Fundamental or forgotten? Is Pierre Paul Broca still relevant in modern neuroscience?

The ability to speak is a unique human capacity, but where is it located in our brains? This question is closely connected to the pioneering work of Pierre Paul Broca in the 1860s. Based on post-mortem observations of aphasic patients' brains, Broca located language production in the 3rd convolution of the left frontal lobe and thus reinitiated the localizationist view of brain functions. However, contemporary neuroscience has partially rejected this view in favor of a network-based perspective. This leads to the question, whether Broca's findings are still relevant today. In this mini-review, we discuss current and historical implications of Broca's work by focusing on his original contribution and contrasting it with contemporary knowledge. Borrowing from Broca's famous quote, our review shows that humans indeed "speak with the left hemisphere"- but Broca's area is not the sole "seat of articulatory language".

Visuospatial attention in the lateralised brain of pigeons - a matter of ontogenetic light experiences.

The ontogenetic mechanisms leading to complementary hemispheric specialisations of the two brain halves are poorly understood. In pigeons, asymmetrical light stimulation during development triggers the left-hemispheric dominance for visuomotor control but light effects on right-hemispheric specialisations are largely unknown. We therefore tested adult pigeons with and without embryonic light experience in a visual search task in which the birds pecked peas regularly scattered on an area in front of them. Comparing the pecking pattern of both groups indicates that the embryonic light conditions differentially influence biased visuospatial attention under mono- and binocular seeing conditions. When one eye was occluded, dark-incubated pigeons peck only within the limits of the visual hemifield of the seeing eye. Light-exposed pigeons also peck into the contralateral field indicating enlarged monocular visual fields of both hemispheres. While dark-incubated birds evinced an attentional bias to the right halfspace when seeing with both eyes, embryonic light exposure shifted this to the left. Thus, embryonic light experience modifies processes regulating biased visuospatial attention of the adult birds depending on the seeing conditions during testing. These data support the impact of light onto the emergence of functional dominances in both hemispheres and point to the critical role of interhemispheric processes.

The Functional Genetics of Handedness and Language Lateralization: Insights from Gene Ontology, Pathway and Disease Association Analyses.

Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting genes may influence the ontogenesis of hemispheric asymmetries. Recently, it has been suggested that analyzing the genetics of hemispheric asymmetries on the level of gene ontology sets, rather than at the level of individual genes, might be more informative for understanding the underlying functional cascades. Here, we performed gene ontology, pathway and disease association analyses on genes that have previously been associated with handedness and language lateralization. Significant gene ontology sets for handedness were anatomical structure development, pattern specification (especially asymmetry formation) and biological regulation. Pathway analysis highlighted the importance of the TGF-beta signaling pathway for handedness ontogenesis. Significant gene ontology sets for language lateralization were responses to different stimuli, nervous system development, transport, signaling, and biological regulation. Despite the fact that some authors assume that handedness and language lateralization share a common ontogenetic basis, gene ontology sets barely overlap between phenotypes. Compared to genes involved in handedness, which mostly contribute to structural development, genes involved in language lateralization rather contribute to activity-dependent cognitive processes. Disease association analysis revealed associations of genes involved in handedness with diseases affecting the whole body, while genes involved in language lateralization were specifically engaged in mental and neurological diseases. These findings further support the idea that handedness and language lateralization are ontogenetically independent, complex phenotypes.

Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries.

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-ß signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans.