Faculty Bibliography

Neural entrainment, the alignment between neural oscillations and rhythmic stimulation, is omnipresent in current theories of speech processing - nevertheless, the underlying neural mechanisms are still largely unknown. Here, we hypothesized that laminar recordings in non-human primates provide us with important insight into these mechanisms, in particular with respect to processing in cortical layers. We presented one monkey with human everyday speech sounds and recorded neural (as current-source density, CSD) oscillations in primary auditory cortex (A1). We observed that the high-excitability phase of neural oscillations was only aligned with those spectral components of speech the recording site was tuned to; the opposite, low-excitability phase was aligned with other spectral components. As low- and high-frequency components in speech alternate, this finding might reflect a particularly efficient way of stimulus processing that includes the preparation of the relevant neuronal populations to the upcoming input. Moreover, presenting speech/noise sounds without systematic fluctuations in amplitude and spectral content and their time-reversed versions, we found significant entrainment in all conditions and cortical layers. When compared with everyday speech, the entrainment in the speech/noise conditions was characterized by a change in the phase relation between neural signal and stimulus and the low-frequency neural phase was dominantly coupled to activity in a lower gamma-band. These results show that neural entrainment in response to speech without slow fluctuations in spectral energy includes a process with specific characteristics that is presumably preserved across species.

Previous research demonstrated that while selectively attending to relevant aspects of the external world, the brain extracts pertinent information by aligning its neuronal oscillations to key time points of stimuli or their sampling by sensory organs. This alignment mechanism is termed oscillatory entrainment. We investigated the global, long-timescale dynamics of this mechanism in the primary auditory cortex of nonhuman primates, and hypothesized that lapses of entrainment would correspond to lapses of attention. By examining electrophysiological and behavioral measures, we observed that besides the lack of entrainment by external stimuli, attentional lapses were also characterized by high-amplitude alpha oscillations, with alpha frequency structuring of neuronal ensemble and single-unit operations. Entrainment and alpha-oscillation-dominated periods were strongly anticorrelated and fluctuated rhythmically at an ultra-slow rate. Our results indicate that these two distinct brain states represent externally versus internally oriented computational resources engaged by large-scale task-positive and task-negative functional networks.

Neuronal persistent activity has been primarily assessed in terms of electrical mechanisms, without attention to the complex array of molecular events that also control cell excitability. We developed a multiscale neocortical model proceeding from the molecular to the network level to assess the contributions of calcium (Ca(2+)) regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in providing additional and complementary support of continuing activation in the network. The network contained 776 compartmental neurons arranged in the cortical layers, connected using synapses containing AMPA/NMDA/GABAA/GABAB receptors. Metabotropic glutamate receptors (mGluR) produced inositol triphosphate (IP3) which caused the release of Ca(2+) from endoplasmic reticulum (ER) stores, with reuptake by sarco/ER Ca(2+)-ATP-ase pumps (SERCA), and influence on HCN channels. Stimulus-induced depolarization led to Ca(2+) influx via NMDA and voltage-gated Ca(2+) channels (VGCCs). After a delay, mGluR activation led to ER Ca(2+) release via IP3 receptors. These factors increased HCN channel conductance and produced firing lasting for ∼1min. The model displayed inter-scale synergies among synaptic weights, excitation/inhibition balance, firing rates, membrane depolarization, Ca(2+) levels, regulation of HCN channels, and induction of persistent activity. The interaction between inhibition and Ca(2+) at the HCN channel nexus determined a limited range of inhibition strengths for which intracellular Ca(2+) could prepare population-specific persistent activity. Interactions between metabotropic and ionotropic inputs to the neuron demonstrated how multiple pathways could contribute in a complementary manner to persistent activity. Such redundancy and complementarity via multiple pathways is a critical feature of biological systems. Mediation of activation at different time scales, and through different pathways, would be expected to protect against disruption, in this case providing stability for persistent activity.

While the function of the pulvinar remains one of the least explored among the thalamic nuclei despite occupying the most thalamic volume in primates, it has long been suspected to play a crucial role in attentive stimulus processing. In this issue of Neuron, Zhou et al. (2016) use simultaneous pulvinar-visual cortex recordings and pulvinar inactivation to provide evidence that the pulvinar is essential for intact stimulus processing, maintenance of neuronal oscillatory dynamics, and mediating the effects of attention.

A large number of physiomic pathologies can produce hyperexcitability in cortex. Depending on severity, cortical hyperexcitability may manifest clinically as a hyperkinetic movement disorder or as epilpesy. We focus here on dystonia, a movement disorder that produces involuntary muscle contractions and involves pathology in multiple brain areas including basal ganglia, thalamus, cerebellum, and sensory and motor cortices. Most research in dystonia has focused on basal ganglia, while much pharmacological treatment is provided directly at muscles to prevent contraction. Motor cortex is another potential target for therapy that exhibits pathological dynamics in dystonia, including heightened activity and altered beta oscillations. We developed a multiscale model of primary motor cortex, ranging from molecular, up to cellular, and network levels, containing 1715 compartmental model neurons with multiple ion channels and intracellular molecular dynamics. We wired the model based on electrophysiological data obtained from mouse motor cortex circuit mapping experiments. We used the model to reproduce patterns of heightened activity seen in dystonia by applying independent random variations in parameters to identify pathological parameter sets. These models demonstrated degeneracy, meaning that there were many ways of obtaining the pathological syndrome. There was no single parameter alteration which would consistently distinguish pathological from physiological dynamics. At higher dimensions in parameter space, we were able to use support vector machines to distinguish the two patterns in different regions of space and thereby trace multitarget routes from dystonic to physiological dynamics. These results suggest the use of in silico models for discovery of multitarget drug cocktails.

The functional significance of the alpha rhythm is widely debated. It has been proposed that alpha reflects sensory inhibition and/or a temporal sampling or "parsing" mechanism. There is also continuing disagreement over the more fundamental questions of which cortical layers generate alpha rhythms and whether the generation of alpha is equivalent across sensory systems. To address these latter questions, we analyzed laminar profiles of local field potentials (LFPs) and concomitant multiunit activity (MUA) from macaque V1, S1, and A1 during both spontaneous activity and sensory stimulation. Current source density (CSD) analysis of laminar LFP profiles revealed alpha current generators in the supragranular, granular, and infragranular layers. MUA phase-locked to local current source/sink configurations confirmed that alpha rhythms index local neuronal excitability fluctuations. CSD-defined alpha generators were strongest in the supragranular layers, whereas LFP alpha power was greatest in the infragranular layers, consistent with some of the previous reports. The discrepancy between LFP and CSD findings appears to be attributable to contamination of the infragranular LFP signal by activity that is volume-conducted from the stronger supragranular alpha generators. The presence of alpha generators across cortical depth in V1, S1, and A1 suggests the involvement of alpha in feedforward as well as feedback processes and is consistent with the view that alpha rhythms, perhaps in addition to a role in sensory inhibition, may parse sensory input streams in a way that facilitates communication across cortical areas. SIGNIFICANCE STATEMENT: The alpha rhythm is thought to reflect sensory inhibition and/or a temporal parsing mechanism. Here, we address two outstanding issues: (1) whether alpha is a general mechanism across sensory systems and (2) which cortical layers generate alpha oscillations. Using intracranial recordings from macaque V1, S1, and A1, we show alpha band activity with a similar spectral and laminar profile in each of these sensory areas. Furthermore, alpha generators were present in each of the cortical layers, with a strong source in superficial layers. We argue that previous findings, locating alpha generators exclusively in the deeper layers, were biased because of use of less locally specific local field potential measurements. The laminar distribution of alpha band activity appears more complex than generally assumed.

Earlier studies demonstrate that when the frequency of rhythmic tone sequences or streams is task relevant, ongoing excitability fluctuations (oscillations) of neuronal ensembles in primary auditory cortex (A1) entrain to stimulation in a frequency dependent way that sharpens frequency tuning. The phase distribution across A1 neuronal ensembles at time points when attended stimuli are predicted to occur reflects the focus of attention along the spectral attribute of auditory stimuli. This study examined how neuronal activity is modulated if only the temporal features of rhythmic stimulus streams are relevant. We presented macaques with auditory clicks arranged in 33 Hz (gamma timescale) quintets, repeated at a 1.6 Hz (delta timescale) rate. Such multi-scale, hierarchically organized temporal structure is characteristic of vocalizations and other natural stimuli. Monkeys were required to detect and respond to deviations in the temporal pattern of gamma quintets. As expected, engagement in the auditory task resulted in the multi-scale entrainment of delta- and gamma-band neuronal oscillations across all of A1. Surprisingly, however, the phase-alignment, and thus, the physiological impact of entrainment differed across the tonotopic map in A1. In the region of 11-16 kHz representation, entrainment most often aligned high excitability oscillatory phases with task-relevant events in the input stream and thus resulted in response enhancement. In the remainder of the A1 sites, entrainment generally resulted in response suppression. Our data indicate that the suppressive effects were due to low excitability phase delta oscillatory entrainment and the phase amplitude coupling of delta and gamma oscillations. Regardless of the phase or frequency, entrainment appeared stronger in left A1, indicative of the hemispheric lateralization of auditory function.

Recent electrophysiological and neuroimaging studies provide converging evidence that attending to sounds increases the response selectivity of neuronal ensembles even at the first cortical stage of auditory stimulus processing in primary auditory cortex (A1). This is achieved by enhancement of responses in the regions that process attended frequency content, and by suppression of responses in the surrounding regions. The goals of our study were to define the extent to which A1 neuronal ensembles are involved in this process, determine its effect on the frequency tuning of A1 neuronal ensembles, and examine the involvement of the different cortical layers. To accomplish these, we analyzed laminar profiles of synaptic activity and action potentials recorded in A1 of macaques performing a rhythmic intermodal selective attention task. We found that the frequency tuning of neuronal ensembles was sharpened due to both increased gain at the preferentially processed or best frequency and increased response suppression at all other frequencies when auditory stimuli were attended. Our results suggest that these effects are due to a frequency-specific counterphase entrainment of ongoing delta oscillations, which predictively orchestrates opposite sign excitability changes across all of A1. This results in a net suppressive effect due to the large proportion of neuronal ensembles that do not specifically process the attended frequency content. Furthermore, analysis of laminar activation profiles revealed that although attention-related suppressive effects predominate the responses of supragranular neuronal ensembles, response enhancement is dominant in the granular and infragranular layers, providing evidence for layer-specific cortical operations in attentive stimulus processing.