Asymmetric Lateralization during Pain Processing

Pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”. This complex perception arises from the coordinated activity of several brain areas processing either sensory–discriminative or affective–motivational components. Functional studies performed in healthy volunteers revealed that affective–emotional components of pain are processed bilaterally but present a clear lateralization towards the right hemisphere, regardless of the site of stimulation. Studies at the cellular level performed in experimental animal models of pain have shown that neuronal activity in the right amygdala is clearly pronociceptive, whilst activation of neurons in the left amygdala might even exert antinociceptive effects. A shift in lateralization becomes evident during the development of chronic pain; thus, in patients with neuropathic pain symptoms, there is increased activity in ipsilateral brain areas related with pain. These observations extend the asymmetrical left–right lateralization within the nervous system and provide a new hypothesis for the pathophysiology of chronic forms of pain. In this article, we will review experimental data from preclinical and human studies on functional lateralization in the brain during pain processing, which will help to explain the affective disorders associated with persistent, chronic pain.

It Is Not Just in the Genes

Asymmetries in the functional and structural organization of the nervous system are widespread in the animal kingdom and especially characterize the human brain. Although there is little doubt that asymmetries arise through genetic and nongenetic factors, an overarching model to explain the development of functional lateralization patterns is still lacking. Current genetic psychology collects data on genes relevant to brain lateralizations, while animal research provides information on the cellular mechanisms mediating the effects of not only genetic but also environmental factors. This review combines data from human and animal research (especially on birds) and outlines a multi-level model for asymmetry formation. The relative impact of genetic and nongenetic factors varies between different developmental phases and neuronal structures. The basic lateralized organization of a brain is already established through genetically controlled embryonic events. During ongoing development, hemispheric specialization increases for specific functions and subsystems interact to shape the final functional organization of a brain. In particular, these developmental steps are influenced by environmental experiences, which regulate the fine-tuning of neural networks via processes that are referred to as ontogenetic plasticity. The plastic potential of the nervous system could be decisive for the evolutionary success of lateralized brains.

A Novel Perspective for Examining and Comparing Real and Virtual Test Tasks Performed by the Dominant and Non-Dominant Hand in Healthy Adults

This study presents a novel perspective for the study of functional lateralization in a virtual reality environment. In the model study of handedness, the recognition of the dominant and non-dominant hand in real and virtual conditions was assessed using selected tests, such as a real light exposure test of Piórkowski’s apparatus and classical clinical tests, as well as virtual test tasks, in healthy adults. Statistically significant differences between the dominant and non-dominant hand were observed for tests carried out both in classical conditions and the virtual environment. The results and findings of other studies suggest that the virtual reality approach is a very promising and sensitive tool in the research on functional asymmetries in healthy and disease for motor skills and cognition processes.

Molecular laterality encodes stress susceptibility in the medial prefrontal cortex

Functional lateralization of the prefrontal cortex has been implicated in stress and emotional disorders, yet underlying gene expression changes remains unknown. Here, we report molecular signatures lateralized by chronic social defeats between the two medial prefrontal cortices (mPFCs). Stressed mice show 526 asymmetrically expressed genes between the mPFCs. This cortical asymmetry selectively occurs in stressed mice with depressed social activity, but not in resilient mice with normal behavior. We have isolated highly asymmetric genes including connective tissue growth factor (CTGF), a molecule that modulates wound healing at the periphery. Knockdown of CTGF gene in the right mPFC by shRNA led to a stress-resistant behavioral phenotype. Overexpression of CTGF in the right mPFC using viral transduction induces social avoidance while the left mPFC thereof prevent stress-induced social avoidance. Our study provides a molecular window into the mechanism of stress-induced socioemotional disorders, which can pave the way for new interventions by targeting cortical asymmetry.

Callosal fiber length scales with brain size according to functional lateralization, evolution, and development

Brain size significantly impacts the organization of white matter fibers. Fiber length scaling – the degree to which fiber length varies according to brain size – was overlooked. We investigated how fiber lengths within the corpus callosum, the most prominent white matter tract, vary according to brain size. The results showed substantial variation in length scaling among callosal fibers, replicated in two large healthy cohorts (~2000 individuals). The underscaled callosal fibers mainly connected the precentral gyrus and parietal cortices, whereas the overscaled callosal fibers mainly connected the prefrontal cortices. The variation in such length scaling was biologically meaningful: larger scaling corresponded to larger neurite density index but smaller fractional anisotropy values; cortical regions connected by the callosal fibers with larger scaling were more lateralized functionally as well as phylogenetically and ontogenetically more recent than their counterparts. These findings highlight an interaction between interhemispheric communication and organizational and adaptive principles underlying brain development and evolution.

Functional Lateralization of the Mirror Neuron System in Monkey and Humans

To date, both in monkeys and humans, very few studies have addressed the issue of the lateralization of the cortical parietal and premotor areas involved in the organization of voluntary movements and in-action understanding. In this review, we will first analyze studies in the monkey, describing the functional properties of neurons of the parieto-frontal circuits, involved in the organization of reaching-grasping actions, in terms of unilateral or bilateral control. We will concentrate, in particular, on the properties of the mirror neuron system (MNS). Then, we will consider the evidence about the mirror neuron mechanism in humans, describing studies in which action perception, as well as action execution, produces unilateral or bilateral brain activation. Finally, we will report some investigations demonstrating plastic changes of the MNS following specific unilateral brain damage, discussing how this plasticity can be related to the rehabilitation outcome

Hemispheric asymmetry of entrained auditory steady state responses arise from the structural connectome

Structure-function relationships are of fundamental importance to biological systems. In the human auditory system, it has been demonstrated that asymmetric neuroanatomic embedding of primary auditory cortices in the whole brain network is predictive of functional lateralisation. However, a mechanistic and causal basis of the functional asymmetry due to the underlying structural constraints is poorly understood. The present article takes the help of computational modelling to demonstrate how functional lateralization emerges from the symmetries in structural connectome. First, we demonstrate a well-known lateralisation effect observed during entrainment of external rhythmic auditory stimulus at the level of cortical sources from EEG data. Subsequently, we simulate the dynamics of whole brain cortical responses from large-scale neurodynamic model using realistic connection topologies. Considering the effects of time-delay stemming from physical fibre distances computed from diffusion imaging metrics, and neuronal scaling and coupling based on empirical data, we could elucidate the biophysically realistic parameter regimes where the structural connectome is predictive of functional lateralisation. Thus our study provides a roadmap in causally linking structural symmetries to higher order brain function.

Functional Aspects of Hypothalamic Asymmetry

Anatomically, the brain is a symmetric structure. However, growing evidence suggests that certain higher brain functions are regulated by only one of the otherwise duplicated (and symmetric) brain halves. Hemispheric specialization correlates with phylogeny supporting intellectual evolution by providing an ergonomic way of brain processing. The more complex the task, the higher are the benefits of the functional lateralization (all higher functions show some degree of lateralized task sharing). Functional asymmetry has been broadly studied in several brain areas with mirrored halves, such as the telencephalon, hippocampus, etc. Despite its paired structure, the hypothalamus has been generally considered as a functionally unpaired unit, nonetheless the regulation of a vast number of strongly interrelated homeostatic processes are attributed to this relatively small brain region. In this review, we collected all available knowledge supporting the hypothesis that a functional lateralization of the hypothalamus exists. We collected and discussed findings from previous studies that have demonstrated lateralized hypothalamic control of the reproductive functions and energy expenditure. Also, sporadic data claims the existence of a partial functional asymmetry in the regulation of the circadian rhythm, body temperature and circulatory functions. This hitherto neglected data highlights the likely high-level ergonomics provided by such functional asymmetry.