Intracortical Excitation Research Articles

Considerable effects of lateralization and aging in intracortical excitation and inhibition.

Findings based on the use of transcranial magnetic stimulation and electromyography (TMS-EMG) to determine the effects of motor lateralization and aging on intracortical excitation and inhibition in the primary motor cortex (M1) are inconsistent in the literature. TMS and electroencephalography (TMS-EEG) measures the excitability of excitatory and inhibitory circuits in the brain cortex without contamination from the spine and muscles. This study aimed to investigate the effects of motor lateralization (dominant and non-dominant hemispheres) and aging (young and older) and their interaction effects on intracortical excitation and inhibition within the M1 in healthy adults, measured using TMS-EMG and TMS-EEG. This study included 21 young (mean age = 28.1 ± 3.2 years) and 21 older healthy adults (mean age = 62.8 ± 4.2 years). A battery of TMS-EMG measurements and single-pulse TMS-EEG were recorded for the bilateral M1. Two-way repeated-measures analysis of variance was used to investigate lateralization and aging and the lateralization-by-aging interaction effect on neurophysiological outcomes. The non-dominant M1 presented a longer cortical silent period and larger amplitudes of P60, N100, and P180. Corticospinal excitability in older participants was significantly reduced, as supported by a larger resting motor threshold and lower motor-evoked potential amplitudes. N100 amplitudes were significantly reduced in older participants, and the N100 and P180 latencies were significantly later than those in young participants. There was no significant lateralization-by-aging interaction effect in any outcome. Lateralization and aging have independent and significant effects on intracortical excitation and inhibition in healthy adults. The functional decline of excitatory and inhibitory circuits in the M1 is associated with aging.

Clinical and Physiological Effects of Single Day Accelerated Theta Burst Transcranial Focused Ultrasound in Parkinson’s Disease (P4-11.008)

<h3>Objective:</h3> To evaluate the tolerability and efficacy of an accelerated schedule of theta burst focused ultrasound stimulation (tbTUS) delivered to the primary motor cortex in Parkinson’s disease (PD) patients assessed by transcranial magnetic stimulation (TMS) and United Parkinson’s Disease Rating Scale (UPDRS)-Part III. <h3>Background:</h3> Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate deeper in the brain with more focal stimulation compared to currently used forms of NIBS. TUS delivered in a theta burst pattern (tbTUS) for 80s induces sustained increases in motor cortex excitability lasting at least 30 minutes and is a promising NIBS protocol for treatment of neurological disorders. Accelerated stimulation schedules with several treatments per day can shorten treatment duration and improve accessibility. <h3>Design/Methods:</h3> Three sets of tbTUS were delivered in consecutive order to the right and left primary motor cortices at 30-minute intervals. 10 PD patients attended one visit each for real and sham treatments in random order. Before and after interventions, TMS measures of motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), short-interval intracortical excitation (SICF), and UPDRS-Part III scores were collected. Patients and UPDRS raters were blinded to the stimulation condition. <h3>Results:</h3> Real but not sham tbTUS treatment led to increased MEP amplitude and SICF. While both conditions led to similar changes in UPDRS-III scores, rigidity subscores were reduced only with real treatment. There were no adverse effects. <h3>Conclusions:</h3> The study is ongoing, and more patients are being recruited. Preliminary findings show that accelerated tbTUS is a safe and tolerable treatment schedule for PD patients. Improvements in rigidity suggests that tbTUS could be further studied as a non-invasive treatment for PD. Future research may investigate the optimal time between sonications with a longer treatment duration and a larger number of patients. <b>Disclosure:</b> Yi Rong Ding has nothing to disclose. Dr. Samuel has nothing to disclose. Dr. Grippe has nothing to disclose. Dr. SARICA has nothing to disclose. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Insightec. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Scientific. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Functional Neuromodulation. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merz. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Paladin Labs. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Chen has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Canadian Journal of Neurological Sciences. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Movement Disorders. The institution of Dr. Chen has received research support from Canadian Institutes of Health Research. The institution of Dr. Chen has received research support from NIH. The institution of Dr. Chen has received research support from Natural Science and Engineering Research Council of Canada. Dr. Chen has received research support from Parkinson Foundation. The institution of Dr. Chen has received research support from National Organization for Rare Disease. The institution of Dr. Chen has received research support from Merz.

Probing the link between cortical inhibitory and excitatory processes and muscle fascicle dynamics

During movements, neural signals are translated into muscle fibre shortening, lengthening or they remain isometric. This study investigated cortical excitatory and inhibitory processes in relation to muscle fascicle dynamics during fixed-end rapid contractions. Fourteen adults performed submaximal and maximal ankle dorsiflexions. Single and paired pulse transcranial magnetic stimulation over the cortical representation projecting to the tibialis anterior (TA) was applied during rest, the activation and deactivation phase of contractions to test for short- (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Ultrasound images were taken to measure muscle fascicle dynamics of the superficial (TASF) and deep (TADP) TA compartments. The results show significantly greater maximal shortening velocities (p = 0.003, d = 0.26, CI [4.89, 18.52]) and greater maximal fascicle shortening (p = 0.003, d = 0.86, CI [0.29, 3.13]) in TASF than TADP during submaximal dorsiflexions. Significantly lower SICI levels during activation compared to deactivation (p = 0.019, d = 1.12, CI [19.82, 1.76]) and at rest (p < 0.0001) were observed. ICF was significantly greater during activation (p = 0.03) than during rest while LICI did not modulate significantly. Maximal TASF but not TADP shortening velocity correlated with SICI levels at activation (p = 0.06) and with the rate of torque development (p = 0.02). The results suggest that SICI might be related to muscle fascicle behavior and that intracortical inhibition and excitation are phase-dependently modulated.

The use of blood flow restriction does not enhance adaptations of corticospinal excitability or intracortical inhibition after acute resistance training

Resistance exercise with blood flow restriction (BFR) is considered a safe and powerful training tool. Low-load (LL) resistance training with BFR results in comparable hypertrophy compared to conventional heavy-load (HL) resistance training (Centner et al., 2019). Additionally, LL training with BFR (LL-BFR) induces comparable (Grønfeldt et al., 2020) or slightly lower (Centner et al., 2019) effects on muscle strength than HL training. It is generally accepted that increases in maximum strength are mediated by muscular hypertrophy and/or neural adaptations. However, the effect of BFR on neural adaptations is scarcely investigated. The aim of this study was therefore to investigate the effects of BFR on acute neural adaptations following a single bout of resistance training.&#x0D; Fifteen male participants (21-35 years) volunteered to participate in this study. On three separate days, participants performed a strength training session of the right elbow flexors with either LL, LL-BFR or HL. Neuromuscular adaptations were investigated before and after each resistance training session by means of transcranial magnetic stimulation (single- and paired-pulse TMS) and peripheral nerve stimulation (Mmax). Data were acquired during submaximal sustained isometric contractions. During LL-BFR, the cuff was inflated to 50% of the individual arterial occlusion pressure to restrict venous outflow in the working musculature during exercise.&#x0D; The preliminary data analysis with mixed linear models revealed that, compared to baseline values, normalized MEPs (% of Mmax) from the trained biceps brachii were enhanced for HL (Cohen’s d = 0.51) but not LL-BFR (Cohen’s d = 0.03) when compared to LL. None of the groups showed relevant changes in short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). The size of Mmax decreased slightly for HL (Cohen’s d = -0.18) but not LL-BFR (Cohen’s d = 0.06) when compared to LL.&#x0D; This is the first study that investigated acute neural adaptations in response to resistance training with and without BFR. We observed increased MEP amplitudes after HL but not LL what is in line with previous evidence (Mason et al., 2019). Since training with BFR results in a rapid increase in motoneuronal excitability (Copithorne et al., 2020), the increased MEP are less likely caused by changes at the cortical site.&#x0D; Centner, C., Wiegel, P., Gollhofer, A., &amp; König, D. (2019). Effects of blood flow restriction training on muscular strength and hypertrophy in older individuals: A systematic review and meta-analysis. Sports Medicine, 49, 95-108. https://doi.org/10.1007/s40279-018-0994-1&#x0D; Copithorne, D. B., Rice, C. L., &amp; McNeil, C. J. (2020). Effect of blood flow occlusion on corticospinal excitability during sustained low-intensity isometric elbow flexion. Journal of Neurophysiology, 123(3), 1113-1119. https://doi.org/10.1152/jn.00644.2019&#x0D; Grønfeldt, B. M., Lindberg Nielsen, J., Mieritz, R. M., Lund, H., &amp; Aagaard, P. (2020). Effect of blood-flow restricted vs heavy-load strength training on muscle strength: Systematic review and meta-analysis. Scandinavian Journal of Medicine &amp; Science in Sports, 30(5), 837-848. https://doi.org/10.1111/sms.13632&#x0D; Mason, J., Howatson, G., Frazer, A. K., Pearce, A. J., Jaberzadeh, S., Avela, J., &amp; Kidgell, D. J. (2019). Modulation of intracortical inhibition and excitation in agonist and antagonist muscles following acute strength training. European Journal of Applied Physiology, 119, 2185-2199. https://doi.org/10.1007/s00421-019-04203-9

Neural network modelling reveals changes in directional connectivity between cortical and hypothalamic regions with increased BMI

Background/ObjectivesObesity has been ascribed to corticostriatal regions taking control over homeostatic areas. To test this assumption, we applied an effective connectivity approach to reveal the direction of information flow between brain regions and the valence of connections (excitatory versus inhibitory) as a function of increased BMI and homeostatic state.Subjects/MethodsForty-one participants (21 overweight/obese) underwent two resting-state fMRI scans: after overnight fasting (hunger) and following a standardised meal (satiety). We used spectral dynamic causal modelling to unravel hunger and increased BMI-related changes in directed connectivity between cortical, insular, striatal and hypothalamic regions.ResultsDuring hunger, as compared to satiety, we found increased excitation of the ventromedial prefrontal cortex over the ventral striatum and hypothalamus, suggesting enhanced top-down modulation compensating energy depletion. Increased BMI was associated with increased excitation of the anterior insula over the hypothalamus across the hunger and satiety conditions. The interaction of hunger and increased BMI yielded decreased intra-cortical excitation from the dorso-lateral to the ventromedial prefrontal cortex.ConclusionsOur findings suggest that excess weight and obesity is associated with persistent top-down excitation of the hypothalamus, regardless of homeostatic state, and hunger-related reductions of dorso-lateral to ventromedial prefrontal inputs. These findings are compatible with eating without hunger and reduced self-regulation views of obesity.

Training at asymptote stabilizes motor memories by reducing intracortical excitation

Learning similar motor skills in close succession is limited by interference, a phenomenon that takes place early after acquisition when motor memories are unstable. Interference can be bidirectional, as the first memory can be disrupted by the second (retrograde interference), or the second memory can be disrupted by the first (anterograde interference). The heightened plastic state of primary motor cortex after learning is thought to underlie interference, as unstable motor memories compete for neural resources. While time-dependent consolidation processes reduce interference, the passage of time (~6 h) required for memory stabilization limits our capacity to learn multiple motor skills at once. Here, we demonstrate in humans that prolonged training at asymptote of an initial motor skill reduces both retrograde and anterograde interference when a second motor skill is acquired in close succession. Neurophysiological assessments via transcranial magnetic stimulation reflect this online stabilization process. Specifically, excitatory neurotransmission in primary motor cortex increased after short training and decreased after prolonged training at performance asymptote. Of note, this reduction in intracortical excitation after prolonged training was proportional to better skill retention the following day. Importantly, these neurophysiological effects were not observed after motor practice without learning or after a temporal delay. Together, these findings indicate that prolonged training at asymptote improves the capacity to learn multiple motor skills in close succession, and that downregulation of excitatory neurotransmission in primary motor cortex may be a marker of online motor memory stabilization.

Determination of anodal tDCS intensity threshold for reversal of corticospinal excitability: an investigation for induction of counter-regulatory mechanisms

Transcranial direct current stimulation is applied to modulate activity, and excitability of the brain. Basically, LTP-like plasticity is induced when anodal tDCS (a-tDCS) is applied over the primary motor cortex. However, it has been shown that specific parameters of a-tDCS can induce a plasticity reversal. We aimed to systematically assess the intensity threshold for reversal of the direction of plasticity induced by a-tDCS, monitored by corticospinal excitability (CSE), and explored mechanisms regulating this reversal. Fifteen healthy participants received a-tDCS in pseudo-random order for 26 min with four intensities of 0.3, 0.7, 1, and 1.5 mA. To measure CSE changes, single-pulse TMS was applied over the left M1, and motor evoked potentials of a contralateral hand muscle were recorded prior to a-tDCS, immediately and 30-min post-intervention. Paired-pulse TMS was used to evaluate intracortical excitation and inhibition. CSE increased significantly following a-tDCS with an intensity of 0.7 mA; however, the expected effect decreased and even reversed at intensities of 1 and 1.5 mA. ICF was significantly increased while SICI and LICI decreased at 0.7 mA. On the other hand, a significant decrease of ICF, but SICI and LICI enhancement was observed at intensities of 1, and 1.5 mA. The present findings show an intensity threshold of ≥ 1 mA for 26 min a-tDCS to reverse LTP- into LTD-like plasticity. It is suggested that increasing stimulation intensity, with constant stimulation duration, activates counter-regulatory mechanisms to prevent excessive brain excitation. Therefore, stimulation intensity and plasticity induced by a-tDCS might non-linearly correlate in scenarios with prolonged stimulation duration.

Increasing excitation versus decreasing inhibition in auditory cortex: consequences on the discrimination performance between communication sounds.

Enhancing cortical excitability can be achieved by either reducing intracortical inhibition or by enhancing intracortical excitation. Here we compare the consequences of reducing intracortical inhibition and of enhancing intracortical excitation on the processing of communication sounds in the primary auditory cortex. Local application of gabazine and of AMPA enlarged the spectrotemporal receptive fields and increased the responses to communication to the same extent. The Mutual Information (an index of the cortical neurons' ability to discriminate between natural sounds) was increased in both cases, as were the noise and signal correlations. Spike-timing reliability was only increased after gabazine application and post-excitation suppression was affected in the opposite way: it was increased when reducing the intracortical inhibition but was eliminated by enhancing the excitation. A computational model suggests that these results can be explained by an additive effect vs. a multiplicative effect ABSTRACT: The level of excitability of cortical circuits is often viewed as one of the critical factors controlling perceptive performance. In theory, enhancing cortical excitability can be achieved either by reducing inhibitory currents or by increasing excitatory currents. Here, we evaluated whether reducing inhibitory currents or increasing excitatory currents in auditory cortex similarly affects the neurons' ability to discriminate between communication sounds. We attenuated the inhibitory currents by application of gabazine (GBZ), and increased the excitatory currents by applying AMPA in the auditory cortex while testing frequency receptive fields and responses to communication sounds. GBZ and AMPA enlarged the receptive fields and increased the responses to communication sounds to the same extent. The spike-timing reliability of neuronal responses was largely increased when attenuating the intracortical inhibition but not after increasing the excitation. The discriminative abilities of cortical cells increased in both cases but this increase was more pronounced after attenuating the inhibition. The shape of the response to communication sounds was modified in the opposite direction: reducing inhibition increased post-excitation suppression whereas this suppression tended to disappear when increasing the excitation. A computational model indicates that the additive effect promoted by AMPA vs. the multiplicative effect of GBZ on neuronal responses, together with the dynamics of spontaneous cortical activity, can explain these differences. Thus, although apparently equivalent for increasing cortical excitability, acting on inhibition vs. on excitation impacts differently the cortical ability to discriminate natural stimuli, and only modulating inhibition changed efficiently the cortical representation of communication sounds.

Modulation of intracortical inhibition and excitation in agonist and antagonist muscles following acute strength training.

Transcranial magnetic stimulation (TMS) usually investigates the corticospinal responses of the agonist muscle to strength training, despite the role of the antagonist muscle in strength development. We examined the intracortical responses from an agonist and antagonist muscle following a single session of heavy-loaded strength training (dominant-arm only) to identify the early antagonistic responses to a single session that may accompany improvements in strength. Corticospinal and motor cortical excitability and inhibition was collected from agonist and antagonist muscles prior to and following a single session of heavy-loaded wrist flexor training in 18 individuals. Training consisted of four sets 6-8 repetitions at 80% of 1-repetition maximum (1-RM). Recruitment curves for corticospinal excitability and inhibition of the right wrist flexor and wrist extensor muscles were constructed and assessed by examining the area under the recruitment curve. Intracortical measures were obtained using paired-pulse TMS. Following a single training session, increases in corticospinal excitability were observed in both the agonist and antagonist muscles. This was accompanied by decreases in corticospinal inhibition in both muscles. Intracortical inhibition was reduced and intracortical facilitation was increased for the agonist muscle only. Intracortical measures in the antagonist muscle remained unchanged after training. These findings indicate that the corticospinal responses to a single session of strength training are similar between agonist and antagonist muscles, but the intrinsic cortico-cortical circuitry of the antagonist remains unchanged. The corticospinal responses are likely due to increased involvement/co-activation of the antagonist muscle during training as the agonist muscle fatigues.

Modulatory Effects of Motor State During Paired Associative Stimulation on Motor Cortex Excitability and Motor Skill Learning.

Repeated pairing of electrical stimulation of a peripheral nerve with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) representation for a target muscle can induce neuroplastic adaptations in the human brain related to motor learning. The extent to which the motor state during this form of paired associative stimulation (PAS) influences the degree and mechanisms of neuroplasticity or motor learning is unclear. Here, we investigated the effect of volitional muscle contraction during PAS on: (1) measures of general corticomotor excitability and intracortical circuit excitability; and (2) motor performance and learning. We assessed measures of corticomotor excitability using TMS and motor skill performance during a serial reaction time task (SRTT) at baseline and at 0, 30, 60 min post-PAS. Participants completed a SRTT retention test 1 week following the first two PAS sessions. Following the PAS intervention where the hand muscle maintained an active muscle contraction (PASACTIVE), there was lower short interval intracortical inhibition compared to PAS during a resting motor state (PASREST) and a sham PAS condition (PASCONTROL). SRTT performance improved within the session regardless of PAS condition. SRTT retention was greater following both PASACTIVE and PASREST after 1 week compared to PASCONTROL. These findings suggest that PAS may enhance motor learning retention and that motor state may be used to target different neural mechanisms of intracortical excitation and inhibition during PAS. This observation may be important to consider for the use of therapeutic noninvasive brain stimulation in neurologic patient populations.

Selective Strengthening of Intracortical Excitatory Input Leads to Receptive Field Refinement during Auditory Cortical Development.

In the primary auditory cortex (A1) of rats, refinement of excitatory input to layer (L)4 neurons contributes to the sharpening of their frequency selectivity during postnatal development. L4 neurons receive both feedforward thalamocortical and recurrent intracortical inputs, but how potential developmental changes of each component can account for the sharpening of excitatory input tuning remains unclear. By combining in vivo whole-cell recording and pharmacological silencing of cortical spiking in young rats of both sexes, we examined developmental changes at three hierarchical stages: output of auditory thalamic neurons, thalamocortical input and recurrent excitatory input to an A1 L4 neuron. In the thalamus, the tonotopic map matured with an expanded range of frequency representations, while the frequency tuning of output responses was unchanged. On the other hand, the tuning shape of both thalamocortical and intracortical excitatory inputs to a L4 neuron became sharpened. In particular, the intracortical input became better tuned than thalamocortical excitation. Moreover, the weight of intracortical excitation around the optimal frequency was selectively strengthened, resulting in a dominant role of intracortical excitation in defining the total excitatory input tuning. Our modeling work further demonstrates that the frequency-selective strengthening of local recurrent excitatory connections plays a major role in the refinement of excitatory input tuning of L4 neurons.SIGNIFICANCE STATEMENT During postnatal development, sensory cortex undergoes functional refinement, through which the size of sensory receptive field is reduced. In the rat primary auditory cortex, such refinement in layer (L)4 is mainly attributed to improved selectivity of excitatory input a L4 neuron receives. In this study, we further examined three stages along the hierarchical neural pathway where excitatory input refinement might occur. We found that developmental refinement takes place at both thalamocortical and intracortical circuit levels, but not at the thalamic output level. Together with modeling results, we revealed that the optimal-frequency-selective strengthening of intracortical excitation plays a dominant role in the refinement of excitatory input tuning.

Fine Control of Sound Frequency Tuning and Frequency Discrimination Acuity by Synaptic Zinc Signaling in Mouse Auditory Cortex.

Neurons in the auditory cortex are tuned to specific ranges of sound frequencies. Although the cellular and network mechanisms underlying neuronal sound frequency selectivity are well studied and reflect the interplay of thalamocortical and intracortical excitatory inputs and further refinement by cortical inhibition, the precise synaptic signaling mechanisms remain less understood. To gain further understanding on these mechanisms and their effects on sound-driven behavior, we used in vivo imaging as well as behavioral approaches in awake and behaving female and male mice. We discovered that synaptic zinc, a modulator of neurotransmission and responsiveness to sound, sharpened the sound frequency tuning of principal and parvalbumin-expressing neurons and widened the sound frequency tuning of somatostatin-expressing inhibitory neurons in layer 2/3 of the primary auditory cortex. In the absence of cortical synaptic zinc, mice exhibited reduced acuity for detecting changes in sound frequencies. Together, our results reveal that cell-type-specific effects of zinc contribute to cortical sound frequency tuning and enhance acuity for sound frequency discrimination.SIGNIFICANCE STATEMENT Neuronal tuning to specific features of sensory stimuli is a fundamental property of cortical sensory processing that advantageously supports behavior. Despite the established roles of synaptic thalamocortical and intracortical excitation and inhibition in cortical tuning, the precise synaptic signaling mechanisms remain unknown. Here, we investigated these mechanisms in the mouse auditory cortex. We discovered a previously unknown signaling mechanism linking synaptic zinc signaling with cell-specific cortical tuning and enhancement in sound frequency discrimination acuity. Given the abundance of synaptic zinc in all sensory cortices, this newly discovered interaction between synaptic zinc and cortical tuning can provide a general mechanism for modulating neuronal stimulus specificity and sensory-driven behavior.

Transcranial Alternating Current Stimulation at Beta Frequency: Lack of Immediate Effects on Excitation and Interhemispheric Inhibition of the Human Motor Cortex.

Transcranial alternating current stimulation (tACS) is a form of noninvasive brain stimulation and is capable of influencing brain oscillations and cortical networks. In humans, the endogenous oscillation frequency in sensorimotor areas peaks at 20 Hz. This beta-band typically occurs during maintenance of tonic motor output and seems to play a role in interhemispheric coordination of movements. Previous studies showed that tACS applied in specific frequency bands over primary motor cortex (M1) or the visual cortex modulates cortical excitability within the stimulated hemisphere. However, the particular impact remains controversial because effects of tACS were shown to be frequency, duration and location specific. Furthermore, the potential of tACS to modulate cortical interhemispheric processing, like interhemispheric inhibition (IHI), remains elusive. Transcranial magnetic stimulation (TMS) is a noninvasive and well-tolerated method of directly activating neurons in superficial areas of the human brain and thereby a useful tool for evaluating the functional state of motor pathways. The aim of the present study was to elucidate the immediate effect of 10 min tACS in the β-frequency band (20 Hz) over left M1 on IHI between M1s in 19 young, healthy, right-handed participants. A series of TMS measurements (motor evoked potential (MEP) size, resting motor threshold (RMT), IHI from left to right M1 and vice versa) was performed before and immediately after tACS or sham using a double-blinded, cross-over design. We did not find any significant tACS-induced modulations of intracortical excitation (as assessed by MEP size and RMT) and/or IHI. These results indicate that 10 min of 20 Hz tACS over left M1 seems incapable of modulating immediate brain activity or inhibition. Further studies are needed to elucidate potential aftereffects of 20 Hz tACS as well as frequency-specific effects of tACS on intracortical excitation and IHI.

Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex

Throughout the brain, the recruitment of feedforward and recurrent inhibition shapes neural responses. However, disentangling the relative contributions of these often-overlapping cortical circuits is challenging. The piriform cortex provides an ideal system to address this issue because the interneurons responsible for feedforward and recurrent inhibition are anatomically segregated in layer (L) 1 and L2/3 respectively. Here we use a combination of optical and electrical activation of interneurons to profile the inhibitory input received by three classes of principal excitatory neuron in the anterior piriform cortex. In all classes, we find that L1 interneurons provide weaker inhibition than L2/3 interneurons. Nonetheless, feedforward inhibitory strength covaries with the amount of afferent excitation received by each class of principal neuron. In contrast, intracortical stimulation of L2/3 evokes strong inhibition that dominates recurrent excitation in all classes. Finally, we find that the relative contributions of feedforward and recurrent pathways differ between principal neuron classes. Specifically, L2 neurons receive more reliable afferent drive and less overall inhibition than L3 neurons. Alternatively, L3 neurons receive substantially more intracortical inhibition. These three features--balanced afferent drive, dominant recurrent inhibition, and differential recruitment by afferent vs. intracortical circuits, dependent on cell class--suggest mechanisms for olfactory processing that may extend to other sensory cortices.

Abstract TP144: Intracortical Circuits Reveal Muscle- and Task-specific Dysfunction Contributing to Weakness Following Stroke

Introduction: Weakness is a prominent clinical manifestation following stroke. While central factors, including activation impairment, contribute to hemiparetic weakness, specific mechanisms remain poorly understood. Here we probed functioning of the corticospinal pathway and intracortical circuits mediating dynamic force production. Hypothesis: We hypothesized that impairments of intracortical inhibition and excitation contribute to deficits in plantarflexor (PF) force production capacity following stroke. Methods: We studied 19 chronic stroke survivors (age: 66.0±9.6 yrs; chronicity: 77.3±60.9 mo) and 7 controls (age: 61.3±9.7 yrs) and used the Short Physical Performance Battery to group stroke survivors by functional ability (i.e., HIGH, MED, LOW). We obtained peak isometric PF force during a series of maximal voluntary contractions. Single and paired pulse transcranial magnetic stimulation (TMS) was delivered over the ipsilesional hemisphere during isometric and dynamic PF contractions to assess corticomotor excitability, short intracortical inhibition (SICI), and short intracortical facilitation (SICF). Results: Peak isometric force (p=0.04) and cortical excitability in both medial gastrocnemius (MG) and soleus (SO) were progressively reduced across functional levels post-stroke (p’s&lt;0.01). Controls revealed task-dependent modulation of motor evoked responses (MEPs) between isometric and dynamic contractions in MG, but not SOL while the MED and LOW groups failed to modulate MEPs. SICF revealed no differences between muscles, contraction type, or groups. In SO, controls revealed attenuation of SICI during movement. Stroke survivors revealed a progressive reduction in SICI during isometric PF across functional level while SICI increased during dynamic PF, resulting in a pattern reversal between controls and LOW (p=0.02). Conclusion: Deficits in dynamic PF post-stroke appear to be driven by changes in SICI rather than SICF, suggesting dysregulation of GABA-A. Impaired intracortical inhibition could reduce PF capacity by interfering with selective muscle recruitment during dynamic tasks.

Cell-Specific Activity-Dependent Fractionation of Layer 2/3→5B Excitatory Signaling in Mouse Auditory Cortex

Auditory cortex (AC) layer 5B (L5B) contains both corticocollicular neurons, a type of pyramidal-tract neuron projecting to the inferior colliculus, and corticocallosal neurons, a type of intratelencephalic neuron projecting to contralateral AC. Although it is known that these neuronal types have distinct roles in auditory processing and different response properties to sound, the synaptic and intrinsic mechanisms shaping their input-output functions remain less understood. Here, we recorded in brain slices of mouse AC from retrogradely labeled corticocollicular and neighboring corticocallosal neurons in L5B. Corticocollicular neurons had, on average, lower input resistance, greater hyperpolarization-activated current (Ih), depolarized resting membrane potential, faster action potentials, initial spike doublets, and less spike-frequency adaptation. In paired recordings between single L2/3 and labeled L5B neurons, the probabilities of connection, amplitude, latency, rise time, and decay time constant of the unitary EPSC were not different for L2/3→corticocollicular and L2/3→corticocallosal connections. However, short trains of unitary EPSCs showed no synaptic depression in L2/3→corticocollicular connections, but substantial depression in L2/3→corticocallosal connections. Synaptic potentials in L2/3→corticocollicular connections decayed faster and showed less temporal summation, consistent with increased Ih in corticocollicular neurons, whereas synaptic potentials in L2/3→corticocallosal connections showed more temporal summation. Extracellular L2/3 stimulation at two different rates resulted in spiking in L5B neurons; for corticocallosal neurons the spike rate was frequency dependent, but for corticocollicular neurons it was not. Together, these findings identify cell-specific intrinsic and synaptic mechanisms that divide intracortical synaptic excitation from L2/3 to L5B into two functionally distinct pathways with different input-output functions.

Tonically balancing intracortical excitation and inhibition by GABAergic gliotransmission.

For sensory cortices to respond reliably to feature stimuli, the balancing of neuronal excitation and inhibition is crucial. A typical example might be the balancing of phasic excitation within cell assemblies and phasic inhibition between cell assemblies. The former controls the gain of and the latter the tuning of neuronal responses. A change in ambient GABA concentration might affect the dynamic behavior of neurons in a tonic manner. For instance, an increase in ambient GABA concentration enhances the activation of extrasynaptic receptors, augments an inhibitory current, and thus inhibits neurons. When a decrease in ambient GABA concentration occurs, the tonic inhibitory current is reduced, and thus the neurons are relatively excited. We simulated a neural network model in order to examine whether and how such a tonic excitatory-inhibitory mechanism could work for sensory information processing. The network consists of cell assemblies. Each cell assembly, comprising principal cells (P), GABAergic interneurons (Ia, Ib), and glial cells (glia), responds to one particular feature stimulus. GABA transporters, embedded in glial plasma membranes, regulate ambient GABA levels. Hypothetical neuron-glia signaling via inhibitory (Ia-to-glia) and excitatory (P-to-glia) synaptic contacts was assumed. The former let transporters import (remove) GABA from the extracellular space and excited stimulus-relevant P cells. The latter let them export GABA into the extracellular space and inhibited stimulus-irrelevant P cells. The main finding was that the glial membrane transporter gave a combinatorial excitatory-inhibitory effect on P cells in a tonic manner, thereby improving the gain and tuning of neuronal responses. Interestingly, it worked cooperatively with the conventional, phasic excitatory-inhibitory mechanism. We suggest that the GABAergic gliotransmission mechanism may provide balanced intracortical excitation and inhibition so that the best perceptual performance of the cortex can be achieved.

Linear transformation of thalamocortical input by intracortical excitation

Neurons in thalamorecipient layers of sensory cortices integrate thalamocortical and intracortical inputs. Although their functional properties can be inherited from the convergence of thalamic inputs, the roles of intracortical circuits in thalamocortical transformation of sensory information remain unclear. Here, by reversibly silencing intracortical excitatory circuits with optogenetic activation of parvalbumin-positive inhibitory neurons in mouse primary visual cortex, we compared visually-evoked thalamocortical input with total excitation in the same layer 4 pyramidal neurons. We found that intracortical excitatory circuits preserve the orientation and direction tuning of thalamocortical excitation, with a linear amplification of thalamocortical signals by about threefold. The spatial receptive field of thalamocortical input is slightly elongated, and is expanded by intracortical excitation in an approximately proportional manner. Thus, intracortical excitatory circuits faithfully reinforce the representation of thalamocortical information, and may influence the size of the receptive field by recruiting additional inputs.

Intracortical multiplication of thalamocortical signals in mouse auditory cortex

Cortical processing of sensory information initiates from the transformation of thalamically-relayed signals. By optogenetically silencing intracortical circuits to isolate thalamic inputs to layer 4 neurons, we show that intracortical excitation linearly amplifies thalamocortical responses underlying frequency and direction selectivity with preserved spectral range and tuning, and prolongs the response duration. This signal pre-amplification and prolongation enhances the salience of thalamocortically-relayed information and ensures its robust, faithful and more persistent representation.

Synaptic Mechanisms Underlying Functional Dichotomy between Intrinsic-Bursting and Regular-Spiking Neurons in Auditory Cortical Layer 5

Corticofugal projections from the primary auditory cortex (A1) have been shown to play a role in modulating subcortical processing. However, functional properties of the corticofugal neurons and their synaptic circuitry mechanisms remain unclear. In this study, we performed in vivo whole-cell recordings from layer 5 (L5) pyramidal neurons in the rat A1 and found two distinct neuronal classes according to their functional properties. Intrinsic-bursting (IB) neurons, the L5 corticofugal neurons, exhibited early and rather unselective spike responses to a wide range of frequencies. The exceptionally broad spectral tuning of IB neurons was attributable to their broad excitatory inputs with long temporal durations and inhibitory inputs being more narrowly tuned than excitatory inputs. This uncommon pattern of excitatory-inhibitory interplay was attributed initially to a broad thalamocortical convergence onto IB neurons, which also receive temporally prolonged intracortical excitatory input as well as feedforward inhibitory input at least partially from more narrowly tuned fast-spiking inhibitory neurons. In contrast, regular-spiking neurons, which are mainly corticocortical, exhibited sharp frequency tuning similar to L4 pyramidal cells, underlying which are well-matched purely intracortical excitation and inhibition. The functional dichotomy among L5 pyramidal neurons suggests two distinct processing streams. The spectrally and temporally broad synaptic integration in IB neurons may ensure robust feedback signals to facilitate subcortical function and plasticity in a general manner.