The characterization of the neurobiological basis of suicide is in delineating the risk factors associated with suicide. The Neurobiological Basis of Suicide focuses on how and why these neurobiological factors are crucial in the pathogenic mechanisms of suicidal behavior and how these findings can be transformed into potential therapeutic applications. Clement C. Tong, Isaac Sakinofsky, and James L. Routledge eBooks are available through VitalSource. Most VitalSource eBooks are available in a reflowable EPUB format which allows you to resize text to suit you and enables other accessibility features.
Where the content of the eBook requires a specific layout, or contains maths or other special characters, the eBook will be available in PDF PBK format, which cannot be reflowed. For both formats the functionality available will depend on how you access the ebook via Bookshelf Online in your browser or via the Bookshelf app on your PC or mobile device. The focus is on aspects of speech, language including the conceptual abilities required for thought , and learning and memory.
We are currently working with individuals with autism especially those with little or no speech , aphasia, amnesia, with age-related conditions including Alzheimer's disease , women who have had chemotherapy, and healthy individuals with a range of abilities. It describes the cellular and molecular mechanisms by which complex nervous systems emerge during embryonic development and throughout life.
Developmental Neuroscience covers all stages of invertebrate, vertebrate and human brain development. The study focus on original research on both basic and clinical aspects of the developing nervous system, ranging from simpler invertebrate systems and in vitro neural models to models of regeneration, chronic neurological diseases and aging. Its main aims will be to facilitate the transfer of basic information to clinical applications and to promote an understanding of the fundamental mechanisms of neural growth, development and pathology.
It is the interface between neuroscience and behavioral disorders. It is the study of effective diagnosis and treatment for patients with neuropsychiatric disorders. It deals critical subjects such as Alzheimers disease, traumatic brain injury, Parkinson disease, epilepsy, and seizure disorders, and is devoted to reporting discoveries in clinical neuroscience that are relevant to understanding the brain based disorders of patients.
Journal of Neuropsychiatry focuses on basic research as well as on applied, clinical research that will stimulate systematic experimental, cognitive, and behavioral investigations as well as improve the effectiveness, range, and depth of clinical practice. Field of Clinical Neuropsychiatry that deals with particularly illness course and treatment effectiveness. Related Journals of Neuropsychiatry and Clinical Neurosciences.
Behavioral Neurology is a subspecialty of neurology that studies the neurological basis of behavior, memory, and cognition, the impact of neurological damage and disease upon these functions, and the treatment. Behavioral neurology is that specialty of one, which deals with the study of neurological basis of behavior, memory, and cognition, and their impact of damage and disease and treatment. Affective neurology is the study of the neural mechanisms of emotion. This interdisciplinary field combines neuroscience with the psychological study of personality, emotion, and mood.
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The study deals with the scientific competences in the subspecialty of affective neuroscience, dealing with the latest developments in the field taught by leading scientists. The materials despite of being natural or synthetic, which helps to replace or treat brain tissues on interaction with biological systems.
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The study of cognitive processes and their implementation in the brain. Cognitive neuroscientists use methods drawn from brain damage, neuropsychology, cognitive psychology, functional neuroimaging, and computer modeling. Behavioral neuroscience also known as biological psychology, biopsychology, or psychobiology is the application of the principles of biology to the study of physiological, genetic, and developmental mechanisms of behavior in humans and non-human animals.
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Bondy et al.
These positive associated results Bondy et al. Anguelova et al. A total of 1, cases suicide victims and attempters and 1, controls including Caucasian US and Chinese population were analyzed, and a significant association of the s allele with suicidal behavior was demonstrated Anguelova et al. A recent meta-analysis including 2, cases and 3, controls also supported the association of the 5-HTTLPR in suicidal behavior Schild et al. Clayden et al. However, the rs polymorphism was significantly associated with a higher risk for suicide attempts Clayden et al.
Compared with the sample size of suicide attempters, the number of suicide victims was relatively smaller, which might have caused a loss of significance in a number of studies. BDNF, a member of the neurotrophin family of growth factors, is also a promising candidate gene for suicide behavior Dwivedi, This polymorphism is a missense mutation at position 66 resulting in a valine to methionine substitution.
Pregelj et al. A significant difference in the frequency of the Met genotype was found between female suicide victims and female control group.
The Neurobiological Basis of Suicide by Yogesh Dwivedi (ebook)
Recently, Ratta-Apha et al. The Met-allele was shown to be associated with attempted suicide, but not with death by suicide Ratta-Apha et al. Genome-wide association study GWAS provides a powerful tool for analyzing more than one million single nucleotide polymorphisms SNPs at a time. This approach has been applied in identifying novel genes in suicide research. To date, nine original GWAS studies have been performed to test for association with suicidal behavior Laje et al. Generally, few genome-wide significant and reproducible findings have been demonstrated for suicidal behavior.
In this review we focused on GWAS studies in suicide victims. Galfalvy et al. Caucasian subjects, including 68 suicides and 31 non-suicide deaths, were genotyped using low-coverage sequencing. Due to smaller effect sizes, no variants reached genome-wide significance. Willour et al. These associated SNPs were subsequently tested for association in a large and independent bipolar sample, but no significant associations could be established after correcting for multiple testing Willour et al.
Overall only a few of these GWAS studies presented significant data after correction for multiple testing, however they do suggest interesting candidate genes that may be worthwhile to follow up in future studies. We could speculate that individual genetic susceptibility factors for suicide are likely to have only minor effects and very large pooled analyses of cases and controls will be necessary to identify them.
Epigenetic regulation is heritable and known to influence gene function by different biochemical modifications other than altering the DNA sequence Eccleston et al. Despite their close association with disease pathophysiology and active participation in regulating developmental pathways Portela and Esteller, ; Cantone and Fisher, , epigenetic modification is a relatively new concept in suicide neurobiology El-Sayed et al. DNA methylation based epigenetic modifications confer silencing in gene expression involving a covalent attachment of a methyl group to cytosine residues Moore et al.
A summary of these methylation-based studies is provided in Table 3. An overall change in methylation pattern was identified in the SAT1 promoter region of 10 suicide completers, which included three highly polymorphic sites Fiori and Turecki, In agreement with the hypothesis, a strong negative correlation was noted between the overall promoter methylation and SAT1 gene transcription.
As mentioned above, the presence of three highly polymorphic sites rs, rs, and rs on SAT1 promoter added an additional layer of haplotype specific gene regulation driven by DNA methylation. Amongst the three sites, rs showed methylation enrichment in the suicide group albeit no significant correlation with SAT1 expression. Interestingly, the hyperfunctional status for all four genes was found to be associated with promoter hypomethylation. This hypomethylation status was further supported by the significant negative correlation between two specific CpG sites CpG9 and 16 and AMD1 gene expression whereas CpG was found to be negatively correlated with gain of function of ARG2 gene.
This was not found to be true for OAZ1 and OAZ2 genes, although site-specific as well as overall differences in methylation between controls and suicide victims were noticed for all four genes investigated Gross et al.
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Moreover, lower expression of BDNF gene was noticed in those suicide subjects who had earlier shown exon IV promoter hypermethylation Keller et al. These observations suggest that epigenetic influence on neurotrophic deficiency results in improper modulation of neural plasticity Dwivedi, ; Duclot and Kabbaj, , a common finding in suicide brains Dwivedi et al. DNA based methylation in dysregulating gene function was further evidenced from studies in astrocytes of suicide subjects Maussion et al. T1 isoform expression Maussion et al. Structural characterization of TRKB. Methylation analysis of these four CpG sites showed significant methylation enrichment in the suicide group compared to the control group; additional statistical analysis established a significant correlation between methylation and expression levels.
Contrary to this, earlier reports on decreased TRKB. Addressing the epigenetic influence on suicide neurobiology remains incomplete without discussing the functional involvement of the HPA axis. In a postmortem brain expression and methylation study, hippocampal NR3C1 expression was found to be significantly decreased in 12 suicide victims. A recent report has identified similar site-specific DNA methylation changes related to three non-coding glucocorticoid GR transcript variants 1 B , I C , and 1 H in hippocampal regions of suicide victims with a history of childhood abuse Labonte et al.
This indicates an integral role of coordinated DNA methylation response to alter the GR functionality, resulting in HPA axis dysregulation in suicide subjects. Taken together, the studies discussed herein suggest the functional implication of DNA methylation based epigenetic modifications in dysregulating multiple cellular pathways in brain areas primarily involved in neurocognitive and vegetative functions. These cellular abnormalities may give rise to an overall dysfunctional state in information processing and may eventually contribute to the individual's capability of suicide Turecki, b.
Postmortem findings of gene expression and gene function studies point to a hyperactivation of the HPA-system, a downregulated serotonin system and decreased levels of BDNF compared to non-psychiatric control subjects or psychiatric patients who died of reasons other than suicide.
In this review, we are focusing primarily on postmortem brain studies, since the reliability and the validity of peripheral biomarkers has been questioned before Blasco-Fontecilla et al. Several early studies investigated the association between the HPA-axis and suicide by autoradiographic and ligand binding techniques, describing an overexpression of CRH and a subsequent downregulation of the corresponding receptors Nemeroff et al.
A very recent study examined postmortem transcription levels in depressed suicide victims, depressed subjects who died from non-suicidal causes, and subjects without any psychiatric history. Interestingly, depressed suicide victims carried a distinctive transcription profile, different from prior findings: CRH mRNA was significantly increased in the suicide group, CRHR1 and GR failed to show significance but were upregulated compared to the other two groups and CRHR2 showed an insignificant downregulation Zhao et al.
The abundant serotonin receptor 5HT 2A has been the focus of neurobiological suicide studies for a long time. The majority of publications reported an increased level of 5HT 2A receptors in the cortical area of suicide victims Stanley and Mann, ; Turecki et al. Of all 14 serotonin receptors, 5HT2C is one of the less examined ones: Pandey et al. They found no significant differences in mRNA expression levels, but higher levels of protein in the PFC of suicide victims Pandey et al.
Recent publications suggest that a highly edited isoform of the pre-mRNA of serotonin receptor 2C is overrepresented in the brains of suicide victims and is significantly correlated to gene expression levels of associated genes Niswender et al. In line with functional polymorphisms found in postmortem brain samples of suicide victims, BDNF also shows corresponding changes in gene expression and gene function. Generally speaking, most of the studies were able to find suicide-specific effects, which did not correlate with any underlying condition or psychiatric disorder Dwivedi, Decreased gene expression in the hippocampus and PFC but not in the entorhinal cortex have been presented by Karege et al.
A recent study comparing depressed subjects to suicide subjects and controls: BDNF and its receptors showed a merely insignificant upregulation in the suicide group Zhao et al. Decreased receptor expression of TRKB in suicide victims has also been reported in several other studies in hippocampus Dwivedi et al. In line with the above mentioned findings, phosphoinositide 3 PI 3 -kinase, a key enzyme in the neurotrophin pathway, was found to be decreased in PFC and hippocampus of suicide victims both mRNA and protein levels; Dwivedi et al.
Cyclic-AMP response element binding CREB is an important transcription factor that interacts with promoters of genes involved in neuronal signaling Sheng et al. Irrespective of the diagnosis, CREB mRNA and protein expression were found to be significantly decreased in the PFC and hippocampus of suicide victims, compared to subjects without any psychiatric history Dwivedi et al.
In a sample of teenage suicide victims, these findings were replicated in the PFC only Pandey et al. Taken together, these findings indicate that changes in the serotonin and the neurotrophin system as well as changes in the HPA axis and CREB are contributing to the capability of suicide on the level of gene expression. When addressing suicide in the form of a model—as inclusive as it can be—many factors unavoidably will be left out. Suicide is a heterogeneous disorder and every suicidal act is unique in its causes, forms and intentions.
Causes usually a psychiatric disorder and intentions might influence the method used violent vs. All these differences make it difficult to address suicide in the form of a model. Nevertheless, suicide models are indispensable for an on-going scientific dialogue as well as for the purpose of education. This review is an attempt to construct a combined model of Mann's Stress-Diathesis and Joiner's Interpersonal Theory, describing suicide as a total of cognitive and neurobiological features. Predisposing factors, increasing the vulnerability of an individual might be found in the genetic code.
These genetic variations might further increase the individual's vulnerability to post-transcriptional and post-translational changes resulting from traumatic experiences and stress throughout the lifespan. This brings us to the point that the graphic depiction of this model is a simplification of our current knowledge about the neurobiology of suicide, albeit true with psychological models too. We claim that there is a need for translational theories that have the capability of reaching practicing clinicians and scientists, and contribute to mental health education in general.
With psychiatric research in particular, there is a necessity for established models to which greater audiences can relate. Further research, particularly epigenetic studies, is needed to support the presence of a life-long, evolving capability of suicide and identify neurobiological correlates of susceptibility as well as protective factors.
Each author contributed substantially in preparing the manuscript. BL contributed to the life span model writing and overall conclusion. BR contributed to epigenetic section of the manuscript. QW contributed to the genetic section of the manuscript. BB contributed to the neurobiological correlates section of the manuscript. YD designed the study and integrated the overall hypothesis. He also oversaw the writing and editing of the manuscript.
All authors read the manuscript in entirety and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abbar, M. Suicidal behaviors and the tryptophan hydroxylase gene. Psychiatry 52, — Anguelova, M. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Psychiatry 8, — Arsenault-Lapierre, G. Psychiatric diagnoses in suicides: a meta-analysis.
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