Search

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent direct neural mechanisms and indirect sensory co-stimulation effects remain hotly debated. Understanding how TMS modulates neural activity at different scales and how stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging due to the limited spatiotemporal resolution of available non-invasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in non-human primates and show that mesoscale early TMS-evoked potentials are dose and location dependent. Further, we employ several control conditions to dissociate direct neural responses from auditory and somatosensory co-activation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.

In this work, we present a dataset that combines functional magnetic imaging (fMRI) and electroencephalography (EEG) to use as a resource for understanding human brain function in these two imaging modalities. The dataset can also be used for optimizing preprocessing methods for simultaneously collected imaging data. The dataset includes simultaneously collected recordings from 22 individuals (ages: 23-51) across various visual and naturalistic stimuli. In addition, physiological, eye tracking, electrocardiography, and cognitive and behavioral data were collected along with this neuroimaging data. Visual tasks include a flickering checkerboard collected outside and inside the MRI scanner (EEG-only) and simultaneous EEG-fMRI recordings. Simultaneous recordings include rest, the visual paradigm Inscapes, and several short video movies representing naturalistic stimuli. Raw and preprocessed data are openly available to download. We present this dataset as part of an effort to provide open-access data to increase the opportunity for discoveries and understanding of the human brain and evaluate the correlation between electrical brain activity and blood oxygen level-dependent (BOLD) signals.

Significance Our results indicate that nonhuman primates detect complex repeating acoustic sequences in a continuous auditory stream, which is an important precursor for human speech learning and perception. We demonstrate that oscillatory entrainment, known to support the attentive perception of rhythmic stimulus sequences, can occur for rhythms defined solely by stimulus context rather than physical boundaries. As opposed to acoustically driven entrainment by rhythmic tone sequences demonstrated previously, this form of entrainment relies on the brain’s ability to group auditory inputs based on their statistical regularities. The internally initiated, context-driven modulation of excitability in the medial pulvinar prior to A1 supports the notion of top-down entrainment., Prior studies have shown that repetitive presentation of acoustic stimuli results in an alignment of ongoing neuronal oscillations to the sequence rhythm via oscillatory entrainment by external cues. Our study aimed to explore the neural correlates of the perceptual parsing and grouping of complex repeating auditory patterns that occur based solely on statistical regularities, or context. Human psychophysical studies suggest that the recognition of novel auditory patterns amid a continuous auditory stimulus sequence occurs automatically halfway through the first repetition. We hypothesized that once repeating patterns were detected by the brain, internal rhythms would become entrained, demarcating the temporal structure of these repetitions despite lacking external cues defining pattern on- or offsets. To examine the neural correlates of pattern perception, neuroelectric activity of primary auditory cortex (A1) and thalamic nuclei was recorded while nonhuman primates passively listened to streams of rapidly presented pure tones and bandpass noise bursts. At arbitrary intervals, random acoustic patterns composed of 11 stimuli were repeated five times without any perturbance of the constant stimulus flow. We found significant delta entrainment by these patterns in the A1, medial geniculate body, and medial pulvinar. In A1 and pulvinar, we observed a statistically significant, pattern structure-aligned modulation of neuronal firing that occurred earliest in the pulvinar, supporting the idea that grouping and detecting complex auditory patterns is a top-down, context-driven process. Besides electrophysiological measures, a pattern-related modulation of pupil diameter verified that, like humans, nonhuman primates consciously detect complex repetitive patterns that lack physical boundaries.

Salient auditory stimuli typically exhibit rhythmic temporal patterns. A growing body of evidence suggests that, in primary auditory cortex (A1), attention is associated with entrainment of delta rhythms (1 – 4 Hz) by these auditory stimuli. It is thought that this entrainment involves phase reset of ongoing spontaneous oscillations in A1 by thalamus matrix afferents, but precise mechanisms are unknown. Furthermore, naturalistic stimuli can vary widely in terms of their rhythmicity: some cycles can be longer than others and frequency can drift over time. It is not clear how the auditory system accommodates this natural variability. We show that in rhesus macaque monkey A1 in vivo, bottom-up gamma (40 Hz) click trains influence ongoing spontaneous delta rhythms by inducing an initial delta-timescale transient response, followed by entrainment to gamma and suppression of delta. We then construct a computational model to reproduce this effect, showing that transient thalamus matrix activation can reset A1 delta oscillations by directly activating deep (layer 5) IB cells, promoting bursting, and beginning a new delta cycle. In contrast, long duration gamma-rhythmic input stimuli induce a steady-state containing entrainment of superficial RS and FS cells at gamma, and suppression of delta oscillations. This suppression is achieved in the model by two complementary pathways. First, long-duration thalamus matrix input causes IB cells to switch from bursting to sparse firing, which disrupts the IB bursts associated with delta. Second, thalamus core input activates deep FS cells (by way of layer 4), which fire at gamma frequency and actively inhibit the delta oscillator. Together, these two fundamental operations of reset and suppression can respectively advance and delay the phase of the delta oscillator, allowing it to follow rhythms exhibiting the type of variability found in the natural environment. We discuss these findings in relation to functional implications for speech processing.Author summaryNeurons organize their firing into synchronous, rhythmic patterns. These neural oscillations have been shown to entrain to rhythmic stimuli in the external world, such as patterns of speech or patterns of movement. By entraining to a particular input stimulus, these oscillations are thought to help us attend to that stimulus and to exclude others. To understand how this synchronization emerges, we constructed a physiologically detailed mathematical model of the primary auditory cortex. By fitting this model to a variety of experimental data, we suggest fundamental mechanisms by which neurons of the auditory cortex can synchronize their activity to rhythmic external stimuli. This result will be useful for understanding the mechanism and limitations of oscillatory entrainment, which are thought to underlie the processing of naturalistic auditory inputs like speech or music. Furthermore, this model, though simplified, was shown to generalize and reproduce a wide range of experimental results, and can thus be used as a starting point for building more complex models of auditory cortex.

Summary: Complementing long-standing traditions centered on histology, fMRI approaches are rapidly maturing in delineating brain areal organization at the macroscale. The non-human primate (NHP) provides the opportunity to overcome critical barriers in translational research. Here, we establish the data requirements for achieving reproducible and internally valid parcellations in individuals. We demonstrate that functional boundaries serve as a functional fingerprint of the individual animals and can be achieved under anesthesia or awake conditions (rest, naturalistic viewing), though differences between awake and anesthetized states precluded the detection of individual differences across states. Comparison of awake and anesthetized states suggested a more nuanced picture of changes in connectivity for higher-order association areas, as well as visual and motor cortex. These results establish feasibility and data requirements for the generation of reproducible individual-specific parcellations in NHPs, provide insights into the impact of scan state, and motivate efforts toward harmonizing protocols. : Noninvasive fMRI in macaques is an essential tool in translation research. Xu et al. establish the individual functional parcellation of the macaque cortex and demonstrate that brain organization is unique, reproducible, and valid, serving as a fingerprint for an individual macaque. Keywords: macaque, parcellation, cortical areas, gradient, functional connectivity

A long history of postmortem studies has provided significant insight into human brain structure and organization. Cadavers have also proven instrumental for the measurement of artifacts and nonneural effects in functional imaging, and more recently, the study of biophysical properties critical to brain stimulation. However, death produces significant changes in the biophysical properties of brain tissues, making an ex vivo to in vivo comparison complex, and even questionable. This study directly compares biophysical properties of electric fields arising from transcranial electric stimulation (TES) in a nonhuman primate brain pre- and postmortem. We show that pre- vs. postmortem, TES-induced intracranial electric fields differ significantly in both strength and frequency response dynamics, even while controlling for confounding factors such as body temperature. Our results clearly indicate that ex vivo cadaver and in vivo measurements are not easily equitable. In vivo examinations remain essential to establishing an adequate understanding of even basic biophysical phenomena in vivo.

Broadband High-frequency Activity (BHA; 70-150 Hz), also known as "high gamma," a key analytic signal in human intracranial recordings is often assumed to reflect local neural firing (multiunit activity; MUA). Accordingly, BHA has been used to study neuronal population responses in auditory (1,2), visual (3,4), language (5), mnemonic processes (6-9) and cognitive control (10,11). BHA is arguably the electrophysiological measure best correlated with the Blood Oxygenation Level Dependent (BOLD) signal in fMRI (12-13). However, beyond the fact that BHA correlates with neuronal spiking (12, 14-16), the neuronal populations and physiological processes generating BHA are not precisely defined. Although critical for interpreting intracranial signals in human and non-human primates, the precise physiology of BHA remains unknown. Here, we show that BHA dissociates from MUA in primary visual and auditory cortex. Using laminar multielectrode data in monkeys, we found a bimodal distribution of stimulus-evoked BHA across depth of a cortical column: an early-deep, followed by a later-superficial layer response. Only, the early-deep layer BHA had a clear local MUA correlate, while the more prominent superficial layer BHA had a weak or undetectable MUA correlate. In many cases, particularly in V1 (70%), supragranular sites showed strong BHA in lieu of any detectable increase in MUA. Due to volume conduction, BHA from both the early-deep and the later-supragranular generators contribute to the field potential at the pial surface, though the contribution may be weighted towards the late-supragranular BHA. Our results demonstrate that the strongest generators of BHA are in the superficial cortical layers and show that the origins of BHA include a mixture of the neuronal action potential firing and dendritic processes separable from this firing. It is likely that the typically-recorded BHA signal emphasizes the latter processes to a greater extent than previously recognized.

BHA (aka high gamma) correlates with neuronal firing, but is generated mainly by dendritic processes separable from firing., Broadband high-frequency activity (BHA; 70 to 150 Hz), also known as “high gamma,” a key analytic signal in human intracranial (electrocorticographic) recordings, is often assumed to reflect local neural firing [multiunit activity (MUA)]. As the precise physiological substrates of BHA are unknown, this assumption remains controversial. Our analysis of laminar multielectrode data from V1 and A1 in monkeys outlines two components of stimulus-evoked BHA distributed across the cortical layers: an “early-deep” and “late-superficial” response. Early-deep BHA has a clear spatial and temporal overlap with MUA. Late-superficial BHA was more prominent and accounted for more of the BHA signal measured near the cortical pial surface. However, its association with local MUA is weak and often undetectable, consistent with the view that it reflects dendritic processes separable from local neuronal firing.

Cortical connectivity conforms to a series of organizing principles that are common across species. Spatial proximity, similar cortical type, and similar connectional profile all constitute factors for determining the connectivity between cortical regions. We previously demonstrated another principle of connectivity that is closely related to the spatial layout of the cerebral cortex. Using functional connectivity from resting-state fMRI in the human cortex, we found that the further a region is located from primary cortex, the more distant are its functional connections with the other areas of the cortex. However, it remains unknown whether this relationship between cortical layout and connectivity extends to other primate species. Here, we investigated this relationship using both resting-state functional connectivity as well as gold-standard tract-tracing connectivity in the macaque monkey cortex. For both measures of connectivity, we found a gradient of connectivity distance extending between primary and frontoparietal regions. In the human cortex, the further a region is located from primary areas, the stronger its connections to distant portions of the cortex, with connectivity distance highest in frontal and parietal regions. The similarity between the human and macaque findings provides evidence for a phylogenetically conserved relationship between the spatial layout of cortical areas and connectivity. Electronic supplementary material The online version of this article (10.1007/s00429-018-1811-1) contains supplementary material, which is available to authorized users.

Introduction Transcranial electric stimulation (TES) is an emerging technique to non-invasively modulate brain function. However, the spatiotemporal distribution of electric fields during TES remains poorly understood. Objectives In this study we perform direct intracranial measurements of the electric field generated by transcranial alternating current (tACS) in epilepsy patients and cebus monkeys and evaluate the capacity of finite element method (FEM) models to predict the spatial distribution of measured electric fields. Methods Two presurgical epilepsy patients, with ca. 100 intracranially implanted electrodes participated in a single TES session. Two sponge electrodes (25 cm2) were attached over the left and right temporal cortex and a current of 1 mA with a frequency of 1 Hz was applied for 2 min. In two cebus monkeys three electrodes, with a total of 32 contacts were permanently implanted with posterior-anterior orientation. In multiple sessions intracranial EEG was recorded during TES. We varied the frequency of stimulation from 1–150 Hz and computed amplitude and phase relationships of recorded voltages. We constructed FEM models with increasing anatomical complexity for one epilepsy patient and compared the measured and simulated electric fields. Results Voltage magnitude slightly decreased with stimulation frequency up to 10% and small phase differences between electrode contacts up to a few degrees were observed. Electric field strengths were strongest in superficial brain regions with maximum values of 0.5 mV/mm ( Download : Download high-res image (1MB) Download : Download full-size image Fig. 1). Comparison of measured and simulated potentials and electric fields showed very high correlation values for the potentials (r = 0.95) and correlations of r = 0.7 for the electric fields. Evaluating the predictive value of increasingly complex FEM models highlighted the importance of accurate skull modeling especially in the vicinity of skull defects ( Download : Download high-res image (746KB) Download : Download full-size image Fig. 2). Conclusion We conducted a comprehensive evaluation of intracranial electric field during TES in both human patients and monkeys. Our results indicate that TES currents spread in a linear ohmic manner and capacitive effects are small indicating that the quasi-static approximation is well justified in the low frequency range. The spatial variation of the electric fields can be captured using realistic FEM models.

Neural oscillations play a crucial role in communication between remote brain areas. Transcranial electric stimulation with alternating currents (TACS) can manipulate these brain oscillations in a non-invasive manner. Recently, TACS using multiple electrodes with phase shifted stimulation currents were developed to alter long-range connectivity. Typically, an increase in coordination between two areas is assumed when they experience an in-phase stimulation and a disorganization through an anti-phase stimulation. However, the underlying biophysics of multi-electrode TACS has not been studied in detail. Here, we leverage direct invasive recordings from two non-human primates during multi-electrode TACS to characterize electric field magnitude and phase as a function of the phase of stimulation currents. Further, we report a novel “traveling wave” stimulation where the location of the electric field maximum changes over the stimulation cycle. Our results provide a mechanistic understanding of the biophysics of multi-electrode TACS and enable future developments of novel stimulation protocols., Transcranial alternating current stimulation (TACS) of the brain is widely used in neuroscience, but the electric fields produced when multiple stimulation electrodes are used are not well understood. Here, the authors directly record electric fields in primate brains during multi-electrode TACS.

Complementing longstanding traditions centered around histology, functional magnetic resonance imaging approaches are rapidly maturing in their ability to delineate brain areal organization at the macroscale. In particular, automated approaches focused on the detection of gradient-based boundaries in functional connectivity (FC) properties between cortical areas have demonstrated the ability to characterize human brain organization at the individual level and recapitulate previously established cytoarchitectonic brain areas. The use of non-human primates (NHP) provides the opportunity to overcome critical barriers in the advancement of translational research. Here, we establish the data and scanning condition requirements for achieving reproducible, stable and internally valid areal parcellations at the individual levels, which have good correspondences with previously established postmortem areas; the inclusion of data from two independent imaging sites ensures the reproducibility of our findings. We demonstrate that highly reproducible areal organizations for fingerprinting can be achieved whether subjects were scanned under anesthesia or awake (rest, naturalistic viewing), though differences between awake and anesthetized states precluded the detection of individual differences across states. Individual differences were notably more stable across differing awake states. Comparison of awake and anesthetized states suggested a more nuanced picture of changes in connectivity for higher order association areas, as well as visual and motor cortex. These results establish feasibility and data requirements for the generation of reproducible individual-specific parcellations in NHP, as well as provide insights into the impact of scan state on findings.

The laminar location of the cell bodies and terminals of interareal connections determines the hierarchical structural organization of the cortex and has been intensively studied. However, we still have only a rudimentary understanding of the connectional principles of feedforward (FF) and feedback (FB) pathways. Quantitative analysis of retrograde tracers was used to extend the notion that the laminar distribution of neurons interconnecting visual areas provides an index of hierarchical distance (percentage of supragranular labeled neurons [SLN]). We show that: 1) SLN values constrain models of cortical hierarchy, revealing previously unsuspected areal relations; 2) SLN reflects the operation of a combinatorial distance rule acting differentially on sets of connections between areas; 3) Supragranular layers contain highly segregated bottom-up and top-down streams, both of which exhibit point-to-point connectivity. This contrasts with the infragranular layers, which contain diffuse bottom-up and top-down streams; 4) Cell filling of the parent neurons of FF and FB pathways provides further evidence of compartmentalization; 5) FF pathways have higher weights, cross fewer hierarchical levels, and are less numerous than FB pathways. Taken together, the present results suggest that cortical hierarchies are built from supra- and infragranular counterstreams. This compartmentalized dual counterstream organization allows point-to-point connectivity in both bottom-up and top-down directions.

Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reaches the brain, and how it distributes across the brain. Lack of this basic information precludes a firm mechanistic understanding of TES effects. In this study we directly measure the spatial and temporal characteristics of the electric field generated by TES using stereotactic EEG (s-EEG) electrode arrays implanted in cebus monkeys and surgical epilepsy patients. We found a small frequency dependent decrease (10%) in magnitudes of TES induced potentials and negligible phase shifts over space. Electric field strengths were strongest in superficial brain regions with maximum values of about 0.5 mV/mm. Our results provide crucial information of the underlying biophysics in TES applications in humans and the optimization and design of TES stimulation protocols. In addition, our findings have broad implications concerning electric field propagation in non-invasive recording techniques such as EEG/MEG.

Introduction Cellular targets of transcranial electric stimulation (TES) are not well understood. Due to a number of factors including size, packing, myelination and orientation of predominant cell types and related variations in conductivity across layers, some cortical layers may be more susceptible to stimulation than others. Current biophysical models of TES do not account for laminar specific differences in the electric field distribution. Objectives In this study we systematically mapped the electric field distribution during TES across cortical layers as a function of electrode montage, stimulation frequency and cortical depth. Methods Using laminar multielectrode recordings (100 μm spacing, 24 contacts, implanted in V1) in an anesthetized cebus monkey we recorded TES induced potentials for two montages: 1. Anterior-Posterior current direction, electrodes placed over V1 and forehead. 2. Left–Right current direction, electrodes placed over bilateral temples. Stimulation intensity was 100 μA applied through round (3.14 cm2) Ag/AgCl electrodes. Measurements were performed using alternating currents with frequencies from 1–150 Hz for different depths (from dura through GM and WM). Electric fields were computed as the first spatial derivative of recorded potentials. Results We found a marked influence of the laminar structure on the electric field distribution ( Download : Download high-res image (624KB) Download : Download full-size image Fig. 1A) with locally increased field strengths (Layer IV/V). This effect was dependent on current direction (Fig. 1B). The amplitude and phase of recorded potentials varied in a frequency and spatially dependent manner ( Download : Download high-res image (444KB) Download : Download full-size image Fig. 2). Conclusion Our results highlight differential effects of electric field propagation across cortical layers. Locally enhanced electric fields are likely due to currents passing across conductivity mismatches between layers. This effect is dependent on current orientation. Magnitude and phase of recorded potentials varied across the depth of cortex demonstrating changes in local electric properties of brain tissue. Larger phase shifts in deeper WM regions could be related to stronger capacitive influences from myelinated axons. In summary our results show previously unreported laminar specific effects of TES electric fields making a first step in the identification of cell specific targets for TES.

SUMMARY Inhibition plays an essential role in shaping and refining the brain’s representation of sensory stimulus attributes. In primary auditory cortex (A1), so-called ‘‘sideband’’ inhibition helps to sharpen the tuning of local neuronal responses. Several distinct types of anatomical circuitry could underlie sideband inhibition, including direct thalamocortical (TC) afferents, as well as indirect intracortical mechanisms. The goal of the present study was to characterize sideband inhibition in A1 and to determine its mechanism by analyzing laminar profiles of neuronal ensemble activity. Our results indicate that both lemniscal and nonlemniscal TC afferents play a role in inhibitory responses via feedforward inhibition and oscillatory phase reset, respectively. We propose that the dynamic modulation of excitability in A1 due to the phase reset of ongoing oscillations may alter the tuning of local neuronal ensembles and can be regarded as a flexible overlay on the more obligatory system of lemniscal feedforward type responses.

The superior temporal gyrus (STG) is on the inferior–lateral brain surface near the external ear. In macaques, 2/3 of the STG is occupied by an auditory cortical region, the “parabelt,” which is part of a network of inferior temporal areas subserving communication and social cognition as well as object recognition and other functions. However, due to its location beneath the squamous temporal bone and temporalis muscle, the STG, like other inferior temporal regions, has been a challenging target for physiological studies in awake-behaving macaques. We designed a new procedure for implanting recording chambers to provide direct access to the STG, allowing us to evaluate neuronal properties and their topography across the full extent of the STG in awake-behaving macaques. Initial surveys of the STG have yielded several new findings. Unexpectedly, STG sites in monkeys that were listening passively responded to tones with magnitudes comparable to those of responses to 1/3 octave band-pass noise. Mapping results showed longer response latencies in more rostral sites and possible tonotopic patterns parallel to core and belt areas, suggesting the reversal of gradients between caudal and rostral parabelt areas. These results will help further exploration of parabelt areas.

The primary visual cortex (area 17 or V1) is not thought to receive input from nonvisual extrastriate cortical areas. However, this has yet to be shown to be the case using sensitive tracers in the part of area 17 subserving the peripheral visual field. Here we show using retrograde tracers that peripheral area 17 subserving the visual field at an eccentricity of 10-20 degrees receives projections from the core and parabelt areas of the auditory cortex as well as from the polysensory area of the temporal lobe (STP). The relative strength of these projections was calculated for each injection by computing the proportions of retrogradely labeled neurons located in the auditory and STP areas with respect to number of labeled neurons constituting the established projection from the superior temporal sulci (STS) motion complex (middle temporal area, medial superior temporal, fundus of the superior temporal area). In peripheral area V1 the projection from auditory cortex corresponds to 9.5% of that of the STS motion complex and STP to 35% of that from the STS motion complex. Compared to peripheral area 17, central and paracentral area 17 showed considerably weaker inputs from auditory cortex (0.2-0.8%) but slightly more from STP cortex (3.5-6.1%). The present results show that the connectivity of area 17 is eccentricity dependent. Direct projections from auditory and STP cortex to peripheral area 17 have important consequences for higher visual functions of area 17, including multimodal integration at early stages of the visual cortical pathway.

Our working model of the primate auditory cortex recognizes three major regions (core, belt, parabelt), subdivided into thirteen areas. The connections between areas are topographically ordered in a manner consistent with information flow along two major anatomical axes: core-belt-parabelt and caudal-rostral. Remarkably, most of the connections supporting this model were revealed using retrograde tracing techniques. Little is known about laminar circuitry, as anterograde tracing of axon terminations has rarely been used. The purpose of the present study was to examine the laminar projections of three areas of auditory cortex, pursuant to analysis of all areas. The selected areas were: middle lateral belt (ML); caudomedial belt (CM); and caudal parabelt (CPB). Injections of anterograde tracers yielded data consistent with major features of our model, and also new findings that compel modifications. Results supporting the model were: (1) feedforward projection from ML and CM terminated in CPB; (2) feedforward projections from ML and CPB terminated in rostral areas of the belt and parabelt; and (3) feedback projections typified inputs to the core region from belt and parabelt. At odds with the model was the convergence of feedforward inputs into rostral medial belt from ML and CPB. This was unexpected since CPB is at a higher stage of the processing hierarchy, with mainly feedback projections to all other belt areas. Lastly, extending the model, feedforward projections from CM, ML, and CPB overlapped in the temporal parietal occipital area (TPO) in the superior temporal sulcus, indicating significant auditory influence on sensory processing in this region. The combined results refine our working model and highlight the need to complete studies of the laminar inputs to all areas of auditory cortex. Their documentation is essential for developing informed hypotheses about the neurophysiological influences of inputs to each layer and area.

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation

SummaryAlthough we have convincing evidence that attention to auditory stimuli modulates neuronal responses at or before the level of primary auditory cortex (A1), the underlying physiological mechanisms are unknown. We found that attending to rhythmic auditory streams resulted in the entrainment of ongoing oscillatory activity reflecting rhythmic excitability fluctuations in A1. Strikingly, although the rhythm of the entrained oscillations in A1 neuronal ensembles reflected the temporal structure of the attended stream, the phase depended on the attended frequency content. Counter-phase entrainment across differently tuned A1 regions resulted in both the amplification and sharpening of responses at attended time points, in essence acting as a spectrotemporal filter mechanism. Our data suggest that selective attention generates a dynamically evolving model of attended auditory stimulus streams in the form of modulatory subthreshold oscillations across tonotopically organized neuronal ensembles in A1 that enhances the representation of attended stimuli.

The operation of real world networks is largely determined by their weighted and spatial characteristics. Surprisingly little is known about these features in cortex. We generated in macaque, a consistent database of inter-areal connections comprising projection densities (link weights) and physical lengths. Contrary to previous assumptions, the cortical connection matrix is dense (66%) and therefore, not a small-world graph. Link weights are both highly specific and heterogeneous and we show that it is these properties that characterize the network. The embedding of this weighted network is governed by a distance rule that predicts both its binary features as well as the global and local communication efficiencies. Analysis of the efficiency of this weighted network suggests that small changes in global communication efficiency are offset by large changes in local efficiency. These findings indicate a weight-based hierarchical layering in cortical architecture and processing.

Studies in humans and monkeys report widespread multisensory interactions at or near primary visual and auditory areas of neocortex. The range and scale of these effects has prompted increased interest in interconnectivity between the putatively ‘‘unisensory’’ cortices at lower hierarchical levels. Recent anatomical tract-tracing studies have revealed direct projections from auditory cortex to primary visual area (V1) and secondary visual area (V2) that could serve as a substrate for auditory influences over low-level visual processing. To better understand the significance of these connections, we looked for reciprocal projections from visual cortex to caudal auditory cortical areas in macaque monkeys. We found direct projections from area prostriata and the peripheral visual representations of area V2. Projections were more abundant after injections of temporoparietal area and caudal parabelt than after injections of caudal medial belt and the contiguous areas near the fundus of the lateral sulcus. Only one injection was confined to primary auditory cortex (area A1) and did not demonstrate visual connections. The projections from visual areas originated mainly from infragranular layers, suggestive of a ‘‘feedback’’-type projection. The selective localization of these connections to peripheral visual areas and caudal auditory cortex suggests that they are involved in spatial localization.

Functional studies have demonstrated multisensory responses in auditory cortex, even in the primary and early auditory association areas. The features of somatosensory and visual responses in auditory cortex suggest that they are involved in multiple processes including spatial, temporal and object-related perception. Tract tracing studies in monkeys have demonstrated several potential sources of somatosensory and visual inputs to auditory cortex. These include potential somatosensory inputs from the retroinsular (RI) and granular insula (Ig) cortical areas, and from the thalamic posterior (PO) nucleus. Potential sources of visual responses include peripheral field representations of areas V2 and prostriata, as well as the superior temporal polysensory area (STP) in the superior temporal sulcus, and the magnocellular medial geniculate thalamic nucleus (MGm). Besides these sources, there are several other thalamic, limbic and cortical association structures that have multisensory responses and may contribute cross-modal inputs to auditory cortex. These connections demonstrated by tract tracing provide a list of potential inputs, but in most cases their significance has not been confirmed by functional experiments. It is possible that the somatosensory and visual modulation of auditory cortex are each mediated by multiple extrinsic sources.

It is generally agreed that information flow through the cortex is constrained by a hierarchical architecture. Recent experimental evidence suggests that projections descending the hierarchy and targeting the primary visual cortex (area V1) may play an essential role in perceptual processes. We have, therefore, reexamined feedback projections to area V1, using retrograde tracer injections in this area. In addition to well-known areas, quantification of labeling in higher cortical areas reveals a number of hitherto unknown long-distance feedback connections originating from auditory (A1), multisensory (STP) cortices, but also from a perirhinal area (36). These feedback projections from advanced cortical stations, a global feature shared by areas that belong to the ventral visual stream, could play an important role in early multisensory integration and spatial awareness and could provide the physical substrate for the involvement of area V1 in visual consciousness.

It is generally agreed that information flow through the cortex is constrained by a hierarchical architecture. Lack of precise data on areal connectivity leads to indeterminacy of existing models. The authors introduce two quantitative parameters (SLN and FLN) that hold the promise of resolving such indeterminacy. In the visual system, using a very incomplete database, provisional hierarchies are in line with the recent proposal of higher functions of area V1 and suggest a hitherto unsuspected central function of the frontal eye field.