Asymmetries in the subcortical region of the Brain

J.Maher. R.Mushantaf. N.Bazak.

Introduction

The subcortical region of the brain primarily functions to control and deliver psychological processes which in turn pre-determine behaviours and mood dispositions. This area of the brain controls coordination of movement, learning and memory – hence it is a very significant and important region. The subcortical structures receive a wide array of different input signals from the cerebrum, peripheral sense organs and stretch receptors. These structures process these inputs and through the use of recurrent feedback loops, information is interpreted and integrated and a response is formulated. The response is known as an output. These output signals contribute to sequencing, timing and preciseness of motor and non-motor movements, learning, language development, and automation of cognitive functioning.

Extra asymmetries or disturbed asymmetries of the subcortical region can cause impairments to the above functions and can lead to a disruption of ‘normal’ behaviours and ultimately to the development of conditions such as schizophrenia. The role of asymmetrics of the subcortical region is the focus of this paper. It is important to understand that asymmetries exist and can serve very important but differing functions. Important too is an understanding of what can happen when there are abnormalities to the asymmetries. As an example of an abnormal asymmetry, this paper briefly examines the condition of Schizophrenia. Schizophrenia is strongly associated with volumetric alterations within the cortical region. As a result features such as smaller bilateral hippocampus, amygdala, thalamus and accumbens can be observed. Similarly the opposite occurs regarding the bilateral caudate and putamen, which are seen to increase.

The focus of this paper is to examine in detail the abnormal levels of asymmetries which occur in the subcortical region and how these impact normal functioning and contribute to the development of the condition.

Studies of asymmetries in the subcortical region of the brain is primarily concerned with the ratio of white matter to grey matter in the anatomical structures. These structures are primarily comprised of the Basal Ganglia, Planum Temporale, Thalamus and the Limbic System. Grey matter is comprised of the cell bodies of the neurons, while the white matter is comprised of the tendrils, known as dendrites and axons, that spread out from the cell bodies to connect the cell to other neurons. Signals pass between these tendrils through the release and capture of neurotransmitter and neuromodulator chemicals such as, for example, glutamate, dopamine, acetylcholine, noradrenalin, serotonin and endorphins.

This paper will review the literature to provide an understanding of asymmetry of the subcortical system. It will focus on examining the role of the hypothalamic, limbic and the production of hormones.

Asymmetry of the Subcortical System

Firstly we need to understand what exactly lateralization is, by scientific terms lateralization refers to ’how neural functions or cognitive function tend to be dominant in one hemisphere of the brain’. There is evidence to show that lateralization occurs in the hypothalamic, limbic, and other brain structures. These structures were also identified as physiological structures which are all directly or indirectly involved in the control of the endocrine glands, as a result asymmetries in the brain can have an effect on the endocrine system. Data suggest predominance of the right half of brain structures in controlling gonadal function (Gerendai and Halász, 2001).

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Hypothalamus

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Hypothalamus

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The hypothalamus is a section responsible for the production of many of the body’s essential hormones (thyrotropin-releasing, gonadotropin-releasing, growth hormone-releasing, corticotrophin-releasing, somatostatin, and dopamine) that help control different cells and organs.

Experimental observations supporting the view regarding the hypothalamus asymmetries were conducted and a special experiment was designed: brain lesion on either the right or left side of the brain, was performed in animals subjected to removal of the right or the left endocrine gland, following this changes in biochemical parameters were measured in the right and left halves of the hypothalamus following right- or left-sided complete removal of the ovary. The results of the experiment, were the gonadotropic hormone-releasing hormone (GnRH) content of the hypothalamus halves, studied in hemi-ovariectomized rats, indicated that in intact control animals the GnRH content is significantly higher in the right half of the hypothalamus than in the left half (Gerendai et al,1978).

Further studies, similar to the previously mentioned, indicated that in the male rat the right side of the hypothalamus also contains significantly more GnRH than the left (Bakalkin et al,1984).

This simple experiment proved the presence of asymmetries in the Hypothamlic system, it also displayed how asymmetries on either the left or right has an effect on the gonads on the opposite side of the body.

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Hypophysis/ Pituitary gland

The pituitary gland is a pea-sized structure located at the base of the brain, just below the hypothalamus, to which it is attached via nerve fibers. It is part of the endocrine system and produces critical hormones (LH, TSH, FSH, ACTH). So far little studies have been conducted on the pituitary to prove asymmetries however it is highly likely to be true also.

Hippocampus

The hippocampus is a small region of the brain that forms part of the limbic system and is primarily associated with memory and spatial navigation. two detailed experiments were conducted and very nicely prove asymmetries existing in this region.

A. Left-right asymmetry of the Hippocampal synapses with differential subunit allocation of Glutamate receptors

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Hypophysis/ Pituitary gland

The pituitary gland is a pea-sized structure located at the base of the brain, just below the hypothalamus, to which it is attached via nerve fibers. It is part of the endocrine system and produces critical hormones (LH, TSH, FSH, ACTH). So far little studies have been conducted on the pituitary to prove asymmetries however it is highly likely to be true also.

Hippocampus

The hippocampus is a small region of the brain that forms part of the limbic system and is primarily associated with memory and spatial navigation. two detailed experiments were conducted and very nicely prove asymmetries existing in this region.

A. Left-right asymmetry of the Hippocampal synapses with differential subunit allocation of Glutamate receptors

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Left-right asymmetry of the brain has been studied primarily concerning the viewpoint of psychological examination and functional imaging in primates, leaving its molecular and synaptic aspects largely unaddressed and largely remaining unknown.

Studies have found that there are two key areas regarding in the hippocampus focused on for their role in asymmetries. They are known as areas CA1 and CA3 of the dorsal hippocampus. Among inotropic (ligand-gated ion channel) glutamate receptor subunits, six major glutamate receptor subunits (GluR1, GluR2, GluR3, NR1, NR2A, and NR2B) are expressed in the hippocampal CA1 pyramidal cell synapses.

The hippocampus CA1 pyramidal cell synapses differ in size, shape, and glutamate receptor expression depending on the laterality of presynaptic origin. CA1 synapses receiving neuronal input from the right, CA3 pyramidal cells are larger and have more perforated GluR1 expression level twice as high as those receiving input from the left CA3 (Shinohara et al, 2008).

It was also found that the synaptic density of GluR1 increases as the size of a synapse increases, whereas that of NR2B decreases because of the relatively constant NR2B expression in CA1 regardless of synapse size. Densities of other major glutamate receptor subunits show no correlation with synapse size, thus resulting in higher net expression in synapses having right input.

Overall and in relation to the asymmetries their study demonstrates universal left-right asymmetry of hippocampal synapses with a fundamental relationship between synaptic area and the expression of glutamate receptor subunits.

Findings from the report also observed asymmetrical distributions of NR2B subunits of NMDA receptors in the mouse hippocampus. Ipsilateral CA3-CA1 pyramidal cell synapses in the stratum radiatum in the left CA1, were 1.5 times more sensitive to NR2B subunit specific antagonist than those in the right CA1. The contralateral CA3-CA1 pyramidal synapses had the opposite asymmetry.

Rearrangement of these glutamate receptor subunit compositions serves as a molecular switch for synaptic plasticity. When synaptic activity is elevated upon the induction of long-term potentiation (LTP), GluR1-containing AMPA receptors are inserted into postsynaptic sites. Such synaptic insertion of GluR1 is necessary for an enlargement of spines, which accompanies LTP induction. The experiment then found that the synaptic sizes differed between CA1 pyramidal cell synapses receiving input from the left and the right CA3 pyramidal cells.

This report identifies morphological left-right asymmetry at the synaptic level. The study found that the size of a synapse had a significant correlation with the laterality of the presynaptic innervations in the apical dendrite of hippocampal CA1 pyramidal cells. In addition, individual expression of ionotropic glutamate receptor subunits exhibited a close relation to the size of a synapse. The report therefore concluded by propose a simple principle in which asymmetrical distributions of glutamate receptors in CA1 pyramidal cells can be explained by the relationship between sizes of glutamatergic synapses and the levels of ionotropic glutamate receptor subunits in individual synapses.

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B. Brain asymmetries have been demonstrated in neurotransmitter metabolism and neuroendocrine modulation.

As the hippocampus modulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis in stress and basal conditions, it was though perhaps the hippocampal corticoid receptors may be asymmetrically distributed and that asymmetry may differ according to behavioural lateralization of animals. In order to answer these questions, binding capacity of mineralocorticoid (MR) and glucocorticoid (GR) receptors was determined in right and left hippocampi of mice previously selected for paw preference. The results show that regardless of behavioural lateralization, there was a tendency for a right dominance in MR binding capacity in the hippocampus. The affinity of MRs did not depend on behavioural lateralization. GR binding capacity was similar in each hemisphere and no relationship was found between GR binding capacity and paw preference scores. These results suggest that hippocampal receptors for corticoids may play an important role in the asymmetrical brain control of immune reactivity (Neveu et al, 1998).

Brain Stem

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B. Brain asymmetries have been demonstrated in neurotransmitter metabolism and neuroendocrine modulation.

As the hippocampus modulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis in stress and basal conditions, it was though perhaps the hippocampal corticoid receptors may be asymmetrically distributed and that asymmetry may differ according to behavioural lateralization of animals. In order to answer these questions, binding capacity of mineralocorticoid (MR) and glucocorticoid (GR) receptors was determined in right and left hippocampi of mice previously selected for paw preference. The results show that regardless of behavioural lateralization, there was a tendency for a right dominance in MR binding capacity in the hippocampus. The affinity of MRs did not depend on behavioural lateralization. GR binding capacity was similar in each hemisphere and no relationship was found between GR binding capacity and paw preference scores. These results suggest that hippocampal receptors for corticoids may play an important role in the asymmetrical brain control of immune reactivity (Neveu et al, 1998).

Brain Stem

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At the beginning of asymmetrical studies it was thought Lateralization of neural function is generally localized only at the level of the cerebral cortex and perhaps the thalamus. This view was challenged by identifying a neural asymmetry at the level of the brainstem. Brainstem auditory evoked potentials (BAEPs) were analysed and it was found that peak III (+) amplitude was significantly larger in response to right than to left ear stimulation. This brainstem asymmetry finding may represent the general and often noticeable tendency of humans to orient right and/or may be a precursor of higher level asymmetries (Levine et al,1988).

Three structural types of right–left fiber distributions could be delineated (Dietrich et al, 2017):

1.Evenly distributed pathways at the lower pontine level from the vestibular nuclei to the pontine crossing.

2.A moderate, ponto-mesencephalic right-sided lateralization between the pontine and mesencephalic crossings.

3.A further increase of the right-sided lateralization above the mesencephalic crossing leading to the thalamic vestibular sub nuclei.

The increasing lateralization along the brainstem was the result of an asymmetric number of pontine and mesencephalic crossing fibers which was higher for left-to-right crossings. The dominance of the right vestibular meso-diencephalic circuitry in right-handers corresponds to the right-hemispheric dominance of the vestibular cortical network (Dietrich et al, 2017).

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Amygdala

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Amygdala

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The amygdala has a profound importance on brain processes interconnected socially and emotionally. Some examples are facial recognition, general social understanding and memory through emotion (Tranel and Bechara, 2009). Another example of the amygdala’s role in the management of associated learning through fear is through its production of gastrin-releasing peptide (GRP). GRP excites local interneurons through gastrin-releasing pepide receptors (GRPRs). Deficiency of GRPRs in mice leads to an increase and persistence in fear-related memory after “single-trail associative learning”, this lead to the idea that agonists of GRPRs could help in therapies of fear-related disorders (Chaperon et al, 2012).

Emotions elicited by a certain stimulus can be related to memory of that stimulus and this relation can either be great on the right or left amygdala. Which side as a greater effect correlates to a person’s gender, the left side for women and the right side for men. Through certain experiments it was seen that there was an innate difference between men and women and their asymmetries in the amygdala’s function. Right-sided damage to the amygdalas of women did not develop significant changes in social status, employment status, or interpersonal functioning (which are connected to emotional memory) whereas left-sided damage lead severe changes and impairments in these characteristics. The opposite effect was seen with men; left-sided damage lead to no or little impairment while right-sided damage lead to impairments (Kocsik et al, 2010).

Another example of the effect of amygdalae asymmetries is the left and right central amygdalae (CeA) which are 2 nuclei in the limbic region processing somatic and visceral pain. These 2 nuclei are asymmetrical; pain-like responses on both sides of the body are preferentially driven by the right CeA, and nociceptive, or damage to tissue causing sharp pain, stimuli on both sides of the body affect the right CeA (Sadler et al, 2017).

Therefore, we can conclude that there is much scientific evidence of ’natural’ asymmetries in the subcorietal region of the brain. The following section will examine the condition of Schizophernia as an example of how disturbed asymmetries can lead to changes in ’normal’ behaviours and the development of abnormal behaviours.

Extra Asymmetries or disturbed asymmetries.

Schizophrenia

Schizophrenia is a severe illness that affects about 1% of the population (Jablensky, 2000). Schizophrenia presents with a diversity of symptoms that represent multiple psychological domains, for example, perception, inference, concept formation, language, volition, motor activity, social interaction, and emotion.

In the sense of the word ‘cognition’ the condition involves some type of abnormality in receiving and processing information from the external world, relating it to information that has already been processed and stored previously and acting on that information to produce some type of reaction or response. The disturbance encompasses not just executive functions, but several forms of memory, attention, emotion, and motor activity. Its underlying neural network is not only cortical, but also subcortical.

To express the diversity of the disturbance we refer to it as "cognitive dysmetria." As a neurological symptom, dysmetria expresses itself in the coordination of motor activity. Slowing of reaction times is one of the most consistent features. Studies have also documented the presence of motor system "soft signs" in first-episode neuroleptic naive patients (Gupta et al, 1995). These soft signs include the classical indices of motor dysmetria e.g., dysdiadokokinesia.

Schizophrenia has been genetically studied also and it has been linked to the NOTCH-4 gene, which is a neurogenic locus notch homolog protein-4 located on chromosome 6p. This gene is then thought to be involved with type-1 transmembrane protein which in turn is thought to be involved with developmental processes by controlling cell fate decisions (Su et al,2013).

The majority of studies of schizophrenia have focused on the cerebral cortex, in particular on temporal lobe regions such as the hippocampus. The thalamus is conventionally divided into relay and diffuse projection nuclei (Andreasen et al, 1998). The relay nuclei project to sensory and motor cortical regions and receive projections from the same cortical areas. These recurrent connections may allow the thalamus to modulate sensory and motor input. The diffuse projection nuclei are believed to be part of a system that governs the level of arousal of the brain.

Several neuropathological studies have reported abnormalities of the thalamus (Bogerts, 1993). In particular substantial cell loss in the medial dorsal nucleus of the thalamus, the nucleus that serves as the major relay station to the prefrontal cortex (Pakkenberg, 1990).

Another abnormality leading to schizophrenic symptoms is connected to the brain stem. There are abnormal laterization, or asymmetry, in subcortical regions such as the brain stem. Specifically a lack of asymmetry between the Nucleus Oliva and the cochlear nuclei which would lead to a lack of the functional medial olivocochlear asymmetry normally found in healthy individuals, and leads to increased evoked otoacoustic emission intensity in the right ear (Källstrand et al, 2011). Which means that the lack of medial asymmetry lead to an increase of intensity of otoacoustic emissions, most probably causing the patient to hear sounds that are not from their environment. The diverse symptoms of schizophrenia reflect abnormalities in connectivity in the circuitry that links prefrontal and thalamic regions and where cerebro-cerebellar connectivity may also be disrupted.

Conclusions

This paper has sought to review the literature to establish the nature and type of work undertaken to date relating to scientific evidence of asymmetries in the subcortical region of the brain. Research has undoubtedly proven that asymmetries do exist and has highlighted the importance of understanding the role and function of the asymmetries in the various component modules of the right side of the brain.

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