Eric Tardif

Intrinsic connectivity of human auditory areas: a tracing study with DiI

The human supratemporal plane contains the primary as well as several other auditory areas. We have investigated the intrinsic connectivity of these areas by means of antero‐ and retrograde labelling with the carbocyanin dye DiI (1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate). A total of 30 injections was placed in both hemispheres of four freshly fixed postmortem brains. Labelled neurons and axons were found in cortex around the injection. The retrograde labelling varied from faint to Golgi‐like; most of the retrograde labelled neurons were layers II–III pyramids and only a few were nonpyramidal neurons. Labelled axons were dense in all layers near the injection site, while they became relatively rare in layer IV further away. The tangential spread of labelling differed among auditory areas. On Heschls gyrus (corresponding to the primary auditory cortex and cytoarchitectonic areas TD and part of TB) intrinsic connectivity involved a relatively narrow part of cortex. They spread over larger parts of cortex in plana polare and temporale (areas TG, TA and the remaining part of TB). A number of injections also produced anisotropic labelling patterns. These results reveal differences in intrinsic connectivity between auditory areas. They suggest that intrinsic connections within the primary auditory area, area TD and part of TB that is on Heschls gyrus, involve mainly nearby units or modules, probably with similar coding properties, whereas in surrounding areas, connections spread over more distant units and may play an important role in the integration of different auditory features.

Differential Changes in Synaptic Proteins in the Alzheimer Frontal Cortex with Marked Increase in PSD-95 Postsynaptic Protein

We investigated how synaptic plasticity is related to the neurodegeneration process in the human dorsolateral prefrontal cortex. Pre- and postsynaptic proteins of Brodmanns area 9 from patients with Alzheimers disease (AD) and age-matched controls were quantified by immunohistochemical methods and Western blots. The main finding was a significant increase in the expression of postsynaptic density protein PSD-95 in AD brains, revealed on both sections and immunoblots, while the expression of spinophilin, associated to spines, remained quantitatively unchanged despite qualitative changes with age and disease. Presynaptic protein alpha-synuclein indicated an increased immunohistochemical level, while synaptophysin remained unchanged. MAP2, a somatodendritic microtubule protein, as well as AD markers such as amyloid-beta protein and phosphorylated protein tau showed an increased expression on immunosections in AD. Altogether these changes suggest neuritic and synaptic reorganization in the process of AD. In particular, the significant increase in PSD-95 expression suggests a change in NMDA receptors trafficking and may represent a novel marker of functional significance for the disease.

Patterns of calcium-binding proteins support parallel and hierarchical organization of human auditory areas

The human primary auditory cortex (AI) is surrounded by several other auditory areas, which can be identified by cyto‐, myelo‐ and chemoarchitectonic criteria. We report here on the pattern of calcium‐binding protein immunoreactivity within these areas. The supratemporal regions of four normal human brains (eight hemispheres) were processed histologically, and serial sections were stained for parvalbumin, calretinin or calbindin. Each calcium‐binding protein yielded a specific pattern of labelling, which differed between auditory areas. In AI, defined as area TC [see C. von Economo and L. Horn (1930) Z. Ges. Neurol. Psychiatr.,130, 678–757], parvalbumin labelling was dark in layer IV; several parvalbumin‐positive multipolar neurons were distributed in layers III and IV. Calbindin yielded dark labelling in layers I–III and V; it revealed numerous multipolar and pyramidal neurons in layers II and III. Calretinin labelling was lighter than that of parvalbumin or calbindin in AI; calretinin‐positive bipolar and bitufted neurons were present in supragranular layers. In non‐primary auditory areas, the intensity of labelling tended to become progressively lighter while moving away from AI, with qualitative differences between the cytoarchitectonically defined areas. In analogy to non‐human primates, our results suggest differences in intrinsic organization between auditory areas that are compatible with parallel and hierarchical processing of auditory information.

Learning-Induced Plasticity in Auditory Spatial Representations Revealed by Electrical Neuroimaging

Auditory spatial representations are likely encoded at a population level within human auditory cortices. We investigated learning-induced plasticity of spatial discrimination in healthy subjects using auditory-evoked potentials (AEPs) and electrical neuroimaging analyses. Stimuli were 100 ms white-noise bursts lateralized with varying interaural time differences. In three experiments, plasticity was induced with 40 min of discrimination training. During training, accuracy significantly improved from near-chance levels to ∼75%. Before and after training, AEPs were recorded to stimuli presented passively with a more medial sound lateralization outnumbering a more lateral one (7:1). In experiment 1, the same lateralizations were used for training and AEP sessions. Significant AEP modulations to the different lateralizations were evident only after training, indicative of a learning-induced mismatch negativity (MMN). More precisely, this MMN at 195–250 ms after stimulus onset followed from differences in the AEP topography to each stimulus position, indicative of changes in the underlying brain network. In experiment 2, mirror-symmetric locations were used for training and AEP sessions; no training-related AEP modulations or MMN were observed. In experiment 3, the discrimination of trained plus equidistant untrained separations was tested psychophysically before and 0, 6, 24, and 48 h after training. Learning-induced plasticity lasted <6 h, did not generalize to untrained lateralizations, and was not the simple result of strengthening the representation of the trained lateralizations. Thus, learning-induced plasticity of auditory spatial discrimination relies on spatial comparisons, rather than a spatial anchor or a general comparator. Furthermore, cortical auditory representations of space are dynamic and subject to rapid reorganization.

The spatio-temporal brain dynamics of processing and integrating sound localization cues in humans

Interaural intensity and time differences (IID and ITD) are two binaural auditory cues for localizing sounds in space. This study investigated the spatio-temporal brain mechanisms for processing and integrating IID and ITD cues in humans. Auditory-evoked potentials were recorded, while subjects passively listened to noise bursts lateralized with IID, ITD or both cues simultaneously, as well as a more frequent centrally presented noise. In a separate psychophysical experiment, subjects actively discriminated lateralized from centrally presented stimuli. IID and ITD cues elicited different electric field topographies starting at approximately 75 ms post-stimulus onset, indicative of the engagement of distinct cortical networks. By contrast, no performance differences were observed between IID and ITD cues during the psychophysical experiment. Subjects did, however, respond significantly faster and more accurately when both cues were presented simultaneously. This performance facilitation exceeded predictions from probability summation, suggestive of interactions in neural processing of IID and ITD cues. Supra-additive neural response interactions as well as topographic modulations were indeed observed approximately 200 ms post-stimulus for the comparison of responses to the simultaneous presentation of both cues with the mean of those to separate IID and ITD cues. Source estimations revealed differential processing of IID and ITD cues initially within superior temporal cortices and also at later stages within temporo-parietal and inferior frontal cortices. Differences were principally in terms of hemispheric lateralization. The collective psychophysical and electrophysiological results support the hypothesis that IID and ITD cues are processed by distinct, but interacting, cortical networks that can in turn facilitate auditory localization.

Topography of cortico-striatal connections in man: anatomical evidence for parallel organization

Tracing studies in non‐human primates support the existence of several parallel neuronal circuits involving cerebral cortex, basal ganglia and thalamus. Distinct functional loops were proposed to underlie multiple aspects of normal and pathological behaviour in man. We present here the first anatomical evidence for separate corticostriatal systems in humans. Neural connections of the sensorimotor and prefrontal cortex to the striatum were studied in one human brain using the Nauta method for anterogradely degenerating axons. Axons originating from a lesion in the left sensorimotor cortex, including the face area, were found to terminate in the superolateral part of the ipsilateral putamen, forming a narrow band in its posterior part. Inside the band, the distribution of degenerating axons was inhomogeneous; high‐density clusters of approximately 2.5 mm in diameter were separated by regions with less dense cortical projections. Axons originating from a small lesion in the fundus of the right superior frontal sulcus were found in the upper part of the ipsilateral caudate nucleus. The existence of discrete and anatomically segregated terminal patches originating from distinct cortical regions suggests parallel organization of cortico‐striatal connections in man.

Thalamic projections of the fusiform gyrus in man

Previous retrograde degeneration studies have shown that human extrastriate visual cortex receives projections from the pulvinar, but their precise topographical organization remained unknown. We report on the distribution of thalamic projections originating in the fusiform gyrus, as studied with the Nauta method for anterogradely degenerating axons, in a case of right fusiform gyrus infarction. Ipsilaterally to the lesion, high density of afferents was found in the inferior pulvinar nucleus and a low density in the medial pulvinar nucleus as well as in the postero‐inferior part of the reticular nucleus; no degenerating fibres were found in the lateral geniculate body. Degenerating axons were completely absent in the contralateral thalamus. Thus, there is a precise topographic relationship between parts of the extrastriate cortex and the pulvinar, suggesting segregated thalamocortical pathways for different parts of the extrastriate cortex. As in nonhuman primates, the human inferior temporal cortex has no direct output to the lateral geniculate body.

Patterns of calcium-binding proteins in human inferior colliculus: identification of subdivisions and evidence for putative parallel systems.

The subdivisions of human inferior colliculus are currently based on Golgi and Nissl-stained preparations. We have investigated the distribution of calcium-binding protein immunoreactivity in the human inferior colliculus and found complementary or mutually exclusive localisations of parvalbumin versus calbindin D-28k and calretinin staining. The central nucleus of the inferior colliculus but not the surrounding regions contained parvalbumin-positive neuronal somata and fibres. Calbindin-positive neurons and fibres were concentrated in the dorsal aspect of the central nucleus and in structures surrounding it: the dorsal cortex, the lateral lemniscus, the ventrolateral nucleus, and the intercollicular region. In the dorsal cortex, labelling of calbindin and calretinin revealed four distinct layers.Thus, calcium-binding protein reactivity reveals in the human inferior colliculus distinct neuronal populations that are anatomically segregated. The different calcium-binding protein-defined subdivisions may belong to parallel auditory pathways that were previously demonstrated in non-human primates, and they may constitute a first indication of parallel processing in human subcortical auditory structures.

The path to success in auditory spatial discrimination: electrical neuroimaging responses within the supratemporal plane predict performance outcome.

Auditory scene analysis requires the accurate encoding and comparison of the perceived spatial positions of sound sources. The electrophysiological correlates of auditory spatial discrimination and their relationship to performance accuracy were studied in humans by applying electrical neuroimaging analyses to auditory evoked potentials (AEPs) that were recorded during the completion of a near-threshold S1-S2 paradigm within the right hemispace. Data were sorted as a function of performance accuracy, and AEP responses 75-117 ms after the presentation of the first sound differed topographically between trials leading to correct and incorrect spatial discrimination. Distributed source estimations revealed that this followed from significantly stronger activity within the left (i.e. contralateral) supratemporal plane (STP) and the left inferior parietal lobule prior to correct versus incorrect discrimination performance. Successful spatial discrimination thus depends on the activity of distinct configurations of active brain networks within the contralateral temporo-parietal cortex over a time period when the first sound position is being encoded. Furthermore, significant positive correlations were observed between performance accuracy and the intracranial activity estimated within the left STP. The efficacy of S1 processing within the STP is thus predictive of behavioral performance outcome during auditory spatial discrimination. Our data support a model wherein refinement of spatial representations occurs within the STP and that interactions with parietal structures allow for transformations into coordinate frames that are required for higher-order computations including absolute localization of sound sources.

Intrinsic connectivity of human superior colliculus

The superior colliculus (SC) is believed to play an important role in sensorimotor integration and orienting behavior. It is classically divided into superficial layers predominantly containing visual neurons and deep layers containing multisensory and premotor neurons. Investigations of intrinsic connectivity within the SC in non-human species initially led to controversy regarding the existence of interlaminar connections between superficial and deep layers. It now seems more likely that such connections exist in a number of species, including non-human primates. In the latter, anatomical data concerning intrinsic SC connectivity are restricted to a limited number of intracellularly labeled neurons. No studies have been conducted to investigate the existence of intrinsic connections of human SC. In the present study, DiI (1,1′-dioctadecyl-3,3,3′,3′- tetramethylindocarbocyanine perchlorate) and BDA (biotinylated dextran amine) were two tracers used in post-mortem human brains to examine intrinsic SC connections. Injections into the superficial layers revealed tangential connections within superficial layers and radial superficial-layer to deep-layer connections. Within superficial layers, horizontal connections were found over the entire rostro-caudal axis and were mostly directed laterally, i.e. toward the brachium of the inferior colliculus. Superficial-layer to deep-layer connections were more prominent in sections containing the injection site or located close to it. In these sections, an axon bundle having roughly the same diameter as the injection site crossed all deep layers, and individual axons displayed en passant or terminal boutons. The present results suggest that intrinsic connections within superficial layers and radial superficial-layers to deep-layers exist in human SC. The putative roles of these connections are discussed with regard to visual receptive field organization, as well as visuomotor and multisensory integration.