The Control of Movements via Motor Gamma Oscillations

The ability to perform movements is vital for our daily life. Our actions are embedded in a complex environment where we need to deal efficiently in the face of unforeseen events. Neural oscillations play an important role in basic sensorimotor processes related to the execution and preparation of movements. In this review, I will describe the state of the art regarding the role of motor gamma oscillations in the control of movements. Experimental evidence from electrophysiological studies has shown that motor gamma oscillations accomplish a range of functions in motor control beyond merely signaling the execution of movements. However, these additional aspects associated with motor gamma oscillation remain to be fully clarified. Future work on different spatial, temporal and spectral scales is required to further understand the implications of gamma oscillations in motor control.

Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals, increases failures and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.

Application of evoked response audiometry for specifying aberrant gamma oscillations in schizophrenia

Gamma oscillations probed using auditory steady-state response (ASSR) are promising clinical biomarkers that may give rise to novel therapeutic interventions for schizophrenia. Optimizing clinical settings for these biomarker-driven interventions will require a quick and easy assessment system for gamma oscillations in psychiatry. ASSR has been used in clinical otolaryngology for evoked response audiometry (ERA) in order to judge hearing loss by focusing on the phase-locked response detectability via an automated analysis system. Herein, a standard ERA system with 40- and 46-Hz ASSRs was applied to evaluate the brain pathophysiology of patients with schizophrenia. Both ASSRs in the ERA system showed excellent detectability regarding the phase-locked response in healthy subjects and sharply captured the deficits of the phase-locked response caused by aberrant gamma oscillations in individuals with schizophrenia. These findings demonstrate the capability of the ERA system to specify patients who have aberrant gamma oscillations. The ERA system may have a potential to serve as a real-world clinical medium for upcoming biomarker-driven therapeutics in psychiatry.

Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.

Temporal–spectral signaling of sensory information and expectations in the cerebral processing of pain

The perception of pain is shaped by somatosensory information about threat. However, pain is also influenced by an individual’s expectations. Such expectations can result in clinically relevant modulations and abnormalities of pain. In the brain, sensory information, expectations (predictions), and discrepancies thereof (prediction errors) are signaled by an extended network of brain areas which generate evoked potentials and oscillatory responses at different latencies and frequencies. However, a comprehensive picture of how evoked and oscillatory brain responses signal sensory information, predictions, and prediction errors in the processing of pain is lacking so far. Here, we therefore applied brief painful stimuli to 48 healthy human participants and independently modulated sensory information (stimulus intensity) and expectations of pain intensity while measuring brain activity using electroencephalography (EEG). Pain ratings confirmed that pain intensity was shaped by both sensory information and expectations. In contrast, Bayesian analyses revealed that stimulus-induced EEG responses at different latencies (the N1, N2, and P2 components) and frequencies (alpha, beta, and gamma oscillations) were shaped by sensory information but not by expectations. Expectations, however, shaped alpha and beta oscillations before the painful stimuli. These findings indicate that commonly analyzed EEG responses to painful stimuli are more involved in signaling sensory information than in signaling expectations or mismatches of sensory information and expectations. Moreover, they indicate that the effects of expectations on pain are served by brain mechanisms which differ from those conveying effects of sensory information on pain.

Gabaergic Interneurons in Early Brain Development: Conducting and Orchestrated by Cortical Network Activity

Throughout early phases of brain development, the two main neural signaling mechanisms—excitation and inhibition—are dynamically sculpted in the neocortex to establish primary functions. Despite its relatively late formation and persistent developmental changes, the GABAergic system promotes the ordered shaping of neuronal circuits at the structural and functional levels. Within this frame, interneurons participate first in spontaneous and later in sensory-evoked activity patterns that precede cortical functions of the mature brain. Upon their subcortical generation, interneurons in the embryonic brain must first orderly migrate to and settle in respective target layers before they can actively engage in cortical network activity. During this process, changes at the molecular and synaptic level of interneurons allow not only their coordinated formation but also the pruning of connections as well as excitatory and inhibitory synapses. At the postsynaptic site, the shift of GABAergic signaling from an excitatory towards an inhibitory response is required to enable synchronization within cortical networks. Concomitantly, the progressive specification of different interneuron subtypes endows the neocortex with distinct local cortical circuits and region-specific modulation of neuronal firing. Finally, the apoptotic process further refines neuronal populations by constantly maintaining a controlled ratio of inhibitory and excitatory neurons. Interestingly, many of these fundamental and complex processes are influenced—if not directly controlled—by electrical activity. Interneurons on the subcellular, cellular, and network level are affected by high frequency patterns, such as spindle burst and gamma oscillations in rodents and delta brushes in humans. Conversely, the maturation of interneuron structure and function on each of these scales feeds back and contributes to the generation of cortical activity patterns that are essential for the proper peri- and postnatal development. Overall, a more precise description of the conducting role of interneurons in terms of how they contribute to specific activity patterns—as well as how specific activity patterns impinge on their maturation as orchestra members—will lead to a better understanding of the physiological and pathophysiological development and function of the nervous system.

Targeting Galectin 3 to Counteract Spike-Phase Uncoupling of Fast-Spiking Interneurons to Gamma Oscillations in Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin 3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, possible involvement of gal3 in the disruption of cognition-relevant neuronal network oscillations typical of AD remains unknown. Methods: Here, we investigate the functional implications of gal3 signaling on cognition-relevant gamma oscillations (30-80 Hz) by performing electrophysiological recordings in hippocampal area CA3 of wild-type (WT) and 5xFAD mice in vitro. Results: Gal3 application decreases gamma oscillation power and rhythmicity in an activity-dependent manner and is accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSN) and pyramidal cells (PCs). We found that gal3-induced disruption is mediated by the gal3-carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevents Aβ42-induced degradation of gamma oscillations. Furthermore, we demonstrate that 5xFAD mice lacking gal3 (5xFAD-Gal3KO) exhibit WT-like gamma network dynamics.Conclusions: We report for the first time that gal3 impairs cognition-relevant neuronal network dynamics by spike-phase uncoupling of FSN inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic target to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.

Histone Deacetylase Inhibitor Improves the Dysfunction of Hippocampal Gamma Oscillations and Fast Spiking Interneurons in Alzheimer’s Disease Model Mice

The hippocampal gamma oscillation is important for cognitive function, and its deficit is related to cognitive impairment in Alzheimer’s disease (AD). Recently, it has been recognized that post-translational modification via histone acetylation is a fundamental molecular mechanism for regulating synaptic plasticity and cognitive function. However, little is known regarding the regulation of hippocampal gamma oscillation by histone acetylation. We investigated whether histone acetylation regulated kainate-induced gamma oscillations and their important regulator, fast-spiking interneurons, using acute hippocampal slices of AD model mice (PSAPP transgenic mice). We found a decrease in kainate-induced gamma oscillations in slices from PSAPP mice, accompanied with the increased activity of fast spiking interneurons in basal state and the decreased activity in activated state. The histone deacetylase (HDAC) inhibitor (SAHA, named vorinostat) restored deficits of gamma oscillation in PSAPP mice, accompanied with rescue of activity of fast spiking interneurons in basal and activated state. The effect of SAHA was different from that of the clinical AD drug donepezil, which rescued only function of fast spiking interneurons in basal state. Besides, activator of nuclear receptor family 4a (NR4a) receptor (cytosporone B), as one of the epigenetic modification related to HDAC inhibition, rescued the deficits in gamma oscillations in PSAPP mice. These results suggested a novel mechanism in which HDAC inhibition improved impairment of gamma oscillations in PSAPP mice by restoring the activity of fast spiking interneurons both in basal and activated state. The reversal of gamma oscillation deficits by HDAC inhibition and/or NR4a activation appears to be a potential therapeutic target for treating cognitive impairment in AD patients.

A network model of the modulation of gamma oscillations by NMDA receptors in cerebral cortex

Psychotic drugs such as ketamine induce symptoms close to schizophrenia, and stimulates the production of gamma oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating gamma oscillations, and have integrated the action of drugs such as ketamine to partially block n-methyl-d-Aspartate (NMDA) receptors. The model can reproduce the modulation of gamma oscillations by NMDA-receptor antagonists, assuming that antagonists affect NMDA receptors predominantly on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channnels are blocked an increase of Gamma power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to gamma states, but also to synchronous states with no apparent gamma. We conclude that NMDA antagonists induce increased excitability state, which may or may not produce gamma oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations.

Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer’s Disease: A Case Series

Background: Alzheimer’s disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models. Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). Methods: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28. Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.