Enhancement of low gamma oscillations by volitional conditioning of local field potential in the primary motor and visual cortex of mice.

Volitional control of local field potential oscillations in low gamma band via brain machine interface can not only uncover the relationship between low gamma oscillation and neural synchrony but also suggest a therapeutic potential to reverse abnormal local field potential oscillation in neurocognitive disorders. In nonhuman primates, the volitional control of low gamma oscillations has been demonstrated by brain machine interface techniques in the primary motor and visual cortex. However, it is not clear whether this holds in other brain regions and other species, for which gamma rhythms might involve in highly different neural processes. Here, we established a closed-loop brain-machine interface and succeeded in training mice to volitionally elevate low gamma power of local field potential in the primary motor and visual cortex. We found that the mice accomplished the task in a goal-directed manner and spiking activity exhibited phase-locking to the oscillation in local field potential in both areas. Moreover, long-term training made the power enhancement specific to direct and adjacent channel, and increased the transcriptional levels of NMDA receptors as well as that of hypoxia-inducible factor relevant to metabolism. Our results suggest that volitionally generated low gamma rhythms in different brain regions share similar mechanisms and pave the way for employing brain machine interface in therapy of neurocognitive disorders.

40 Hz light flickering promotes sleep through cortical adenosine signaling.

Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 h after flickering) in extracellular adenosine levels in the primary visual cortex (V1) and other brain regions, as a function of light frequency and intensity, with maximal effects observed at 40 Hz frequency and 4000 lux. We uncovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, the intracellular adenosine generation from AMPK-associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways), and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz (but not 20 and 80 Hz) light flickering for 30 min enhanced non-rapid eye movement (non-REM) and REM sleep for 2-3 h in mice. This somnogenic effect was abolished by ablation of V1 (but not superior colliculus) neurons and by genetic deletion of the gene encoding ENT2 (but not ENT1), but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner. Lastly, 40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.

Non-invasive auditory and visual stimulation attenuates α-Synuclein deposition and improves motor and non-motor symptoms in PD mice.

Parkinson's disease (PD) is characterized by dopaminergic neuron loss and α-synuclein (α-Syn) aggregates, but lacks effective treatments for the disease progression and non-motor symptoms. Recently, combined 40 Hz auditory and visual stimulation is emerging as a promising non-invasive method to decrease amyloid and improve cognition in Alzheimer's disease (AD), but whether this treatment can modify α-Syn-induced PD pathology remains unclear. Here we evaluated the effects of chronic exposure to 40 Hz and 80 Hz auditory and visual stimulation on α-Syn accumulation and the functional effects of 40 Hz stimulation on motor, cognitive and mood dysfunctions in PD mice. We found that 40 Hz and 80 Hz auditory and visual stimulation activated multiple cortical regions, entrained gamma oscillations and markedly attenuated p-α-Syn deposition in neurons, but not astrocytes, microglial cells in the primary and secondary motor cortex (M1, M2), medial prefrontal cortex (mPFC) and the striatum. Moreover, 40 Hz stimulation significantly reduced cell apoptosis in M1, increased the neuromuscular strength selectively in PD mice, which correlated with p-α-Syn reduction in the motor cortex. In addition, 40 Hz stimulation improved spatial working memory and decreased depressive-like behaviors specifically in PD mice, which correlated with p-α-Syn reduction in mPFC, but promoted anxiety-like behaviors and increased stress-related adreno-cortico-tropic-hormone (ACTH), corticosterone levels in the plasma of normal mice. Collectively, we demonstrated that chronic multisensory gamma stimulation (40 Hz and 80 Hz) significantly attenuates α-Syn deposition in neurons of the interconnected cortex and 40 Hz stimulation improved neuromuscular strength, spatial working memory, and reduced depressive behaviors, which support its non-invasive therapeutic potential for modifying PD progression and treating non-motor symptoms.

Sensory eye dominance following surgically correction for acute acquired concomitant esotropia of adulthood.

BACKGROUND: Acute acquired concomitant esotropia (AACE) is an unusual presentation characterized by acute onset of esotropia after infancy. For patients with AACE of adulthood, the outcome of surgery, which is a common treatment, often shows successful recovery of stereopsis. However, whether surgically corrected patients with AACE of adulthood achieved balanced eyes is yet unclear. METHODS: Here, we used a binocular phase combination paradigm to quantitatively assess the ocular dominance of 22 surgically aligned patients with AACE of adulthood, which all had regained normal stereopsis after the surgery and 14 adult controls with normal vision. The sensory eye dominance was quantified as the interocular contrast ratio, termed balance point, at which each eye contributed equally to the perception of cyclopean grating. RESULTS: We found that, normal controls had a mean balance point value close to unity (0.96 ± 0.01), whereas adult AACE patients exhibited apparent interocular imbalance (0.76 ± 0.04), which was significantly different from control group (Mann-Whitney U = 135, P < 0.001, two tailed). In addition, the balance point of adults with AACE didn't correlate with the interval between onset of esotropia and the surgery (r = - 0.262, p = 0.239), or the length of postoperative follow-up period (r = 0.127, p = 0.575). CONCLUSION: Our results suggest that, for patients with AACE of adulthood whose eyes had been straightened, there is still residual sensory imbalance which may be a potential risk factor for AACE of adulthood.

Neural representation and modulation of volitional motivation in response to escalating efforts.

Task-dependent volitional control of the selected neural activity in the cortex is critical to neuroprosthetic learning to achieve reliable and robust control of the external device. The volitional control of neural activity is driven by a motivational factor (volitional motivation), which directly reinforces the target neurons via real-time biofeedback. However, in the absence of motor behaviour, how do we evaluate volitional motivation? Here, we defined the criterion (ΔF/F) of the calcium fluorescence signal in a volitionally controlled neural task, then escalated the efforts by progressively increasing the number of reaching the criterion or holding time after reaching the criterion. We devised calcium-based progressive threshold-crossing events (termed 'Calcium PTE') and calcium-based progressive threshold-crossing holding-time (termed 'Calcium PTH') for quantitative assessment of volitional motivation in response to progressively escalating efforts. Furthermore, we used this novel neural representation of volitional motivation to explore the neural circuit and neuromodulator bases for volitional motivation. As with behavioural motivation, chemogenetic activation and pharmacological blockade of the striatopallidal pathway decreased and increased, respectively, the breakpoints of the 'Calcium PTE' and 'Calcium PTH' in response to escalating efforts. Furthermore, volitional and behavioural motivation shared similar dopamine dynamics in the nucleus accumbens in response to trial-by-trial escalating efforts. In general, the development of a neural representation of volitional motivation may open a new avenue for smooth and effective control of brain-machine interface tasks. KEY POINTS: Volitional motivation is quantitatively evaluated by M1 neural activity in response to progressively escalating volitional efforts. The striatopallidal pathway and adenosine A2A receptor modulate volitional motivation in response to escalating efforts. Dopamine dynamics encode prediction signal for reward in response to repeated escalating efforts during motor and volitional conditioning. Mice learn to modulate neural activity to compensate for repeated escalating efforts in volitional control.

Accumbal adenosine A2A receptor inactivation biases for large and costly rewards in the effort- but not delay-based decision making.

The cost-benefit decision-making (CBDM) is critical to normal human activity and a diminished willingness to expend effort to obtain rewards is a prevalent/noted characteristic of neuropsychiatric disorders such as schizophrenia, Parkinson's disease. Numerous studies have identified nucleus accumbens (NAc) as an important locus for CBDM control but their neuromodulatory and behavioral mechanisms remain largely under-explored. Adenosine A2A receptors (A2ARs), which are highly concentrated in the striatopallidal neurons, can integrate glutamate and dopamine signals for controlling effort-related choice behaviors. While the involvement of A2ARs in effort-based decision making is well documented, the role of other decision variables (reward discrimination) in effort-based decision making and the role of A2AR in delay-based decision making are less clear. In this study, we have developed a well-controlled CBDM behavioral paradigm to manipulate effort/cost and reward independently or in combination, allowing a dissection of four behavioral elements: effort-based CBDM (E-CBDM), delay-based CBDM (D-CBDM), reward discrimination (RD), effort discrimination (ED), and determined the effect of genetic knockdown (KD) of NAc A2AR on the four behavioral elements. We found that A2AR KD in NAc increased the choice for larger, more costly reward in the E-CBDM, but not D-CBDM. Furthermore, this high-effort/high-reward bias was attributable to the increased willingness to engage in effort but not the effect of discrimination of reward magnitude. Our findings substantiate an important role of the NAc A2AR in control of E-CBDM and support that pharmacologically targeting NAc A2ARs would be a useful strategy for treating the aberrant effort-based decision making in neuropsychiatric disorders.

A Joint Lateral Motion-Stereo Constraint.

Purpose: We developed a stereo task that is based on a motion direction discrimination to examine the role that depth can play in disambiguating motion direction. Methods: In this study, we quantified normal adults' static and dynamic (i.e., laterally moving) stereoscopic performance using a psychophysical task, where we dichoptically presented randomly arranged, limited lifetime Gabor elements at two depth planes (one plane was at the fixation plane and the other at an uncrossed disparity relative to the fixation plane). Each plane contained half of the elements. For the dynamic condition, all elements were vertically oriented and moved to the left in one plane and to the right in another plane; for the static condition, the elements were horizontally oriented in one plane and vertically oriented in another plane. Results: For the range of motion speed that we measured (from 0.17°/s to 5.33°/s), we observed clear speed tuning of the stereo sensitivity (P = 3.0 × 10-5). The shape of this tuning did not significantly change with different spatial frequencies. We also found a significant difference in stereo sensitivity between stereopsis with static and laterally moving stimuli (speed = 0.67°/s; P = 0.004). Such difference was not evident when we matched the task between the static and moving stimuli. Conclusions: We report that lateral motion modulates human global depth perception. This motion/stereo constraint is related to motion velocity not stimulus temporal frequency. We speculate that the processing of motion-based stereopsis of the kind reported here occurs in dorsal extrastriate cortex.

Entrainment of Astrocytic and Neuronal Ca2+ Population Dynamics During Information Processing of Working Memory in Mice.

Astrocytes are increasingly recognized to play an active role in learning and memory, but whether neural inputs can trigger event-specific astrocytic Ca2+ dynamics in real time to participate in working memory remains unclear due to the difficulties in directly monitoring astrocytic Ca2+ dynamics in animals performing tasks. Here, using fiber photometry, we showed that population astrocytic Ca2+ dynamics in the hippocampus were gated by sensory inputs (centered at the turning point of the T-maze) and modified by the reward delivery during the encoding and retrieval phases. Notably, there was a strong inter-locked and antagonistic relationship between the astrocytic and neuronal Ca2+ dynamics with a 3-s phase difference. Furthermore, there was a robust synchronization of astrocytic Ca2+ at the population level among the hippocampus, medial prefrontal cortex, and striatum. The inter-locked, bidirectional communication between astrocytes and neurons at the population level may contribute to the modulation of information processing in working memory.

Adenosine A2A receptor blockade improves neuroprosthetic learning by volitional control of population calcium signal in M1 cortical neurons.

Volitional control is at the core of brain-machine interfaces (BMI) adaptation and neuroprosthetic-driven learning to restore motor function for disabled patients, but neuroplasticity changes and neuromodulation underlying volitional control of neuroprosthetic learning are largely unexplored. To better study volitional control at annotated neural population, we have developed an operant neuroprosthetic task with closed-loop feedback system by volitional conditioning of population calcium signal in the M1 cortex using fiber photometry recording. Importantly, volitional conditioning of the population calcium signal in M1 neurons did not improve within-session adaptation, but specifically enhanced across-session neuroprosthetic skill learning with reduced time-to-target and the time to complete 50 successful trials. With brain-behavior causality of the neuroprosthetic paradigm, we revealed that proficiency of neuroprosthetic learning by volitional conditioning of calcium signal was associated with the stable representational (plasticity) mapping in M1 neurons with the reduced calcium peak. Furthermore, pharmacological blockade of adenosine A2A receptors facilitated volitional conditioning of neuroprosthetic learning and converted an ineffective volitional conditioning protocol to be the effective for neuroprosthetic learning. These findings may help to harness neuroplasticity for better volitional control of neuroprosthetic training and suggest a novel pharmacological strategy to improve neuroprosthetic learning in BMI adaptation by targeting striatal A2A receptors.

Aging Affects Fine and Coarse Coding of Orientation Information in Macaque Primary Visual Cortex.

Human visual function degrades with age. Previous studies of visual perception have shown that aged people have worse performance in the coding of orientation information. However, the neuronal mechanism still remains elusive. In this study, we performed in vivo extracellular single-unit recording in the primary visual cortex of senescent and young monkeys, and we used the Chernoff distance to quantify the encoded information of neurons for fine and coarse orientation difference. Our results showed that the Chernoff distance for fine orientation difference in senescent monkeys is significantly smaller than that in young monkeys. In contrast, the Chernoff distance for the coarse coding was comparable in young and old groups. Meanwhile, increased spontaneous response and maximum evoked response was also observed. Further investigation of neuronal correlation showed higher noise and signal correlations in aging monkeys than that in young monkeys. These correlation changes predicted a detrimental effect on the efficiency of population coding of orientation information. Taken together, our results suggest that the information coding efficiency of orientation information is impaired during aging and might account for the degradation of performance in human fine orientation discrimination task.

Action Video Gaming Does Not Influence Short-Term Ocular Dominance Plasticity in Visually Normal Adults.

Action video gaming can promote neural plasticity. Short-term monocular patching drives neural plasticity in the visual system of human adults. For instance, short-term monocular patching of 0.5-5 h briefly enhances the patched eye's contribution in binocular vision (i.e., short-term ocular dominance plasticity). In this study, we investigate whether action video gaming can influence this plasticity in adults with normal vision. We measured participants' eye dominance using a binocular phase combination task before and after 2.5 h of monocular patching. Participants were asked to play action video games, watch action video game movies, or play non-action video games during the period of monocular patching. We found that participants' change of ocular dominance after monocular patching was not significantly different either for playing action video games versus watching action video game movies (Comparison 1) or for playing action video games versus playing non-action video games (Comparison 2). These results suggest that action video gaming does not either boost or eliminate short-term ocular dominance plasticity, and that the neural site for this type of plasticity might be in the early visual pathway.

Corrigendum: The Binocular Balance at High Spatial Frequencies as Revealed by the Binocular Orientation Combination Task.

[This corrects the article DOI: 10.3389/fnhum.2019.00106.].

The Binocular Balance at High Spatial Frequencies as Revealed by the Binocular Orientation Combination Task.

How to precisely quantify the binocular eye balance (i.e., the contribution that each eye makes to the binocular percept) across a range of spatial frequencies using a binocular combination task, is an important issue in both clinical and basic research. In this study, we aimed to compare the precision of a binocular orientation combination paradigm with that of the standard binocular phase combination paradigm in measuring the binocular eye balance at low to high spatial frequencies. Nine normal adults (average age: 24.6 ± 2.0 years old) participated. Subjects viewed an LED screen dichoptically with polarized glasses in a dark room. The method of constant stimuli was used to quantitatively assess the point of subjective equality (PSE), i.e., the interocular contrast ratio when two eyes are balanced in binocular combination, for stimulus spatial frequencies from 0.5 to 8 cycles/degree. Precision was quantified by the variance [i.e., standard error (SE), obtained from 100 bootstrap estimates] associated to the PSE. Using stimuli whose interocular phase difference at the edge of the gratings was matched at 45°, we found that the orientation paradigm provides more precision than the standard binocular phase combination paradigm, especially at high frequencies (Experiment 1). Such differences remained when using stimuli that had three times larger interocular phase difference (Experiment 2) or displayed at four times higher stimuli resolution (Experiment 3). Our results indicate that a binocular combination tasked based on orientation rather than phase, provides a more precise estimate of binocular eye balance in human adults at high spatial frequencies, thus allowing a binocular balance to be assessed within the spatial region where amblyopes are most defective (i.e., high spatial frequencies).

Inverse Occlusion: A Binocularly Motivated Treatment for Amblyopia.

Recent laboratory findings suggest that short-term patching of the amblyopic eye (i.e., inverse occlusion) results in a larger and more sustained improvement in the binocular balance compared with normal controls. In this study, we investigate the cumulative effects of the short-term inverse occlusion in adults and old children with amblyopia. This is a prospective cohort study of 18 amblyopes (10-35 years old; 2 with strabismus) who have been subjected to 2 hours/day of inverse occlusion for 2 months. Patients who required refractive correction or whose refractive correction needed updating were given a 2-month period of refractive adaptation. The primary outcome measure was the binocular balance which was measured using a phase combination task; the secondary outcome measures were the best-corrected visual acuity which was measured with a Tumbling E acuity chart and converted to logMAR units and the stereoacuity which was measured with the Random-dot preschool stereogram test. The average binocular gain was 0.11 in terms of the effective contrast ratio (z = -2.344, p = 0.019, 2-tailed related samples Wilcoxon Signed Rank Test). The average acuity gain was 0.13 logMAR equivalent (t(17) = 4.76, p < 0.001, 2-tailed paired samples t-test). The average stereoacuity gain was 339 arc seconds (z = -2.533, p = 0.011). Based on more recent research concerning adult ocular dominance plasticity, we conclude that inverse occlusion in adults and old children with amblyopia does produce long-term gains to binocular balance and that acuity and stereopsis can improve in some subjects.

Amblyopic Suppression: Passive Attenuation, Enhanced Dichoptic Masking by the Fellow Eye or Reduced Dichoptic Masking by the Amblyopic Eye?

Purpose: To test the amblyopic suppression at mid to low spatial frequencies when compensating for signal attenuation. Methods: Eight amblyopes with (n = 5) or without (n = 3) strabismus and 10 normal controls with normal or corrected to normal visual acuity (≥20/20) and normal stereopsis (≤40 arcseconds) participated. Using a quick contrast sensitivity function approach, we measured individuals' monocular contrast sensitivity functions when the untested eye saw a mean luminance background and when the untested eye saw a bandpass filtered noise whose peak spatial frequency was matched to that of the test grating. Interocular suppression was quantified by the difference in thresholds occurring between these two conditions for each eye. The contrast of the noise mask was set at five times the threshold of the untested eye. Results: Selected spatial frequencies (0.67-1.31 cyc/deg) were identified where neither ceiling (five times the mask contrast threshold in the amblyopic eye <100%) nor floor (threshold of the amblyopic eye when there was a noise mask in the fellow eye <100%) effects occurred for all observers. Within this frequency range, we found no interocular suppressive imbalance in normal observers. However, in amblyopes, the amblyopic eye exerted significantly less suppression than the fellow eye, while the suppression from the fellow eye to the amblyopic eye was similar to that found in the normal controls. Conclusions: We conclude that the reduced dichoptic masking by the amblyopic eye, within the context of normally balanced interocular inhibition, produces the amblyopic suppression at mid to low frequencies.

The Cortical Mechanisms Underlying Ocular Dominance Plasticity in Adults are Not Orientationally Selective.

Recently, it has been shown that short-term monocular deprivation in adult humans can temporally shift the ocular dominance in favor of the deprived eye. It is not clear whether this form of ocular dominance plasticity can be explained by cortical contrast adaptation, which is known to be orientationally selective. Here we show that if only one eye is deprived of a limited band of orientations for a short period of 2.5 h, the deprived eye's contribution to binocular function at all orientations rather than just those corresponding to the previously deprived orientations is strengthened. This isotropic enhancement is quite different from the orientational enhancement previously reported and suggests a separate neuroplastic mechanism specific to binocular function.

Absolute Not Relative Interocular Luminance Modulates Sensory Eye Dominance Plasticity in Adults.

If one eye is patched for a period of 2.5 h in human adults, transient changes in sensory eye dominance result with the previously patched eye's contribution being strengthened. Similar changes result from opaque and translucent occlusion suggesting that it is the deprivation of contrast not luminance information that drives these transient shift of sensory eye dominance. However, this does not rule out the possibility that luminance deprivation per se cannot produce changes in sensory eye dominance, indeed based on what we know of the physiology, where the contrast gain of visual neurons is luminance dependent, one would expect it should. We show that if the mean luminance of one eye is reduced 1000-fold for a period of 2.5 h, there are subsequent changes in sensory eye dominance. With further control experiments we show that this deprivation effect critically depends on the absolute luminance of each eye rather than the relative interocular luminance imbalance. These results indicate that changes in contrast gain at an early, monocular stage of the pathway can result in the transient shift of sensory eye dominance.

Neuronal basis of perceptual learning in striate cortex.

It is well known that, in humans, contrast sensitivity training at high spatial frequency (SF) not only leads to contrast sensitivity improvement, but also results in an improvement in visual acuity as assessed with gratings (direct effect) or letters (transfer effect). However, the underlying neural mechanisms of this high spatial frequency training improvement remain to be elucidated. In the present study, we examined four properties of neurons in primary visual cortex (area 17) of adult cats that exhibited significantly improved acuity after contrast sensitivity training with a high spatial frequency grating and those of untrained control cats. We found no difference in neuronal contrast sensitivity or tuning width (Width) between the trained and untrained cats. However, the trained cats showed a displacement of the cells' optimal spatial frequency (OSF) to higher spatial frequencies as well as a larger neuronal signal-to-noise ratio (SNR). Furthermore, both the neuronal differences in OSF and SNR were significantly correlated with the improvement of acuity measured behaviorally. These results suggest that striate neurons might mediate the perceptual learning-induced improvement for high spatial frequency stimuli by an alteration in their spatial frequency representation and by an increased SNR.