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Connection Between Schizophrenia and Social Isolation

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Schizophrenia is a common and serious mental illness and is one of the leading causes of adult disease burden. It has a lifetime prevalence of approximately between 0.3% and 0.7% and occurs in men and women in their 20s. About 21 million individuals in the world have schizophrenia. The disease is usually characterized by symptoms such as depression, aggressive behavior, anxiety, cognitive impairment, and most importantly social withdrawal. Both early life adversity and genetic factors have been linked to the etiology of schizophrenia. In particular, the isolation during postnatal development results in lasting and severe pathophysiological features and abnormal behaviors that resemble neuropsychiatric disorders in mice. Social isolation refers to disconnectedness, lack of contact with others, characterized by small social networks, lack of participation in social groups and activities, and infrequent social interaction. At the same time, it can be characterized by the subjective experience of falling short of social resources, for instance, support and companionship which commonly resulted in loneliness, desire for intimacy, and lack of belongingness in one’s life. At the same time, social isolation can result from the inability of an individual to sustain or cultivate social relations and lead to emotionally withdrawn behaviors. Social isolation results in stress which in turn leads to overstimulation of the hypothalamus-pituitary axis (HPA). As an outcome, this causes the release of hormones such as glucocorticoids. Similarly, stimulation of HPA is the major contributing factor to the activation of the sympathetic nervous system (SNS) which accelerates the generation of diurnal glucocorticoids. The long-term effect of stress can lead to further social isolation and loneliness which in turn can contribute to the development of schizophrenia.

There are numerous factors that can lead to a putative connection between social isolation and schizophrenia. Dopamine and glutamine are some of the significant biochemical factors that have been associated with the development of schizophrenia. Post-mortem research investigations have continually identified abnormalities in the pre and post-synaptic dopaminergic systems in schizophrenia. Animal model studies have enabled refinement and testing of the primary aspect of the dopaminergic hypothesis. On the other hand, it has been hypothesized that there is a deficit in glutamatergic neurotransmission in schizophrenia, a model that involves the N-methyl-D-aspartate acid receptor (NMDAR). Early-life adversity has been established as a significant risk factor for this disease and is modeled using postweaning social isolation, which results in substantial neurological, behavioral, and neurochemical deficits. 

A study conducted by Li et al. shows that cross-talk of the glutamate N-methyl-d-aspartate acid receptors and dopamine receptors is linked to histidine triad nucleotide-binding protein 1 (HINT1) which is associated with psychiatric conditions. In particular, the researchers studied the expression of HINT1, a subunit of dopamine type-2 receptor (D2R), and N-methyl-d-aspartate acid receptor. HINT1 is a protein that is highly conserved with 14kDa that belongs to the histidine triad family and is expressed in the central nervous system which is responsible for the disorders such as bipolar disorder and schizophrenia among others. The research utilized an animal model and revealed that social isolation results in a series of deficits related to schizophrenia, for instance, cognitive impairment, anxiety disorder, and sensorimotor gating disturbances. The study also reported that social isolation induces HINT1 which is involved in the abnormalities induced by a social disconnection in the different encephalic regions. 

Also, Li et al. observed that HINT1 expression in isolated mice resulted in the decreased prefrontal cortex (PFC), part of the brain that plays important executive roles which are inevitably critical skills required to socialize effectively in humans and animals. At the same time, there was considerable down-regulation of expression in the NR1 subunit of NMDAR in the PFC following the social isolation of mice. Similarly, Li et al. mapped schizophrenia in terms of its genetic causes and demonstrate that HINT1 is a gene that is situated in the chromosome 5q22–33 and located in the 5q31.2 genetic locus. Interestingly, gene HINT1 is located in the region associated with schizophrenia and leads to abnormal dopamine transmission linked to schizophrenia. As such, logically, it is evident that HINT1 interacts with D2RA and NR1 in the development of schizophrenia induced by social isolation.

On the basis of the above analysis, it is clear that social isolation triggers genetic activities that result in the development of schizophrenia. Neurological aspects can also lead to the development of this disease. In particular, abnormalities in the myelination of the neuron can contribute to the development of schizophrenia. Myelin sheath is a layer of the cover the axon of the neuron and acts as an insulator to ensure that nerve signals are conducted rapidly as required. Both neuroimaging and post-mortem studies have suggested a volume of ultrastructural abnormalities and a reduction in the white matter of the prefrontal cortex in schizophrenia. Several families of protein can potentially lead to abnormalities in the white matter of the neuron. Neuroglin 1 (NRG1) is one of such protein which contains epidermal growth factor-like domain activated by the tyrosine kinase of the erbB family. The NRG1-mediate erbB signaling is a critical role in the glial and neural development and regulation of receptors of neurotransmitters that are thought to be involved in the pathophysiological process of schizophrenia. Patients suffering from this disease show a reduced level of erbB3 in their PFC as such modern evidence demonstrated that NRG1 plays a major role in white matter abnormality in patients with schizophrenia.

A new structural magnetic resonance imaging studies provide evidence that alteration in the myelin, the main constituent of white matter as the cause of defects in the neurons and central nervous systems that are related to schizophrenia. In particular, post-mortem evidence suggests a decrease in myelin or integrity of the axonal membrane in patients suffering from schizophrenia. Apart from the NRG1, the myelin-associated glycoprotein (MAG) is also decreased in patients with this disease. MAG is a minor, but a fundamental element of the myelin that is expressed when oligodendrocytes come into contact with axons. MAG is a transmembrane protein that is found in the central and peripheral nervous systems and plays a critical role in the generation and maintenance of the myelin sheath MAG is found in periaxonal region of axon and paranodal of the myelin sheath which is a clear indication that it plays a significant role in ensuring interaction between axons and oligodendrocytes. 

Further, it has been shown to ensure the survival of the oligodendrocytes and provide a trophic signal without which deterioration of oligodendroglial occurs. In animal model studies, mice deficient in MAG have demonstrated various ultrastructural abnormalities in the CNS including demyelination and derailment in myelination. In addition, mice deficient in MAG have abnormal morphology in their myelin sheath and lack a well-developed cytoplasmic collar. Similarly, their neurons contain non-compact regions of the redundant myelin and generation in some parts of the periaxon. These structural changes are similar to those that are observed in schizophrenic brains. As such, this evidence emphasizes the important role of MAG in the development of normal myelin function without which abnormalities occur leading to schizophrenia and other psychotic diseases.

Apart from the white matter, imaging studies have shown that disconnection between the PFC and thalamus is a major contributing factor to the development of schizophrenia. A primary function of the thalamus is to establish the connection as it received input and output from the cortical region as well as from the stem region. Schizophrenia is a neuro-developmental condition that emerges as from a defect in prefrontal-thalamic-cerebellar circuitry. The Thalamus filters, gates, and even generates stimuli to different sites in the brain. The disease arises from the interconnection of neural circuits that can be disrupted by an abnormality at any point. In the prefrontal cortex, the thalamus prioritizes data, putting it within a wide context through the information that is gleaned from other interconnecting cortical regions that help a person to formulate responses or decisions as well as initiate their action. Individuals suffering from schizophrenia usually exhibit impaired social and verbal responses as a result of dysfunction in the circuitry that permits prioritization of information excluding extraneous data and carrying out these functions in efficient, rapid, and well-coordinated ways.

According to Mighdoll et al, defects in myelination can eventually result in functional degradation of significant neural circuits and lead to behavioral and cognitive inefficiencies as well as disorganization that are manifestations of schizophrenia. As such, this shows that schizophrenia is the effect of social isolation that can trigger biochemical reactions and activities that induce behavioral changes. In particular, a study conducted by Liu et al. conducted a research study that affirms that social isolation can trigger ultrastructural and transcriptional changes in the myelinating oligodendrocytes in the adult PFC which can result in considerable alteration in chromatin. Liu et al. further affirm that early life adversity and experiences can result in dysfunctional myelin development. The study utilized an animal model where a group of mice was isolated from 8 weeks. The result showed that isolation led to social withdrawal as the mice spent less time interacting with other mice after they were introduced to a mouse they had not seen before. In addition, these animals demonstrated thinner myelin sheath in their PFC with immature nuclear chromatin. Furthermore, in isolated mice, the axons have thinner myelin, which is associated with the presence of oligodendrocytes with immature nuclear chromatin and a lower proportion of heterochromatin. As such, evidence from these studies indicates that myelination and factors that impact this process, for instance, the role of oligodendroglia can affect neuronal connectivity profoundly. Notably, this must be the case when one takes into account the wide distribution of oligodendrocytes in the brain.

A study conducted by Flynn et al. investigated abnormalities in the myelination as a result of myelin water fraction in patients with schizophrenia. Using MRI and T2 relaxation, the analysis reveals that schizophrenic individuals had 12% lower myelin water fraction in white matter as compared to the healthy subjects. The most prominent effect was observed in the left genu of the corpus callosum. In particular, in the activate phase of schizophrenia, the illness is linked to prominent psychotic symptoms which have been associated with excessive transmission in dopaminergic. Disruption in the water myelin fraction in the white matter results in disruption in the integrity of militated pathways. The evidence signifies that impaired myelination can be a contributing factor to the persistent functional impairment and abnormality in the neural connectivity in schizophrenia.

At the same time, it has been suggested that hypo-glutamatergic and hyper-glutamatergic can co-exist in schizophrenic brain. GABAergic neurons have also been examined extensively in schizophrenia. Patients with this disease have been shown to have decreased density of interneurons, particularly in the anterior region of the cingulated cortex and this has been linked to increasing in GABAA receptor binding in this region. This evidence indicates that there is the possibility of an increased outflow of glutamatergic from the PFC of patients with schizophrenia. As an outcome, this results in loss of GABAergic inhibition leading to hyper-excitatory states in some areas of the brain.

Indeed, there are many putative connections between social isolation and schizophrenia. Social isolation that contributes to schizophrenia is situational conditions in which intimate contact is non-existent or minimal and can also arise from defensive withdrawal as an individual focuses on avoiding decline of self-esteem because of exclusion or rejection by the associates. One of the putative critical connections between social isolation and schizophrenia regards the HINT1, a protein that is involved in the abnormalities induced by a social disconnection in the different encephalic regions. Another factor is the myelination of the brain neurons. Myelin redundancy and structural changes have been observed as the key alteration in schizophrenic patients’ brains. Another connection between social isolation and this disease is the thalamus as a result of the prefrontal cortex-thalamus dysfunction in the circuitry.

References :

  1. Andreasen, N. C., 2017. The role of the thalamus in schizophrenia. The Canadian Journal of Psychiatry, 42(1), pp. 27-33.
  2. Cornwell, E. Y., and Waite, L. J., 2009. Social disconnectedness, perceived isolation, and health among older adults. Journal of Health and Social Behavior, 50(1), pp. 31-48. doi:10.1177/002214650905000103
  3. Davis, K. L., Stewart, D. G., Friedman, J. I., Buchsbaum, M., Harvey, P. D., Hof, P. R., … and Haroutunian, V. 2013. White matter changes in schizophrenia: evidence for myelin-related dysfunction. Archives of general psychiatry, 60(5), p.443-456.
  4. Deoni, S.C., Mercure, E., Blasi, A., Gasston, D., Thomson, A., Johnson, M., Williams, S.C. and Murphy, D.G., 2011. Mapping infant brain myelination with magnetic resonance imaging. Journal of Neuroscience, 31(2), pp.784-791.
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  6. Li, B. J., Liu, P., Chu, Z., Shang, Y., Huan, M. X., Dang, Y. H. and Gao, C. G. 2017. Social isolation induces schizophrenia-like behaviour potentially associated with HINT1, NMDA receptor 1, and dopamine receptor 2. Neuroreport, 28(8), p.462.
  7. Liu, J., Dietz, K., DeLoyht, J. M., Pedre, X., Kelkar, D., Kaur, J., … and Dupree, J. 2012. Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nature neuroscience, 15(12), p.1621
  8. Mighdoll, M. I., Tao, R., Kleinman, J. E., and Hyde, T. M. 2015. Myelin, myelin-related disorders, and psychosis. Schizophrenia research, 161(1), p.85-93.
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