Increased number of excitatory synapsis and decreased number of inhibitory synapsis in the prefrontal cortex in autism.

Previous studies in autism spectrum disorder demonstrated an increased number of excitatory pyramidal cells and a decreased number of inhibitory parvalbumin+ chandelier interneurons in the prefrontal cortex of postmortem brains. How these changes in cellular composition affect the overall abundance of excitatory and inhibitory synapses in the cortex is not known. Herein, we quantified the number of excitatory and inhibitory synapses in the prefrontal cortex of 10 postmortem autism spectrum disorder brains and 10 control cases. To identify excitatory synapses, we used VGlut1 as a marker of the presynaptic component and postsynaptic density protein-95 as marker of the postsynaptic component. To identify inhibitory synapses, we used the vesicular gamma-aminobutyric acid transporter as a marker of the presynaptic component and gephyrin as a marker of the postsynaptic component. We used Puncta Analyzer to quantify the number of co-localized pre- and postsynaptic synaptic components in each area of interest. We found an increase in the number of excitatory synapses in upper cortical layers and a decrease in inhibitory synapses in all cortical layers in autism spectrum disorder brains compared with control cases. The alteration in the number of excitatory and inhibitory synapses could lead to neuronal dysfunction and disturbed network connectivity in the prefrontal cortex in autism spectrum disorder.

Asymmetric Activation of ON and OFF Pathways in the Degenerated Retina.

Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much work has described patterns of spiking in retinal ganglion cells (RGCs) in response to electrical stimulation, but less work has examined the underlying retinal circuitry that is activated by electrical stimulation to drive these responses. Surprisingly, little is known about the role of inhibition in generating electrical responses or how inhibition might be altered during degeneration. Using whole-cell voltage-clamp recordings during subretinal electrical stimulation in the rd10 and wild-type (wt) retina, we found electrically evoked synaptic inputs differed between ON and OFF RGC populations, with ON cells receiving mostly excitation and OFF cells receiving mostly inhibition and very little excitation. We found that the inhibition of OFF bipolar cells limits excitation in OFF RGCs, and a majority of both pre- and postsynaptic inhibition in the OFF pathway arises from glycinergic amacrine cells, and the stimulation of the ON pathway contributes to inhibitory inputs to the RGC. We also show that this presynaptic inhibition in the OFF pathway is greater in the rd10 retina, compared with that in the wt retina.

Investigating cortical excitability and inhibition in patients with schizophrenia: A TMS-EEG study.

BACKGROUND: Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls. MATERIALS AND METHODS: TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons. RESULTS: Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50-160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220-560 ms; 190-420 ms). Patients showed a reduction of both early (50-110 ms) gamma increase and later (180-230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms. CONCLUSION: Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics.

Reciprocal inhibition of the thigh muscles in humans: A study using transcutaneous spinal cord stimulation.

Evaluating reciprocal inhibition of the thigh muscles is important to investigate the neural circuits of locomotor behaviors. However, measurements of reciprocal inhibition of thigh muscles using spinal reflex, such as H-reflex, have never been systematically established owing to methodological limitations. The present study aimed to clarify the existence of reciprocal inhibition in the thigh muscles using transcutaneous spinal cord stimulation (tSCS). Twenty able-bodied male individuals were enrolled. We evoked spinal reflex from the biceps femoris muscle (BF) by tSCS on the lumber posterior root. We examined whether the tSCS-evoked BF reflex was reciprocally inhibited by the following conditionings: (1) single-pulse electrical stimulation on the femoral nerve innervating the rectus femoris muscle (RF) at various inter-stimulus intervals in the resting condition; (2) voluntary contraction of the RF; and (3) vibration stimulus on the RF. The BF reflex was significantly inhibited when the conditioning electrical stimulation was delivered at 10 and 20 ms prior to tSCS, during voluntary contraction of the RF, and during vibration on the RF. These data suggested a piece of evidence of the existence of reciprocal inhibition from the RF to the BF muscle in humans and highlighted the utility of methods for evaluating reciprocal inhibition of the thigh muscles using tSCS.

Assessment of the excitation-inhibition ratio in the Fmr1 KO2 mouse using neuronal oscillation dynamics.

In vitro and ex vivo studies have shown consistent indications of hyperexcitability in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mouse model of autism spectrum disorder. We recently introduced a method to quantify network-level functional excitation-inhibition ratio from the neuronal oscillations. Here, we used this measure to study whether the implicated synaptic excitation-inhibition disturbances translate to disturbances in network physiology in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) gene knockout model. Vigilance-state scoring was used to extract segments of inactive wakefulness as an equivalent behavioral condition to the human resting-state and, subsequently, we performed high-frequency resolution analysis of the functional excitation-inhibition biomarker, long-range temporal correlations, and spectral power. We corroborated earlier studies showing increased high-frequency power in Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mice. Long-range temporal correlations were higher in the gamma frequency ranges. Contrary to expectations, functional excitation-inhibition was lower in the knockout mice in high frequency ranges, suggesting more inhibition-dominated networks. Exposure to the Gamma-aminobutyric acid (GABA)-agonist clonazepam decreased the functional excitation-inhibition in both genotypes, confirming that increasing inhibitory tone results in a reduction of functional excitation-inhibition. In addition, clonazepam decreased electroencephalogram power and increased long-range temporal correlations in both genotypes. These findings show applicability of these new resting-state electroencephalogram biomarkers to animal for translational studies and allow investigation of the effects of lower-level disturbances in excitation-inhibition balance.

Mutual oligosynaptic inhibition of group Ia afferents between the anterior and posterior parts of the deltoid in humans.

The anterior (DA) and posterior parts of the deltoid (DP) show alternating contraction during shoulder flexion and extension movements. It is expected that an inhibitory spinal reflex between the DA and DP exists. In this study, spinal reflexes between the DA and DP were examined in healthy human subjects using post-stimulus time histogram (PSTH) and electromyogram averaging (EMG-A). Electrical conditioning stimulation was delivered to the axillary nerve branch that innervates the DA (DA nerve) and DP (DP nerve) with the intensity below the motor threshold. In the PSTH study, the stimulation to the DA and DP nerves inhibited (decrease in the firing probability) 31 of 54 DA motor units and 31 of 51 DP motor units. The inhibition was not provoked by cutaneous stimulation. The central synaptic delay of the inhibition between the DA and DP nerves was 1.5 ± 0.5 ms and 1.4 ± 0.4 ms (mean ± SD) longer than those of the homonymous facilitation of the DA and DP, respectively. In the EMG-A study, conditioning stimulation to the DA and DP nerves inhibited the rectified and averaged EMG of the DP and DA, respectively. The inhibition diminished with tonic vibration stimulation to the DA and DP and recovered 20-30 min after vibration removal. These findings suggest that oligo(di or tri)-synaptic inhibition mediated by group Ia afferents between the DA and DP exists in humans.

CCK+ Interneurons Contribute to Thalamus-Evoked Feed-Forward Inhibition in the Prelimbic Prefrontal Cortex.

Interneurons in the medial prefrontal cortex (PFC) regulate local neural activity to influence cognitive, motivated, and emotional behaviors. Parvalbumin-expressing (PV+) interneurons are the primary mediators of thalamus-evoked feed-forward inhibition across the mouse cortex, including the anterior cingulate cortex, where they are engaged by inputs from the mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic (PL) cortex, we find that PV+ interneurons are scarce in the principal thalamorecipient layer 3 (L3), suggesting distinct mechanisms of inhibition. To identify the interneurons that mediate MD-evoked inhibition in PL, we combine slice physiology, optogenetics, and intersectional genetic tools in mice of both sexes. We find interneurons expressing cholecystokinin (CCK+) are abundant in L3 of PL, with cells exhibiting fast-spiking (fs) or non-fast-spiking (nfs) properties. MD inputs make stronger connections onto fs-CCK+ interneurons, driving them to fire more readily than nearby L3 pyramidal cells and other interneurons. CCK+ interneurons in turn make inhibitory, perisomatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feed-forward inhibition, but not direct excitation, is also sensitive to CB1R modulation. Our findings indicate that CCK+ interneurons contribute to MD-evoked inhibition in PL, revealing a mechanism by which cannabinoids can modulate MD-PFC communication.

Highly local activation of inhibition at the seizure wavefront in vivo.

The propagation of a seizure wavefront in the cortex divides an intensely firing seizure core from a low-firing seizure penumbra. Seizure propagation is currently thought to generate strong activation of inhibition in the seizure penumbra that leads to its decreased neuronal firing. However, the direct measurement of neuronal excitability during seizures has been difficult to perform in vivo. We used simultaneous optogenetics and calcium imaging (all-optical interrogation) to characterize real-time neuronal excitability in an acute mouse model of seizure propagation. We find that single-neuron excitability is decreased in close proximity to the seizure wavefront but becomes increased distal to the seizure wavefront. This suggests that inhibitory neurons of the seizure wavefront create a proximal circumference of hypoexcitability but do not influence neuronal excitability in the penumbra.

Cell type-specific and frequency-dependent centrifugal modulation in olfactory bulb output neurons in vivo.

Mitral/tufted cells (M/TCs) form complex local circuits with interneurons in the olfactory bulb and are powerfully inhibited by these interneurons. The horizontal limb of the diagonal band of Broca (HDB), the only GABAergic/inhibitory source of centrifugal circuit with the olfactory bulb, is known to target olfactory bulb interneurons, and we have shown targeting also to olfactory bulb glutamatergic neurons in vitro. However, the net efficacy of these circuits under different patterns of activation in vivo and the relative balance between the various targeted intact local and centrifugal circuits was the focus of this study. Here channelrhodopsin-2 (ChR2) was expressed in HDB GABAergic neurons to investigate the short-term plasticity of HDB-activated disinhibitory rebound excitation of M/TCs. Optical activation of HDB interneurons increased spontaneous M/TC firing without odor presentation and increased odor-evoked M/TC firing. HDB activation induced disinhibitory rebound excitation (burst or cluster of spiking) in all classes of M/TCs. This excitation was frequency dependent, with short-term facilitation only at higher HDB stimulation frequency (5 Hz and above). However, frequency-dependent HDB regulation was more potent in the deeper layer M/TCs compared with more superficial layer M/TCs. In all neural circuits the balance between inhibition and excitation in local and centrifugal circuits plays a critical functional role, and this patterned input-dependent regulation of inhibitory centrifugal inputs to the olfactory bulb may help maintain the precise balance across the populations of output neurons in different environmental odors, putatively to sharpen the enhancement of tuning specificity of individual or classes of M/TCs to odors.NEW & NOTEWORTHY Neuronal local circuits in the olfactory bulb are modulated by centrifugal long circuits. In vivo study here shows that inhibitory horizontal limb of the diagonal band of Broca (HDB) modulates all five types of mitral/tufted cells (M/TCs), by direct inhibitory circuits HDB → M/TCs and indirect disinhibitory long circuits HDB → interneurons → M/TCs. The HDB net effect exerts excitation in all types of M/TCs but more powerful in deeper layer output neurons as HDB activation frequency increases, which may sharpen the tuning specificity of classes of M/TCs to odors during sensory processing.

Effects of prolonged vibration to the flexor carpi radialis muscle on intracortical excitability.

Prolonged local vibration (LV) can induce neurophysiological adaptations thought to be related to long-term potentiation or depression. Yet, how changes in intracortical excitability may be involved remains to be further investigated as previous studies reported equivocal results. We therefore investigated the effects of 30 min of LV applied to the right flexor carpi radialis muscle (FCR) on both short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). SICI and ICF were measured through transcranial magnetic stimulation before and immediately after 30 min of FCR LV (vibration condition) or 30 min of rest (control condition). Measurements were performed during a low-intensity contraction (n = 17) or at rest (n = 7). No significant SICI nor ICF modulations were observed, whether measured during isometric contractions or at rest (p = 0.2). Yet, we observed an increase in inter-individual variability for post measurements after LV. In conclusion, while intracortical excitability was not significantly modulated after LV, increased inter-variability observed after LV may suggest the possibility of divergent responses to prolonged LV exposure.

Approximating Nonlinear Functions With Latent Boundaries in Low-Rank Excitatory-Inhibitory Spiking Networks.

Deep feedforward and recurrent neural networks have become successful functional models of the brain, but they neglect obvious biological details such as spikes and Dale's law. Here we argue that these details are crucial in order to understand how real neural circuits operate. Towards this aim, we put forth a new framework for spike-based computation in low-rank excitatory-inhibitory spiking networks. By considering populations with rank-1 connectivity, we cast each neuron's spiking threshold as a boundary in a low-dimensional input-output space. We then show how the combined thresholds of a population of inhibitory neurons form a stable boundary in this space, and those of a population of excitatory neurons form an unstable boundary. Combining the two boundaries results in a rank-2 excitatory-inhibitory (EI) network with inhibition-stabilized dynamics at the intersection of the two boundaries. The computation of the resulting networks can be understood as the difference of two convex functions and is thereby capable of approximating arbitrary non-linear input-output mappings. We demonstrate several properties of these networks, including noise suppression and amplification, irregular activity and synaptic balance, as well as how they relate to rate network dynamics in the limit that the boundary becomes soft. Finally, while our work focuses on small networks (5-50 neurons), we discuss potential avenues for scaling up to much larger networks. Overall, our work proposes a new perspective on spiking networks that may serve as a starting point for a mechanistic understanding of biological spike-based computation.

Optogenetic Inhibition of Rat Anterior Cingulate Cortex Impairs the Ability to Initiate and Stay on Task.

Our prior research has identified neural correlates of cognitive control in the anterior cingulate cortex (ACC), leading us to hypothesize that the ACC is necessary for increasing attention as rats flexibly learn new contingencies during a complex reward-guided decision-making task. Here, we tested this hypothesis by using optogenetics to transiently inhibit the ACC, while rats of either sex performed the same two-choice task. ACC inhibition had a profound impact on behavior that extended beyond deficits in attention during learning when expected outcomes were uncertain. We found that ACC inactivation slowed and reduced the number of trials rats initiated and impaired both their accuracy and their ability to complete sessions. Furthermore, drift-diffusion model analysis suggested that free-choice performance and evidence accumulation (i.e., reduced drift rates) were degraded during initial learning-leading to weaker associations that were more easily overridden in later trial blocks (i.e., stronger bias). Together, these results suggest that in addition to attention-related functions, the ACC contributes to the ability to initiate trials and generally stay on task.

Optogenetic Determination of Dynamic and Cell-Type-Specific Inhibitory Reversal Potentials.

The reversal potential refers to the membrane potential at which the net current flow through a channel reverses direction. The reversal potential is determined by transmembrane ion gradients and, in turn, determines how the channel's activity will affect the membrane potential. Traditional investigation into the reversal potential of inhibitory ligand-gated ion channels (EInh) has relied upon the activation of endogenous receptors, such as the GABA-A receptor (GABAAR). There are, however, challenges associated with activating endogenous receptors, including agonist delivery, isolating channel responses, and the effects of receptor saturation and desensitization. Here, we demonstrate the utility of using a light-gated anion channel, stGtACR2, to probe EInh in the rodent brain. Using mice of both sexes, we demonstrate that the properties of this optically activated channel make it a suitable proxy for studying GABAAR receptor-mediated inhibition. We validate this agonist-independent optogenetic strategy in vitro and in vivo and further show how it can accurately capture differences in EInh dynamics following manipulations of endogenous ion fluxes. This allows us to explore distinct resting EInh differences across genetically defined neuronal subpopulations. Using this approach to challenge ion homeostasis mechanisms in neurons, we uncover cell-specific EInh dynamics that are supported by the differential expression of endogenous ion handling mechanisms. Our findings therefore establish an effective optical strategy for revealing novel aspects of inhibitory reversal potentials and thereby expand the repertoire of optogenetics.

Stroke Recovery-Related Changes in Cortical Reactivity Based on Modulation of Intracortical Inhibition.

BACKGROUND: Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke. METHODS: Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation. RESULTS: From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns (Pcluster<0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics. CONCLUSIONS: The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery.

Learning-induced bidirectional enhancement of inhibitory synaptic metaplasticity.

Training rodents in a particularly difficult olfactory-discrimination (OD) task results in the acquisition of the ability to perform the task well, termed 'rule learning'. In addition to enhanced intrinsic excitability and synaptic excitation in piriform cortex pyramidal neurons, rule learning results in increased synaptic inhibition across the whole cortical network to the point where it precisely maintains the balance between inhibition and excitation. The mechanism underlying such precise inhibitory enhancement remains to be explored. Here, we use brain slices from transgenic mice (VGAT-ChR2-EYFP), enabling optogenetic stimulation of single GABAergic neurons and recordings of unitary synaptic events in pyramidal neurons. Quantal analysis revealed that learning-induced enhanced inhibition is mediated by increased quantal size of the evoked inhibitory events. Next, we examined the plasticity of synaptic inhibition induced by long-lasting, intrinsically evoked spike firing in post-synaptic neurons. Repetitive depolarizing current pulses from depolarized (-70 mV) or hyperpolarized (-90 mV) membrane potentials induced long-term depression (LTD) and long-term potentiation (LTP) of synaptic inhibition, respectively. We found a profound bidirectional increase in the ability to induce both LTD, mediated by L-type calcium channels, and LTP, mediated by R-type calcium channels after rule learning. Blocking the GABAB receptor reversed the effect of intrinsic stimulation at -90 mV from LTP to LTD. We suggest that learning greatly enhances the ability to modify the strength of synaptic inhibition of principal neurons in both directions. Such plasticity of synaptic plasticity allows fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule. KEY POINTS: Olfactory discrimination rule learning results in long-lasting enhancement of synaptic inhibition on piriform cortex pyramidal neurons. Quantal analysis of unitary inhibitory synaptic events, evoked by optogenetic minimal stimulation, revealed that enhanced synaptic inhibition is mediated by increased quantal size. Surprisingly, metaplasticity of synaptic inhibition, induced by intrinsically evoked repetitive spike firing, is increased bidirectionally. The susceptibility to both long-term depression (LTD) and long-term potentiation (LTP) of inhibition is enhanced after learning. LTD of synaptic inhibition is mediated by L-type calcium channels and LTP by R-type calcium channels. LTP is also dependent on activation of GABAB receptors. We suggest that learning-induced changes in the metaplasticity of synaptic inhibition enable the fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule.

Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses.

Latrophilin-1 (Lphn1, aka CIRL1 and CL1; gene symbol Adgrl1) is an adhesion GPCR that has been implicated in excitatory synaptic transmission as a candidate receptor for α-latrotoxin. Here we analyzed conditional knock-in/knock-out mice for Lphn1 that contain an extracellular myc epitope tag. Mice of both sexes were used in all experiments. Surprisingly, we found that Lphn1 is localized in cultured neurons to synaptic nanoclusters that are present in both excitatory and inhibitory synapses. Conditional deletion of Lphn1 in cultured neurons failed to elicit a detectable impairment in excitatory synapses but produced a decrease in inhibitory synapse numbers and synaptic transmission that was most pronounced for synapses close to the neuronal soma. No changes in axonal or dendritic outgrowth or branching were observed. Our data indicate that Lphn1 is among the few postsynaptic adhesion molecules that are present in both excitatory and inhibitory synapses and that Lphn1 by itself is not essential for excitatory synaptic transmission but is required for some inhibitory synaptic connections.

TRPM2 and CaMKII Signaling Drives Excessive GABAergic Synaptic Inhibition Following Ischemia.

Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABAA receptor (GABAAR) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABAAR clustering observed in the first 24 h rebounds to an elevation of GABAergic clustering by 3 d postischemia. This increase in GABAergic inhibition required activation of the Ca2+-permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca2+-signaling, likely downstream of TRPM2 activation, upregulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function.

The effect of transcranial ultrasound pulse repetition frequency on sustained inhibition in the human primary motor cortex: A double-blind, sham-controlled study.

BACKGROUND: Non-invasive brain stimulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation hold promise for inducing brain plasticity. However, their limited precision may hamper certain applications. In contrast, Transcranial Ultrasound Stimulation (TUS), known for its precision and deep brain targeting capabilities, requires further investigation to establish its efficacy in producing enduring effects for treating neurological and psychiatric disorders. OBJECTIVE: To investigate the enduring effects of different pulse repetition frequencies (PRF) of TUS on motor corticospinal excitability. METHODS: T1-, T2-weighted, and zero echo time magnetic resonance imaging scans were acquired from 21 neurologically healthy participants for neuronavigation, skull reconstruction, and the performance of transcranial ultrasound and thermal modelling. The effects of three different TUS PRFs (10, 100, and 1000 Hz) with a constant duty cycle of 10 % on corticospinal excitability in the primary motor cortex were assessed using TMS-induced motor evoked potentials (MEPs). Each PRF and sham condition was evaluated on separate days, with measurements taken 5-, 30-, and 60-min post-TUS. RESULTS: A significant decrease in MEP amplitude was observed with a PRF of 10 Hz (p = 0.007), which persisted for at least 30 min, and with a PRF of 100 Hz (p = 0.001), lasting over 60 min. However, no significant changes were found for the PRF of 1000 Hz and the sham conditions. CONCLUSION: This study highlights the significance of PRF selection in TUS and underscores its potential as a non-invasive approach to reduce corticospinal excitability, offering valuable insights for future clinical applications.

Loss of Midbrain Dopamine Neurons Does Not Alter GABAergic Inhibition Mediated by Parvalbumin-Expressing Interneurons in Mouse Primary Motor Cortex.

The primary motor cortex (M1) integrates sensory and cognitive inputs to generate voluntary movement. Its functional impairments have been implicated in the pathophysiology of motor symptoms in Parkinson's disease (PD). Specifically, dopaminergic degeneration and basal ganglia dysfunction entrain M1 neurons into the abnormally synchronized bursting pattern of activity throughout the cortico-basal ganglia-thalamocortical network. However, how degeneration of the midbrain dopaminergic neurons affects the anatomy, microcircuit connectivity, and function of the M1 network remains poorly understood. The present study examined whether and how the loss of dopamine (DA) affects the morphology, cellular excitability, and synaptic physiology of Layer 5 parvalbumin-expressing (PV+) cells in the M1 of mice of both sexes. Here, we reported that loss of midbrain dopaminergic neurons does not alter the number, morphology, and physiology of Layer 5 PV+ cells in M1. Moreover, we demonstrated that the number of perisomatic PV+ puncta of M1 pyramidal neurons as well as their functional innervation of cortical pyramidal neurons were not altered following the loss of DA. Together, the present study documents an intact GABAergic inhibitory network formed by PV+ cells following the loss of midbrain dopaminergic neurons.