Adaptation in the sensory cortex drives bistable switching during auditory stream segregation.

Current theories of perception emphasize the role of neural adaptation, inhibitory competition, and noise as key components that lead to switches in perception. Supporting evidence comes from neurophysiological findings of specific neural signatures in modality-specific and supramodal brain areas that appear to be critical to switches in perception. We used functional magnetic resonance imaging to study brain activity around the time of switches in perception while participants listened to a bistable auditory stream segregation stimulus, which can be heard as one integrated stream of tones or two segregated streams of tones. The auditory thalamus showed more activity around the time of a switch from segregated to integrated compared to time periods of stable perception of integrated; in contrast, the rostral anterior cingulate cortex and the inferior parietal lobule showed more activity around the time of a switch from integrated to segregated compared to time periods of stable perception of segregated streams, consistent with prior findings of asymmetries in brain activity depending on the switch direction. In sound-responsive areas in the auditory cortex, neural activity increased in strength preceding switches in perception and declined in strength over time following switches in perception. Such dynamics in the auditory cortex are consistent with the role of adaptation proposed by computational models of visual and auditory bistable switching, whereby the strength of neural activity decreases following a switch in perception, which eventually destabilizes the current percept enough to lead to a switch to an alternative percept.

Older adults with a history of falling exhibit altered cortical oscillatory mechanisms during continuous postural maintenance.

Background and Aim: The significant risk of falling in older adults 65 years or older presents a substantial problem for these individuals, their caretakers, and the health-care system at large. As the proportion of older adults in the United States is only expected to grow over the next few decades, a better understanding of physiological and cortical changes that make an older adult more susceptible to a fall is crucial. Prior studies have displayed differences in postural dynamics and stability in older adults with a fall history (FH) and those who are non-fallers (NF), suggesting surplus alterations that occur in some older adults (i.e., FH group) in addition to the natural aging process. Methods: The present study measured postural dynamics while the FH, NF, and young adult (YA) groups performed continuous postural maintenance. In addition, electroencephalography activity was recorded while participants performed upright postural stance to examine any group differences in cortical areas involved in postural control. Results: As expected, older participants (FH and NF) exhibited worse postural stability, as evidenced by increased excursion, compared to the YA group. Further, while NF and YA show increased alpha activity in occipital areas during the most demanding postural task (eyes closed), the FH group did not show any differences in occipital alpha power between postural tasks. Conclusions: As alpha activity reflects suppression of bottom-up processing and thus diversion of cognitive resources toward postural centers during more demanding postural maintenance, deficits in this regulatory function in the FH group are a possible impaired cortical mechanism putting these individuals at greater fall risk. Relevance for Patients: Impaired inhibitory function in older adults may impact postural control and increase their risk of falling. Interventions that aim at addressing cortical processing deficits may improve postural stability and facilitate independent living in this population.

Impoverished Inhibitory Control Exacerbates Multisensory Impairments in Older Fallers.

Impaired temporal perception of multisensory cues is a common phenomenon observed in older adults that can lead to unreliable percepts of the external world. For instance, the sound induced flash illusion (SIFI) can induce an illusory percept of a second flash by presenting a beep close in time to an initial flash-beep pair. Older adults that have enhanced susceptibility to a fall demonstrate significantly stronger illusion percepts during the SIFI task compared to those older adults without any history of falling. We hypothesize that a global inhibitory deficit may be driving the impairments across both postural stability and multisensory function in older adults with a fall history (FH). We investigated oscillatory activity and perceptual performance during the SIFI task, to understand how active sensory processing, measured by gamma (30-80 Hz) power, was regulated by alpha activity (8-13 Hz), oscillations that reflect inhibitory control. Compared to young adults (YA), the FH and non-faller (NF) groups demonstrated enhanced susceptibility to the SIFI. Further, the FH group had significantly greater illusion strength compared to the NF group. The FH group also showed significantly impaired performance relative to YA during congruent trials (2 flash-beep pairs resulting in veridical perception of 2 flashes). In illusion compared to non-illusion trials, the NF group demonstrated reduced alpha power (or diminished inhibitory control). Relative to YA and NF, the FH group showed reduced phase-amplitude coupling between alpha and gamma activity in non-illusion trials. This loss of inhibitory capacity over sensory processing in FH compared to NF suggests a more severe change than that consequent of natural aging.

Temporal Alignment but not Complexity of Audiovisual Stimuli Influences Crossmodal Duration Percepts.

Reliable duration perception is an integral aspect of daily life that impacts everyday perception, motor coordination, and subjective passage of time. The Scalar Expectancy Theory (SET) is a common model that explains how an internal pacemaker, gated by an external stimulus-driven switch, accumulates pulses during sensory events and compares these accumulated pulses to a reference memory duration for subsequent duration estimation. Second-order mechanisms, such as multisensory integration (MSI) and attention, can influence this model and affect duration perception. For instance, diverting attention away from temporal features could delay the switch closure or temporarily open the accumulator, altering pulse accumulation and distorting duration perception. In crossmodal duration perception, auditory signals of unequal duration can induce perceptual compression and expansion of durations of visual stimuli, presumably via auditory influence on the visual clock. The current project aimed to investigate the role of temporal (stimulus alignment) and nontemporal (stimulus complexity) features on crossmodal, specifically auditory over visual, duration perception. While temporal alignment revealed a larger impact on the strength of crossmodal duration percepts compared to stimulus complexity, both features showcase auditory dominance in processing visual duration.

Multisensory temporal processing in early deaf.

Navigating the world relies on understanding progressive sequences of multisensory events across time. Early deaf (ED) individuals are more precise in visual detection of space and motion than their normal hearing (NH) counterparts. However, whether ED individuals show altered multisensory temporal processing abilities is less clear. According to the connectome model, brain development depends on experience, and therefore the lack of audition may affect how the brain responds to remaining senses and how they are functionally connected. We used a temporal order judgment (TOJ) task to examine multisensory (visuotactile) temporal processing in ED and NH groups. We quantified BOLD responses and functional connectivity (FC) in both groups. ED and NH groups performed similarly for the visuotactile TOJ task. Bilateral posterior superior temporal sulcus (pSTS) BOLD responses during the TOJ task were significantly larger in the ED group than in NH. Using anatomically defined pSTS seeds, our FC analysis revealed stronger somatomotor and weaker visual regional connections in the ED group than in NH during the TOJ task. These results suggest that a lack of auditory input might alter the balance of tactile and visual area FC with pSTS when a multisensory temporal task is involved.

Task-dependent audiovisual temporal sensitivity is not affected by stimulus intensity levels.

Flexibility and robustness of multisensory temporal recalibration is paramount for maintaining perceptual constancy of the surrounding natural world. Different environments impart various impediments, distances and routes that alter the propagation times of sight and sound cues comprising a multimodal event. One's ability to rapidly calibrate and account for these external variations allows for maintained perception of synchrony which is crucial for coherent and consistent perception. The two common paradigms used to compare precision of temporal processing between experimental and control groups, the simultaneity judgment (SJ) and temporal order judgment (TOJ) tasks, often use supra-threshold stimuli. However, few studies have specifically examined the effects of normalizing stimulus intensities to participant's unisensory detection thresholds. The current project presented multiple combinations of auditory and visual stimulus intensity levels, based on individual detection thresholds, during a TOJ and a SJ task. While no effect of stimulus intensity was found on temporal sensitivity or perceived temporal synchrony, there was a significant difference in point of subjective simultaneity (PSS) measures between tasks. In addition, PSS estimates were audio-leading, rather than visual-leading as previously reported, suggesting that exposure to the particular combinations of stimulus intensity levels used influenced temporal synchrony perception. Overall, these results support the use of supra-threshold stimuli in TOJ and SJ tasks as a way of minimizing the confound from differences in unisensory processing.

Electrophysiological Dynamics of Visual-Tactile Temporal Order Perception in Early Deaf Adults.

Studies of compensatory plasticity in early deaf (ED) individuals have mainly focused on unisensory processing, and on spatial rather than temporal coding. However, precise discrimination of the temporal relationship between stimuli is imperative for successful perception of and interaction with the complex, multimodal environment. Although the properties of cross-modal temporal processing have been extensively studied in neurotypical populations, remarkably little is known about how the loss of one sense impacts the integrity of temporal interactions among the remaining senses. To understand how auditory deprivation affects multisensory temporal interactions, ED and age-matched normal hearing (NH) controls performed a visual-tactile temporal order judgment task in which visual and tactile stimuli were separated by varying stimulus onset asynchronies (SOAs) and subjects had to discern the leading stimulus. Participants performed the task while EEG data were recorded. Group averaged event-related potential waveforms were compared between groups in occipital and fronto-central electrodes. Despite similar temporal order sensitivities and performance accuracy, ED had larger visual P100 amplitudes for all SOA levels and larger tactile N140 amplitudes for the shortest asynchronous (± 30 ms) and synchronous SOA levels. The enhanced signal strength reflected in these components from ED adults are discussed in terms of compensatory recruitment of cortical areas for visual-tactile processing. In addition, ED adults had similar tactile P200 amplitudes as NH but longer P200 latencies suggesting reduced efficiency in later processing of tactile information. Overall, these results suggest that greater responses by ED for early processing of visual and tactile signals are likely critical for maintained performance in visual-tactile temporal order discrimination.

Increased Right Posterior STS Recruitment Without Enhanced Directional-Tuning During Tactile Motion Processing in Early Deaf Individuals.

Upon early sensory deprivation, the remaining modalities often exhibit cross-modal reorganization, such as primary auditory cortex (PAC) recruitment for visual motion processing in early deafness (ED). Previous studies of compensatory plasticity in ED individuals have given less attention to tactile motion processing. In the current study, we aimed to examine the effects of early auditory deprivation on tactile motion processing. We simulated four directions of tactile motion on each participant's right index finger and characterized their tactile motion responses and directional-tuning profiles using population receptive field analysis. Similar tactile motion responses were found within primary (SI) and secondary (SII) somatosensory cortices between ED and hearing control groups, whereas ED individuals showed a reduced proportion of voxels with directionally tuned responses in SI contralateral to stimulation. There were also significant but minimal responses to tactile motion within PAC for both groups. While early deaf individuals show significantly larger recruitment of right posterior superior temporal sulcus (pSTS) region upon tactile motion stimulation, there was no evidence of enhanced directional tuning. Greater recruitment of right pSTS region is consistent with prior studies reporting reorganization of multimodal areas due to sensory deprivation. The absence of increased directional tuning within the right pSTS region may suggest a more distributed population of neurons dedicated to processing tactile spatial information as a consequence of early auditory deprivation.

Age-Related Effects on Cross-Modal Duration Perception.

Reliable duration perception of external events is necessary to coordinate perception with action, precisely discriminate speech, and for other daily functions. Visual duration perception can be heavily influenced by concurrent auditory signals; however, age-related effects on this process have received minimal attention. In the present study, we examined the effect of aging on duration perception by quantifying (1) duration discrimination thresholds, (2) auditory temporal dominance, and (3) visual duration expansion/compression percepts induced by an accompanying auditory stimulus of longer/shorter duration. Duration discrimination thresholds were significantly greater for visual than auditory tasks in both age groups, however there was no effect of age. While the auditory modality retained dominance in duration perception with age, older adults still performed worse than young adults when comparing durations of two target stimuli (e.g., visual) in the presence of distractors from the other modality (e.g., auditory). Finally, both age groups perceived similar visual duration compression, whereas older adults exhibited visual duration expansion over a wider range of auditory durations compared to their younger counterparts. Results are discussed in terms of multisensory integration and possible decision strategies that change with age.

Aging Impairs Temporal Sensitivity, but not Perceptual Synchrony, Across Modalities.

Encoding the temporal properties of external signals that comprise multimodal events is a major factor guiding everyday experience. However, during the natural aging process, impairments to sensory processing can profoundly affect multimodal temporal perception. Various mechanisms can contribute to temporal perception, and thus it is imperative to understand how each can be affected by age. In the current study, using three different temporal order judgement tasks (unisensory, multisensory, and sensorimotor), we investigated the effects of age on two separate temporal processes: synchronization and integration of multiple signals. These two processes rely on different aspects of temporal information, either the temporal alignment of processed signals or the integration/segregation of signals arising from different modalities, respectively. Results showed that the ability to integrate/segregate multiple signals decreased with age regardless of the task, and that the magnitude of such impairment correlated across tasks, suggesting a widespread mechanism affected by age. In contrast, perceptual synchrony remained stable with age, revealing a distinct intact mechanism. Overall, results from this study suggest that aging has differential effects on temporal processing, and general impairments with aging may impact global temporal sensitivity while context-dependent processes remain unaffected.

KSHV LANA upregulates the expression of epidermal growth factor like domain 7 to promote angiogenesis.

Kaposi's sarcoma (KS) is a highly-vascularized tumor characterized by inflammation and extensive neo-angiogenesis. The KS tumor microenvironment is rich in inflammatory and pro-angiogenic cytokines. Here, we report that the expression of Epidermal growth factor-like domain 7 (EGFL7) is upregulated in Kaposi's sarcoma-associated herpes virus (KSHV) infected cells. EGFL7 is a secreted pro-angiogenic cytokine that has been implicated in angiogenesis and the proliferation of endothelial cells during many pathological conditions. Our data show that KS tumors as well as primary effusion lymphoma cells have increased levels of EGFL7 compared to the uninfected cells. We determined that the expression of a KSHV latent protein, LANA (latency-associated nuclear antigen), is the main viral factor responsible for this upregulation. The modulation of EGFL7 expression by LANA involves sequestration of death domain-associated protein 6 (Daxx) from the EGFL7 promoter. Daxx acts as a suppressor of promoter activity by binding to the avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1), which is the core transcription factor required for the expression of EGFL7. We additionally show that the upregulation of EGFL7 by LANA contributes to the promotion of angiogenesis since siRNA-mediated knockdown of EGFL7 reduced in vitro tubulogenesis in LANA-expressing HUVEC cells. EGFL7 promotes angiogenesis through autocrine as well as paracrine mechanisms as the supernatant from LANA expressing cells depleted of EGFL7 showed reduced tubulogenesis. This study for the first time demonstrates EGFL7 to be an important angiogenic molecule secreted during KSHV infection that could be exploited for blocking KSHV associated malignancies in conjugation with other anti-angiogenic therapies.

Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy.

Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity, and muscle weakness. APMP22 point mutation in L16P (leucine 16 to proline) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (Tr(J)) die early postnatally, fail to make peripheral myelin, and, therefore, are more similar to patients with congenital hypomyelinating neuropathy than those with CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, we examined the structure and function of NMJs in Tr(J)mice. Although synapses appeared to be normally innervated even in end-stage Tr(J)mice, the growth and maturation of the NMJs were altered. In addition, the amplitudes of nerve-evoked muscle endplate potentials were reduced and there was transmission failure during sustained nerve stimulation. These results suggest that the severe congenital hypomyelinating neuropathy that characterizes Tr(J)mice results in structural and functional deficits of the developing NMJ.