConclusionsThis biophysically-based simulation provides a novel method to elucidate mechanisms and inform parameter selection of TMS and other cortical stimulation modalities. It also serves as a foundation for more detailed network models of the response to TMS, which may include endogenous activity, synaptic connectivity, inputs from intrinsic and extrinsic axonal projections, and corticofugal axons in white matter.     

早期症状改善预测焦虑患者rTMS治疗的疗效

目的 探讨重复经颅磁刺激(Repetitive transcranial magnetic stimulation,rTMS)治疗焦虑障碍患者早期症状的改善能否预测最终的临床疗效。方法 选择40例2017年7月-2019年11月本院焦虑障碍患者进行rTMS治疗,早期症状改善的界限值定义为治疗1或2周后汉密尔顿焦虑量表(Hamilton anxiety scale,HAMA)减分率15%～40%,分别计算其预测治疗4周后最终临床疗效的灵敏度、特异度、阳性预报值、阴性预报值,并通过受试者工作特征曲线(Receiver operating characteristic curve,ROC曲线)评估其预测效应。结果 治疗总有效率为62.5%; 以rTMS治疗1周后HAMA减分率15%及20%或治疗2周后HAMA减分率15%、20%、25%、30%及35%为界限值预测临床疗效有相对较高的灵敏度和阴性预报值; 以rTMS治疗1周后HAMA减分率30%、35%及40%或治疗2周后HAMA减分率35%及40%为界限值预测临床疗效有相对较高的特异度和阳性预报值; 以治疗1和2周后HAMA减分率预测治疗4周后临床疗效的ROC曲线下面积分别为0.712(P<0.05)和0.856(P<0.01)。结论 rTMS治疗焦虑障碍早期症状改善可有效预测最终临床疗效。     

重复经颅磁刺激治疗老年抑郁症研究进展

本文目的是对重复经颅磁刺激（rTMS）不同刺激模式在老年抑郁症患者的抑郁症状及认知功能的应用进行综述，进一步探究rTMS不同刺激模式对老年抑郁症治疗效果的改善，希望为老年抑郁症的临床治疗提供新思路。本综述从老年抑郁症研究现况、认知功能特点及rTMS不同刺激模式的效果、安全性等方面进行阐述。     

Binaural responses in the auditory midbrain of chicken (Gallus gallus)

The auditory midbrain is the location in which neurons represent binaural acoustic information necessary for sound localization. The external nucleus of the midbrain inferior colliculus (IC) of the barn owl is a classic example of an auditory space map, but it is unknown to what extent the principles underlying its formation generalize to other, less specialized animals. We characterized the spiking responses of 139 auditory neurons in the IC of the chicken (Gallus gallus) in vivo, focusing on their sensitivities to the binaural localization cues of interaural time (ITD) and level (ILD) differences. Most units were frequency‐selective, with best frequencies distributed unevenly into low‐frequency and high‐frequency (> 2 kHz) clusters. Many units showed sensitivity to either ITD (65%) or ILD (66%) and nearly half to both (47%). ITD selectivity was disproportionately more common among low‐frequency units, while ILD‐only selective units were predominantly tuned to high frequencies. ILD sensitivities were diverse, and we thus developed a decision tree defining five types. One rare type with a bell‐like ILD tuning was also selective for ITD but typically not frequency‐selective, and thus matched the characteristics of neurons in the auditory space map of the barn owl. Our results suggest that generalist birds such as the chicken show a prominent representation of ITD and ILD cues in the IC, providing complementary information for sound localization, according to the duplex theory. A broadband response type narrowly selective for both ITD and ILD may form the basis for a representation of auditory space.     

Pathological responses to single‐pulse electrical stimuli in epilepsy: The role of feedforward inhibition

Delineation of epileptogenic cortex in focal epilepsy patients may profit from single‐pulse electrical stimulation during intracranial EEG recordings. Single‐pulse electrical stimulation evokes early and delayed responses. Early responses represent connectivity. Delayed responses are a biomarker for epileptogenic cortex, but up till now, the precise mechanism generating delayed responses remains elusive. We used a data‐driven modelling approach to study early and delayed responses. We hypothesized that delayed responses represent indirect responses triggered by early response activity and investigated this for 11 patients. Using two coupled neural masses, we modelled early and delayed responses by combining simulations and bifurcation analysis. An important feature of the model is the inclusion of feedforward inhibitory connections. The waveform of early responses can be explained by feedforward inhibition. Delayed responses can be viewed as second‐order responses in the early response network which appear when input to a neural mass falls below a threshold forcing it temporarily to a spiking state. The combination of the threshold with noisy background input explains the typical stochastic appearance of delayed responses. The intrinsic excitability of a neural mass and the strength of its input influence the probability at which delayed responses to occur. Our work gives a theoretical basis for the use of delayed responses as a biomarker for the epileptogenic zone, confirming earlier clinical observations. The combination of early responses revealing effective connectivity, and delayed responses showing intrinsic excitability, makes single‐pulse electrical stimulation an interesting tool to obtain data for computational models of epilepsy surgery.     

Stability and Effect of Parkinsonian State on Deep Brain Stimulation Cortical Evoked Potentials

ObjectivesTo characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming.Materials and MethodsSerial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naïve followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement.ResultsIn the naïve state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45–0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands.ConclusionsOur findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming.