Early hearing loss induces plasticity within extra-striate visual cortex.

Supranormal perceptual performance has been observed within the intact senses of early-deaf or blind humans and animals. For cortical areas deprived of their normal sensory input, numerous studies have shown that the lesioned modality is replaced by that of the intact sensory modalities through a process termed crossmodal plasticity. In contrast, little is known about the effects of loss of a particular sensory modality on the cortical representations of the remaining, intact sensory modalities. In the present study, an area of extrastriate visual cortex from early-deaf adult cats was examined for features of dendritic plasticity known to occur after early-deafness. Using light-microscopy of Golgi-stained pyramidal neurons from the posterolateral lateral suprasylvian (PLLS) cortex, dendritic spine density significantly increased (~19%), while spine head size was slightly but significantly decreased (~9%) following early hearing loss. Curiously, these changes were not localized to regions of the visual PLLS known to receive auditory inputs, but instead showed a broad pattern more reflective of the distribution of the area's visual features. Whereas hearing loss results in crossmodal plasticity in auditory cortices, the same peripheral lesion can also induce intramodal plasticity within representations of the intact sensory systems that may also contribute to supranormal performance.

What is a multisensory cortex? A laminar, connectional, and functional study of a ferret temporal cortical multisensory area.

Now that examples of multisensory neurons have been observed across the neocortex, this has led to some confusion about the features that actually designate a region as "multisensory." While the documentation of multisensory effects within many different cortical areas is clear, often little information is available about their proportions or net functional effects. To assess the compositional and functional features that contribute to the multisensory nature of a region, the present investigation used multichannel neuronal recording and tract tracing methods to examine the ferret temporal region: the lateral rostral suprasylvian sulcal area. Here, auditory-tactile multisensory neurons were predominant and constituted the majority of neurons across all cortical layers whose responses dominated the net spiking activity of the area. These results were then compared with a literature review of cortical multisensory data and were found to closely resemble multisensory features of other, higher-order sensory areas. Collectively, these observations argue that multisensory processing presents itself in hierarchical and area-specific ways, from regions that exhibit few multisensory features to those whose composition and processes are dominated by multisensory activity. It seems logical that the former exhibit some multisensory features (among many others), while the latter are legitimately designated as "multisensory."

Cadaver Rounds: A Comprehensive Exercise That Integrates Clinical Context Into Medical Gross Anatomy.

PROBLEM: The purpose of medical schools is to train students to care for patients; however, the temporal and conceptual gap between course work and patient care may induce students to undervalue preclinical course work, thereby decreasing learning and retention. Bringing clinical context into preclinical courses reduces this problem, and many preclinical programs incorporate "cameo" appearances of clinical material. In contrast, the authors describe a comprehensive program at Virginia Commonwealth University School of Medicine that uses the cadaver as the students' first patient to embed clinical context within preclinical anatomy. APPROACH: As the students' first patient, cadavers undergo modified physical exams, whole-body computed tomography scans, and pathology sample analysis. Students log daily dissection observations onto a "patient chart." Group findings are integrated, on a self-directed basis, into a final grand rounds-style presentation ("Cadaver Rounds") requiring students to synthesize longitudinally collected observations into a plausible clinical condition likely experienced by the cadaver-patient when alive. The entire exercise uses few additional contact hours (about six) and runs concurrently with the existing medical curriculum. OUTCOMES: According to course surveys used to assess students' perceptions of the relevance and effectiveness of Cadaver Rounds (2015-2017), the students' experience was highly positive. Participation by faculty and clinicians has been enthusiastic. NEXT STEPS: The authors hope both to identify additional authentic clinical tasks to import into the dissection lab and to partner with other programs to adopt and evaluate this clinically centered approach to anatomy.

Do the Different Sensory Areas Within the Cat Anterior Ectosylvian Sulcal Cortex Collectively Represent a Network Multisensory Hub?

Current theory supports that the numerous functional areas of the cerebral cortex are organized and function as a network. Using connectional databases and computational approaches, the cerebral network has been demonstrated to exhibit a hierarchical structure composed of areas, clusters and, ultimately, hubs. Hubs are highly connected, higher-order regions that also facilitate communication between different sensory modalities. One region computationally identified network hub is the visual area of the Anterior Ectosylvian Sulcal cortex (AESc) of the cat. The Anterior Ectosylvian Visual area (AEV) is but one component of the AESc that also includes the auditory (Field of the Anterior Ectosylvian Sulcus - FAES) and somatosensory (Fourth somatosensory representation - SIV). To better understand the nature of cortical network hubs, the present report reviews the biological features of the AESc. Within the AESc, each area has extensive external cortical connections as well as among one another. Each of these core representations is separated by a transition zone characterized by bimodal neurons that share sensory properties of both adjoining core areas. Finally, core and transition zones are underlain by a continuous sheet of layer 5 neurons that project to common output structures. Altogether, these shared properties suggest that the collective AESc region represents a multiple sensory/multisensory cortical network hub. Ultimately, such an interconnected, composite structure adds complexity and biological detail to the understanding of cortical network hubs and their function in cortical processing.

Synaptic distribution and plasticity in primary auditory cortex (A1) exhibits laminar and cell-specific changes in the deaf.

The processing sequence through primary auditory cortex (A1) is impaired by deafness as evidenced by reduced neuronal activation in A1 of cochlear-implanted deaf cats. Such a loss of neuronal excitation should be manifest as changes in excitatory synaptic number and/or size, for which the post-synaptic correlate is the dendritic spine. Therefore, the present study sought evidence for this functional disruption using Golgi-Cox/light microscopic techniques that examined spine-bearing neurons and their dendritic spine features across all laminae in A1 of early-deaf (ototoxic lesion <1 month; raised into adulthood >16 months) and hearing cats. Surprisingly, in the early-deaf significant increases in spine density and size were observed in the supragranular layers, while significant reductions in spine density were observed for spiny non-pyramidal, but not pyramidal, neurons in the granular layer. No changes in dendritic spine density consistent with loss of excitatory inputs were seen for infragranular neurons. These results indicate that long-term early-deafness induces plastic changes in the excitatory circuitry of A1 that are laminar and cell-specific. An additional finding was that, unlike the expected abundance of stellate neurons that characterize the granular layer of other primary sensory cortices, pyramidal neurons predominate within layer 4 of A1. Collectively, these observations are important for understanding how neuronal connectional configurations contribute to region-specific processing capabilities in normal brains as well as those with altered sensory experiences.

Cortical and thalamic connectivity of the auditory anterior ectosylvian cortex of early-deaf cats: Implications for neural mechanisms of crossmodal plasticity.

Early hearing loss leads to crossmodal plasticity in regions of the cerebrum that are dominated by acoustical processing in hearing subjects. Until recently, little has been known of the connectional basis of this phenomenon. One region whose crossmodal properties are well-established is the auditory field of the anterior ectosylvian sulcus (FAES) in the cat, where neurons are normally responsive to acoustic stimulation and its deactivation leads to the behavioral loss of accurate orienting toward auditory stimuli. However, in early-deaf cats, visual responsiveness predominates in the FAES and its deactivation blocks accurate orienting behavior toward visual stimuli. For such crossmodal reorganization to occur, it has been presumed that novel inputs or increased projections from non-auditory cortical areas must be generated, or that existing non-auditory connections were 'unmasked.' These possibilities were tested using tracer injections into the FAES of adult cats deafened early in life (and hearing controls), followed by light microscopy to localize retrogradely labeled neurons. Surprisingly, the distribution of cortical and thalamic afferents to the FAES was very similar among early-deaf and hearing animals. No new visual projection sources were identified and visual cortical connections to the FAES were comparable in projection proportions. These results support an alternate theory for the connectional basis for cross-modal plasticity that involves enhanced local branching of existing projection terminals that originate in non-auditory as well as auditory cortices.

Synaptic Basis for Cross-modal Plasticity: Enhanced Supragranular Dendritic Spine Density in Anterior Ectosylvian Auditory Cortex of the Early Deaf Cat.

In the cat, the auditory field of the anterior ectosylvian sulcus (FAES) is sensitive to auditory cues and its deactivation leads to orienting deficits toward acoustic, but not visual, stimuli. However, in early deaf cats, FAES activity shifts to the visual modality and its deactivation blocks orienting toward visual stimuli. Thus, as in other auditory cortices, hearing loss leads to cross-modal plasticity in the FAES. However, the synaptic basis for cross-modal plasticity is unknown. Therefore, the present study examined the effect of early deafness on the density, distribution, and size of dendritic spines in the FAES. Young cats were ototoxically deafened and raised until adulthood when they (and hearing controls) were euthanized, the cortex stained using Golgi-Cox, and FAES neurons examined using light microscopy. FAES dendritic spine density averaged 0.85 spines/µm in hearing animals, but was significantly higher (0.95 spines/µm) in the early deaf. Size distributions and increased spine density were evident specifically on apical dendrites of supragranular neurons. In separate tracer experiments, cross-modal cortical projections were shown to terminate predominantly within the supragranular layers of the FAES. This distributional correspondence between projection terminals and dendritic spine changes indicates that cross-modal plasticity is synaptically based within the supragranular layers of the early deaf FAES.

Laminar and connectional organization of a multisensory cortex.

The transformation of sensory signals as they pass through cortical circuits has been revealed almost exclusively through studies of the primary sensory cortices, for which principles of laminar organization, local connectivity, and parallel processing have been elucidated. In contrast, almost nothing is known about the circuitry or laminar features of multisensory processing in higher order, multisensory cortex. Therefore, using the ferret higher order multisensory rostral posterior parietal (PPr) cortex, the present investigation employed a combination of multichannel recording and neuroanatomical techniques to elucidate the laminar basis of multisensory cortical processing. The proportion of multisensory neurons, the share of neurons showing multisensory integration, and the magnitude of multisensory integration were all found to differ by layer in a way that matched the functional or connectional characteristics of the PPr. Specifically, the supragranular layers (L2/3) demonstrated among the highest proportions of multisensory neurons and the highest incidence of multisensory response enhancement, while also receiving the highest levels of extrinsic inputs, exhibiting the highest dendritic spine densities, and providing a major source of local connectivity. In contrast, layer 6 showed the highest proportion of unisensory neurons while receiving the fewest external and local projections and exhibiting the lowest dendritic spine densities. Coupled with a lack of input from principal thalamic nuclei and a minimal layer 4, these observations indicate that this higher level multisensory cortex shows functional and organizational modifications from the well-known patterns identified for primary sensory cortical regions.

Dendritic spine density in multisensory versus primary sensory cortex.

In sensory areas, neuronal dendritic spines receive sensory-specific inputs whose net activity drives neuronal spiking responses to effective external stimuli. Previous studies indicate that neurons in primary sensory cortical areas, which largely receive inputs from a single sensory modality, exhibit an average of 0.5-1.4 dendritic spines/µm, depending on species. In higher-order, associational cortices, inputs converge from multiple sensory sources onto individual, multisensory neurons. This raises the question: when inputs from two different modalities converge onto individual neurons, how are the dendritic spines apportioned to subserve the generation of robust spiking responses to each modality? As inputs arrive from two different sensory sources, it might be expected that neurons in multisensory areas exhibit approximately double the spine density of neurons in areas that receive just one sensory input. The present study examined this possibility in Golgi-stained neurons from ferret primary auditory (A1) and somatosensory (S1) cortices, as well as from regions in which inputs from two different sensory modalities converge: the lateral rostral suprasylvian sulcus (LRSS) and the rostral posterior parietal (PPr) areas. Dendritic spine density (spines/µm) was measured for pyramidal neurons in layers 2-3 and layers 5-6 for each cortical area from three animals using light microscopy. Primary sensory regions A1 and S1 showed remarkably similar average spine densities (A1 = 1.27 spines/µm ± 0.3 s.d.; S1 = 1.14 spines/µm ± 0.3), but average spine densities from the multisensory areas were lower (LRSS = 0.98 ± 0.3; PPr = 1.04 ± 0.3). Thus, for a given cortical area, dendritic spine density appears to be determined by factors other than the levels of sensory modality convergence.

Auditory influences on non-auditory cortices.

Although responses to auditory stimuli have been extensively examined in the well-known regions of auditory cortex, there are numerous reports of acoustic sensitivity in cortical areas that are dominated by other sensory modalities. Whether in 'polysensory' cortex or in visual or somatosensory regions, auditory responses in non-auditory cortex have been described largely in terms of auditory processing. This review takes a different perspective that auditory responses in non-auditory cortex, either through multisensory subthreshold or bimodal processing, provide subtle but consistent expansion of the range of activity of the dominant modality within a given area. Thus, the features of these acoustic responses may have more to do with the subtle adjustment of response gain within a given non-auditory region than the encoding of their tonal properties.

Auditory projections to extrastriate visual cortex: connectional basis for multisensory processing in 'unimodal' visual neurons.

Neurophysiological studies have recently documented multisensory properties in 'unimodal' visual neurons of the cat posterolateral lateral suprasylvian (PLLS) cortex, a retinotopically organized area involved in visual motion processing. In this extrastriate visual area, a region has been identified where both visual and auditory stimuli were independently effective in activating neurons (bimodal zone), as well as a second region where visually-evoked activity was significantly facilitated by concurrent auditory stimulation but was unaffected by auditory stimulation alone (subthreshold multisensory region). Given their different distributions, the possible corticocortical connectivity underlying these distinct forms of crossmodal convergence was examined using biotinylated dextran amine (BDA) tracer methods in 21 adult cats. The auditory cortical areas examined included the anterior auditory field (AAF), primary auditory cortex (AI), dorsal zone (DZ), secondary auditory cortex (AII), field of the rostral suprasylvian sulcus (FRS), field anterior ectosylvian sulcus (FAES) and the posterior auditory field (PAF). Of these regions, the DZ, AI, AII, and FAES were found to project to the both the bimodal zone and the subthreshold region of the PLLS. This convergence of crossmodal inputs to the PLLS suggests not only that complex auditory information has access to this region but also that these connections provide the substrate for the different forms (bimodal versus subthreshold) of multisensory processing which may facilitate its functional role in visual motion processing.

Sensory and multisensory representations within the cat rostral suprasylvian cortex.

Because the posterior limb of the rostral suprasylvian sulcus (RSp) of the cat resides in close proximity to representations of the somatosensory, auditory, and visual modalities, the surrounding cortices would be expected to be a region where a high degree of multisensory convergence and integration is found. The present experiments tested this notion by using anatomical and electrophysiological methods. Tracer injections into somatosensory, auditory, and visual cortical areas almost all produced terminal labeling within the RSp, albeit at different locations and in different proportions. Inputs from somatosensory cortices primarily targeted the inner portion of the anterior RSp; inputs from auditory cortices generally filled the outer portion of the middle and posterior RSp; inputs from visual cortices terminated in the inner portion of the posterior RSp. These projections did not have sharp borders but often overlapped one another, thereby providing a substrate for multisensory convergence. Electrophysiological recordings confirmed this anatomical organization as well as identifying the presence of multisensory (bimodal) neurons in the areas of overlap between representations. Curiously, however, the proportion of bimodal neurons was only 24% of the neurons sampled in this region, and the majority of these did not show multisensory interactions when combined-modality stimuli were presented. In summary, these experiments indicate that the RSp is primarily auditory in nature, but this representation could be further subdivided into an outer sulcal anterior auditory field (sAAF) and an inner field of the rostral suprasylvian sulcus (FRS).

Crossmodal projections from somatosensory area SIV to the auditory field of the anterior ectosylvian sulcus (FAES) in Cat: further evidence for subthreshold forms of multisensory processing.

To date, evaluation of the neuronal basis for multisensory processing has focused on the convergence pattern that provides excitation from more than one sensory modality. However, a recent study (Dehner et al. in Cereb Cortex 14:387-401, 2004) has demonstrated excitatory-inhibitory multisensory effects that do not follow this conventional pattern and the present investigation documented a similar example of subthreshold cross-modal effects. Neuroanatomical tracers revealed that pyramidal neurons of the somatosensory area SIV project to the auditory field of the anterior ectosylvian sulcus (FAES), but subsequent electrophysiological tests showed that stimulation of SIV failed to elicit the expected orthodromic responses in FAES. Instead, combined auditory-SIV stimulation significantly suppressed FAES responses to auditory cues in approximately 25% of the neurons tested, and facilitated responses in another 5%. These modulatory responses in auditory FAES were similar in kind to those observed in somatosensory SIV and, as such, comprise further evidence for subthreshold forms of multisensory processing in cortex. Consequently, it seems likely that subthreshold cross-modal effects may impact other apparently 'unimodal' areas of the brain.

Cross-modal circuitry between auditory and somatosensory areas of the cat anterior ectosylvian sulcal cortex: a 'new' inhibitory form of multisensory convergence.

Examples of convergence of visual and auditory, or visual and somatosensory, inputs onto individual neurons abound throughout the brain, but substantially fewer incidences of auditory-somatosensory neurons have been reported. The present experiments sought to examine auditory-somatosensory convergence to assess whether there is a feature of this type of convergence that might obscure it from conventional methods of multisensory detection. Auditory-somatosensory convergence was explored in cat anterior ectosylvian sulcus (AES) cortex, where higher-order somatosensory area IV (SIV) and auditory field of the anterior ectosylvian sulcus (FAES) share a common border. While neuroanatomical tracers documented a projection from FAES to SIV, physiological studies failed to reveal the bimodal neurons expected from such cross-modal connectivity. Stimulation of FAES through indwelling electrodes also failed to excite any of the SIV neurons examined. However, when stimulation of auditory FAES was combined with somatosensory stimulation, a large majority (66%) of SIV neurons showed a significant response attenuation. FAES-induced response suppression was specific to SIV, could not be elicited by activating other auditory regions and was blocked by the microiontophoretic application of the GABAergic antagonist bicuculline methiodide. Based on these data, a novel, cross-modal circuit is proposed involving projections from auditory FAES to somatosensory SIV, where local inhibitory interneurons 'reverse the sign' of the cross-modal signals to produce auditory-somatosensory suppression. This form of excitatory-inhibitory multisensory convergence has not been reported before and suggests that the level of interaction between auditory and somatosensory modalities has been substantially underestimated.

Cortico-cortical relations of cat somatosensory areas SIV and SV.

Sensory cortex is characterized by multiple representations of a given modality which are generally highly interconnected and hierarchically arranged. The cat cerebral cortex contains at least five major areas dedicated to somatosensory processing, yet aside from areas SI and SII, little is known regarding the interconnectivity of the other, higher-level regions, such as SIV and SV. Therefore, this investigation examined the anatomical relationship of somatosensory areas SIV and SV to each other. In adult cats, wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) injected into SIV produced retrogradely labeled neurons in SV in a bilaminar pattern. When biotinylated dextran amine (BDA) was injected into SV, orthogradely labeled axon terminals were found in SIV across all laminae but predominated in supragranular locations. In the reciprocal direction, neurons located in both the supra- and infragranular layers of SIV projected across all laminae of SV, but also in a manner that favored the supragranular layers. Because local inhibitory circuits are critical for specific somatosensory response properties, the distribution of GABA-ergic neurons and their co-localized markers calbindin (CB), calretinin (CR) and parvalbumin (PV) was also compared for SIV and SV using immunocytochemical techniques. Although fundamental differences in laminar arrangement were observed between the different GABA-ergic subtypes, the distribution for each subtype was essentially the same in both SIV and SV. Collectively, these connectional, cytoarchitectonic and organizational similarities indicate that SIV and SV are reciprocally connected and share many somatosensory processing and connectional features.

Anterior ectosylvian cortical projections to the rostral suprasylvian multisensory zone in cat.

Recent studies have shown that the anterior ectosylvian sulcal cortex (AESc) and the rostral suprasylvian sulcal cortex (RSSSc) of the cat play integral roles in behavioral and collicular responses to multisensory stimuli. However, substantially more multisensory superior colliculus (SC) neurons are affected by blockade of the AESc than the RSSSc. Although both cortical regions project directly to the SC, a possible explanation for this differential effect is that the AESc may also relay an indirect corticotectal signal via the RSSSc that is reduced when the AESc is deactivated. This possibility was examined by placing orthograde tracer in the auditory field AES (FAES), visual AEV, or between these two regions of the AESc. FAES injections produced labeled boutons in the posterior-lateral bank of the RSSSc, while those placed in AEV failed to label the RSSSc. However, injections between the FAES and AEV regions revealed terminal label in both the posterior lateral bank and fundus. These observations and other studies showing connections between somatosensory portions of the AESc and RSSSc are consistent with the hypothesis that signals from the AESc can take both direct and indirect (through the RSSSc) corticotectal routes to influence processing in the SC.

A comparison of the distribution of GABA-ergic neurons in cortices representing different sensory modalities.

It is well known that sensory receptive field properties are shaped by inhibitory processes. Given the physiological and perceptual distinctions among the different sensory modalities, it might be expected that the contribution of GABA-ergic inhibition to the process would vary from area to area, depending on the sensory modality represented. Furthermore, as receptive field properties become progressively more complex at higher cortical levels, differences in the inhibitory contributions to these computations would be reflected in differences in GABA-ergic neuronal distribution. These possibilities were examined in the cortices surrounding the cat Anterior Ectosylvian Sulcus (AES) which contains higher order visual (AEV), somatosensory (SIV) and auditory (Field AES) representations, and is located between the lower-level primary (AI) and secondary auditory (AII) and somatosensory (SII) areas. Using standard immunocytochemical and light-microscopic techniques, the distribution of GABA-ergic neurons (and their co-localized calcium-binding proteins: calbindin (CB), calretinin (CR) and parvalbumin (PV)) was determined for each area. When normalized for differences in cortical thickness, the depth distribution of each of the immunopositive types was plotted. These data confirmed that there were striking differences in the distribution of GABA-, CB-, CR- and PV-positive neurons. However, the laminar organization for a given marker was remarkably similar for the different subregions, irrespective of modality or hierarchical level. These data indicate that, instead of underlying processing differences among different sensory and hierarchical representations, the distribution of GABA-ergic inhibitory neurons reveals common organizational features across sensory cortex.