When repeated tones are presented among random masker tones, their perceptual organization is often variable. In some trials, they cannot be segregated from the masker tones. In other trials, often with a delay, they form coherent streams, segregated from the masker tones. A strong awareness-related negativity is evoked by each segregated tone of the stream in auditory cortex. A similar negative-going response has been observed when subtle, isolated tones are detected versus missed, raising the question of whether target tones that do not form a stream under informational masking are still perceived or not. Here a paradigm is introduced to probe this question while activity in auditory cortex was recorded with magnetoencephalography. Human listeners (13 female, 8 male) were instructed to indicate when they detected an isochronous stream of tones under multi-tone masking while listening to the stimulus. Thereafter, they indicated if a cue tone, presented subsequently to each trial, was comprised in the target and masker combination. Results confirmed that target tones could still be perceived in the subset of trials where they did not form a coherent stream, but the detectability in the cued frequency report was higher for tones forming a stream. A prominent awareness-related negativity was only observed when the tones formed a stream, suggesting that this response reflects the perceptual organization of the tones into streams and beyond the pure perception of the tones themselves. We speculate that the perceptual organization into a stream further enhances the detectability of the tones comprised in the stream. Significance Statement Tone sequences may form streams that segregate from competing aspects of the auditory scene, a phenomenon considered comparable to visual object grouping. In multi-tone masking, hearing out streams of repeated tones seemingly enhances tone detectability by a degree that makes it difficult to judge whether these tones could at all be perceived if they had not formed a coherent stream. We present a paradigm that allows for probing both, the perception of target-tone frequency and the formation of coherent streams in the same trials. Applying this setup in magnetoencephalography showed that the perceptual organization into a stream is more strongly represented in auditory cortex than the ability to correctly detect a tone frequency within a random tone masker.
Brain oscillations shape cortical excitability in a phase-dependent manner. Cortical excitability reflects the net output of intracortical circuits, including inhibitory and facilitatory pathways. However, whether the phase of ongoing brain rhythms differentially modulates inhibitory and facilitatory responses remains unknown. Paired-pulse transcranial magnetic stimulation (ppTMS) can selectively engage these circuits, providing a unique tool to dissociate their contributions. We combined real-time EEG-guided closed-loop TMS with single- and paired-pulse TMS in 24 healthy adults (13 female) to probe how sensorimotor mu (8–13 Hz) and beta (14–30 Hz) oscillatory phase shapes responses associated with intracortical inhibitory and facilitatory processes. Single-pulse TMS (spTMS), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were delivered at four phases (peak, falling, trough, rising). Motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs) were recorded to assess corticospinal and cortical responses, respectively. We found that MEP amplitude was phase-dependent across all three stimulation types, with spTMS-evoked and ICF-conditioned MEPs showing the largest amplitudes at the rising phase, whereas SICI-conditioned MEPs were largest at the peak phase of the mu oscillation. TEP P60-N100 amplitude was modulated by oscillatory phase across all stimulation types, with maximal responses at the trough phase. SICI showed opposing phase patterns between the two measures, revealing a dissociation between cortical and corticospinal responses. MEP and TEP preferred phases were correlated across participants only in the ICF condition. These findings extend phase-dependent spTMS effects to paired-pulse stimulation and show that ongoing mu phase differentially shapes responses to SICI and ICF across cortical and corticospinal levels. Significance Statement Ongoing brain oscillations are known to shape cortical excitability across their phase cycle. However, whether this effect differentially influences inhibitory and facilitatory responses has remained unresolved. Here, using closed-loop EEG-guided transcranial magnetic stimulation in healthy adults, we probed how SICI- and ICF-conditioned responses vary across different phases of the sensorimotor mu and beta rhythms. We show that corticospinal and cortical responses to inhibitory and facilitatory paired-pulse protocols exhibit distinct phase-dependent patterns in the sensorimotor mu rhythm. These findings extend phase-dependent stimulation effects beyond single-pulse TMS and reveal that the relationship between cortical state and stimulation response differs across paired-pulse protocols.
The structural complexity of axon collateral terminal arbors shapes synaptic connectivity. In corticospinal projections, individual axon collaterals exhibit distinct patterns of terminal arborization, ranging from sparse local branches to dense, highly complex arbors in target regions such as the pontine nuclei. How this complexity is controlled remains poorly understood. Here, using corticopontine projections in male and female mice, we show that protein tyrosine phosphatase receptor type O (PTPRO) selectively restricts higher-order branching of terminal arbors in the pontine nuclei without affecting collateral number. This function requires the intracellular phosphatase domain of PTPRO but not its extracellular region. We demonstrate that PTPRO dephosphorylates tropomyosin receptor kinase B (TrkB), and that the excessive terminal arborization caused by acute PTPRO loss is rescued by TrkB depletion or phosphatidylinositol 3-kinase (PI3K) inhibition. Together, these findings reveal that PTPRO-mediated TrkB dephosphorylation acts as a molecular brake on corticopontine terminal arbor elaboration. Significance Statement How individual axons regulate terminal branching within target regions is a fundamental question in neural circuit development. This study identifies protein tyrosine phosphatase receptor type O (PTPRO), a receptor-type protein tyrosine phosphatase that negatively regulates signaling through tyrosine phosphorylation, as a selective regulator of higher-order branching in corticopontine terminal arbors. PTPRO dephosphorylates tropomyosin receptor kinase B (TrkB), a neurotrophin receptor tyrosine kinase that promotes neuronal growth and branching, thereby restricting terminal arbor complexity without affecting collateral number from the main axon. Given that terminal arbor architecture determines the synaptic territory of each cortical input, PTPRO-dependent constraint on arbor elaboration may represent a general principle by which projection-specific arbor complexity is established across long-range circuits in the central nervous system.
Humans learn by doing and observing but also by imagining the result of simulated actions in their mind. When learning from executed or observed actions, traditional theories posit that behavior improves by minimizing the difference between (1) the perceived outcome derived from sensory feedback and (2) the desired outcome (performance error) or the outcome predicted by an internal model (prediction error, PE). Supporting these theories, decades of electrophysiological studies have documented the role of the dopaminergic system and cerebellum in generating activity patterns compatible with the hypothesized error signals. In comparison, our understanding of the neural basis underlying the ability to learn from simulated actions is far more limited. Here, I argue that this form of self-supervised learning is best described in terms of a quantity known as the predicted performance error (PPE), theorized more than 30 years ago and yet largely overlooked ever since. Complementary to PEs, PPEs reflect error predictions between predicted and desired outcomes. Unlike PEs, however, PPEs exist even in the absence of sensory feedback and can in principle serve to evaluate actions without executing them, based on an efference copy of the underlying motor plan. I review evidence supporting the computation of PPEs in the brain and propose a network implementation based on a corticobasal ganglia loop interacting at multiple timescales with prefrontal, parietal, and hippocampal areas. I then connect PPEs to recent discoveries on motor planning and formulate novel predictions linking PPEs to various high-level brain functions such as metacognition, problem-solving, and deception.
