World Mental Health Day

Today, October 10th, is world mental health day, a day that promotes awareness of mental health conditions and provides support to those who suffer. Truth is we all have a brain, therefore we ALL have mental health. However, the most recent statistics suggest that one in four individuals in the world will be affected by mental health disorders at some point in their lives, and that currently, 450 million people are suffering. The likelihood is, therefore, that you know someone who is dealing with a mental health issue, whether they make that public knowledge. The brilliant thing about studying neuroscience as a degree is that you learn so much more information about these conditions than what your typical google search reveals, and with that, you learn about the constant endeavors of scientists desperately seeking how to treat them. It is sad, but very true that mental health discrimination is still most definitely prevalent in today’s society, and often those that suffer can face shame or stereotyping – the classical ‘it’s all in your head’ springs to mind. Today, we decided to cover the science of some of the most common mental health conditions, and discuss with you why they are very much real. We hope that by understanding some of the known, proven science of why these disorders occur in people, we will raise awareness and also compassion for those that experience them.

Anxiety and OCD – Rosie Porter

Obsessive Compulsive Disorder (OCD) is classified as an anxiety disorder where suffers often experience intrusive thoughts. These thoughts bring about compulsive and repetitive behaviours in an attempt to alleviate their anxiety (Figure 1). It is ranked as one of the world’s top 10 disabling conditions by the World Health Organisation and can affect up to 12 in every 1000 people. While the individual understands the thoughts are irrational, sufferers are unable to control their anxiety and behaviours. Actions such as compulsive cleaning, hoarding and trichotillomania (where a person feels compelled to pull their hair out) are common.

2

Figure 1 The OCD cycle

The underlying pathology behind OCD is still being discovered. However, with recent advances in technology some developments have been made. In a study conducted using resting-state functional-connectivity MRI, the connections in the brains of OCD patients and their family members were compared. The imaging found that siblings of patients had increased connections within and between areas of the brain responsible for cognitive control (fronto-parietal and cingulo-opercular regions). These pathways that are diminished are hypothesised to give an impaired ability to control their own cognition, and therefore their anxiety and behaviour. Patients were also found to have increased connectivity within the fronto-limbic pathway; an area responsible for our emotions (Froukje et al., 2017).

Other studies have found that the orbitofrontal-basal ganglia pathways are altered in OCD (a pathway related to cognitive control of movement), as well as abnormal volume and function in the amygdala (an area responsible for emotion; Nutt and Malizia, 2006). Alterations in the amygdala are seen in most anxiety related disorders, but OCD is unique in that sufferers help relieve their anxiety by performing impulsive behaviours (Figure 1).

Research conducted into the genetic basis behind OCD has flagged up the hSERT gene; hSERT encodes a serotonin transporter in synpases. Serotonin is a neurotransmitter that is thought to be imbalanced in different anxiety disorders and depression. A mutation that has been detected in the hSERT gene (I425V) leads to significantly less serotonin in the synapses of OCD sufferers. This mutation underlies the theory that people can have a genetic predisposition to OCD, that environmental factors can exacerbate.

These discoveries linking dysfunctional neural connections and proteins with behaviour provide evidence for the underlying pathology of the disorder. With further research, the hope is to better understand the disorder and find more effective ways to manage and treat it.

Schizophrenia – by Rachel Coneys


From being one of the most misunderstood and negatively portrayed mental disorders, there has been a new wave in the attempt to decode Schizophrenia’s complex causes and pathologies, to break the misconceptions and develop more effective treatments. Schizophrenia, meaning to ‘spilt mind’ is a severe and progressive psychiatric illness, emerging in young adults at the prime of their lives, spanning all socio-economic and cultural groups. Symptoms vary for each individual and are grouped as positive or negative depending on the type of impairment. Positive symptoms describe experiences such as hallucinations or delusions. Negative symptoms include lack of motivation and social withdrawal.

For over a decade, neuroscientists have been trying to uncover the pathology behind Schizophrenia. A universal belief is that there is a strong genetic predisposition, which when coupled with certain environmental factors, triggers Schizophrenia.

Neurochemical Pathology
Until recently the dominant theory was that of an up-regulation of the neurotransmitter Dopamine within the brain. This was centered on the action of anti-psychotic drugs, which work by blocking dopamine receptors. However it became clear these drugs were ineffective at treating negative symptoms, indicating that another neurochemical system must be involved, otherwise these drugs would work.

The latest theory attributes the major excitatory neurotransmitter Glutamate and the receptor that it binds to, ‘NMDAr’, as key players. The suggestion of an NMDAr ‘hypo-function’ in Schizophrenia came from studying drugs that block this receptor (e.g. Ketamine) and therefore induce psychotic symptoms. Scientists believe that in schizophrenic patients, reduced NMDAr functioning occurs during post-natal development, resulting in structural and behavioural changes. During this period, NMDAr are needed for neuronal signaling and survival, and since NMDAr are widespread throughout our brain, loss of function can have devastating effects. NMDAr dysfunction in the prefrontal cortex (Figure 1) is thought to have a downstream effect on Dopamine and GABA (inhibitory neurotransmitter) networks, resulting in psychosis later on in life. This theory is effective at explaining both the positive and negative symptoms.

1

Figure 1: The Prefrontal cortex is located in the frontal lobe and is implicated in complex executive functions and personality development. NMDAr dysfunction in this area implicates Dopamine and GABA networks, consequently impairing the prefrontal cortex’s functioning.

Genetic Predisposition

Additionally, there is a strong genetic element to Schizophrenia, with a 50% concordance rate in identical twins. Until recently the genetic risk factors were elusive, but thanks to a remarkable study they are being identified. This Genome Wide Association Study found the expression of a certain variant of a gene called ‘C4’ was elevated in patients with Schizophrenia. C4 is implicated in synaptic pruning (removing the connections between neurons that communicate with one another in the brain) during development. They hypothesized the elevated C4 variant leads to excessive synaptic pruning, causing a thinner cerebral cortex (a physiological hallmark in Schizophrenic patients), and consequent psychotic symptoms.

The Future
The identification of clear genetic associations and development of more eloquent neurochemical models is a huge step forward. Increased understanding of causes and pathologies can help pave the way for more effective treatments for patients with the hope of allowing them to live a less debilitating lifestyle.

Major depressive disorder – Molly Campbell

Depression is a disorder that is heterogenous in nature, meaning that there are different types of depression that vary in severity, from mild to extreme, in which a sufferer may present with psychotic symptoms. Major depressive disorder (MDD) is one of the most common psychiatric diseases and is an example of one of the types of depression. The diagnostic and statistical manual of mental disorders bases a diagnosis of MDD on the presence of low mood or inability to experience pleasure, or perhaps both, for more than two weeks; in addition to profound cognitive dysfunction and sleep disturbances. However, it should be considered that difficulty arises in the diagnosis and treatment of MDD due to the fact that these diagnostic criteria are somewhat arbitrary.

A universally effective treatment for MDD remains to be found, and this is due to the fact that the associated neurobiology remains ambiguous. The credibility of the infamous monoamine hypothesis, in which alterations in levels of the monoamine neurotransmitters serotonin and nor-adrenaline were deemed responsible, is now heavily questioned. This is due to the fact that unfortunately, various monoaminergic antidepressant drugs that rely on this theory are not clinically effective across all patients. For some individuals they appear to work, however in the majority they do not, and so alternative neurobiological theories have arisen (Aan het Rot et al., 2009)

One proposed theory – genetics

Multiple scientific studies have aimed to identify a genetic cause for MDD, as there is strong evidence of heritability due its presence through families. An interesting study by Hyde et al (2016) looked at data from 75,607 European individuals that had received a clinical diagnosis. They identified five independent variants from four regions of the genome associated with self-report of clinical diagnosis of MDD. Further analysis found a total of 17 single-nucleotide polymorphisms associated with a diagnosis of MDD. Put simply; it was found that a significant number of individuals who had received a diagnosis of MDD had differences in their DNA compared to individuals that did not have MDD. The genetic variant that was most strongly associated with MDD was MEF2C (unfortunately, genes are often given pretty complicated names!), a gene involved in the regulation of synapses. Synapses are essentially the communication points between neurones, and this gene has also been shown to be involved in epilepsy and intellectual disability.

Whilst this is only one example of research that investigates the neurobiology of MDD, I think it is particularly interesting as it highlights the emerging role of pharmacogenomics in the treatment of mental health conditions – essentially tailoring the treatment for individuals who are suffering based on the make-up of their DNA.

Bipolar Disorder – Kate Pearman

Bipolar disorder (BD) is a psychiatric disorder that progresses through an individual’s lifetime.  More than 3 % of people are affected worldwide. Individuals with BD experience recurring episodes of depression and mania which significantly affect an individual’s quality of life and is positively associated with an increase in risk of suicide. Around a third to a half of BD patients attempt suicide on one occasion in their lifetime and an estimated 15-20% of these attempts are successful (Schaffer et al 2015). BD is also primarily diagnosed in young adulthood and thus affects the economically active population and therefore causes high costs to society (Gardner et al 2006). Therefore, highlighting the severity of this disorder and the need for a greater understanding into the pathology of BD for possibility of more efficacious treatment methods.

Knowledge of the pathogenesis and pathophysiology of BD has significantly increased over the last few decades. BD is one of the most heritable psychiatric disorders however, a multifactorial model in which both gene and environment interact, is thought to describe the disorder most appropriately. Mood disorders were thought to be caused by an imbalance in monoaminergic neurotransmitter systems, in regards to BD the dopaminergic. Although evidence has shown these circuits are likely to have a role in BD, no singular dysfunction of these systems have been identified. However, modulation of synaptic and neural plasticity is thought to be important in the circuitry regulating cognitive functions (Martinowich et al 2009). Neurotrophic molecules like the brain-derived neurotrophic factor, have a strong role in signalling pathways such as dendritic sprouting and neural plasticity. Dendritic spine loss has been observed in post-mortem brain tissue of patients with BD (Konopaske et al 2014). Alternative pathways that can affect neuronal interconnectivity are also being investigated such as mitochondrial dysfunction and endoplasmic reticulum stress, neuroinflammation, oxidation, apoptosis and epigenetic changes, particularly histone and DNA methylation (Berk et al 2011). Also due to the main phenotype of BD being a biphasic energy shift the monitoring of phasic dysregulation in mood, sleep and behaviour is also being investigated. The understanding of underlying pathogenesis of BD is crucial in discovering novel drug targets and the development of biomarkers for the prognosis, risk and therapeutic response.

3

Figure 1- Life chart showing the progression of bipolar disorder, with severity, manic and hypomanic symptoms registered above the phase of euthymia (normal mood state) whereas depressive symptoms depicted below.

 

Thanks for reading…

We hope you found this article an interesting and insightful snapshot of the research into mental health conditions. Please note this article is for informative purposes and should not be used as a tool for self-diagnosis based on the symptoms we have discussed. If you, or anyone you know are suffering from a mental health condition, this is a great source of information for the various charities that can help: https://www.time-to-change.org.uk/what-are-mental-health-problems/mental-health-help-you/other-useful-organisations

 

Mental health is equally as important as physical health, and we at All That Is Neuro wish to help to fight the stigma and encourage awareness.

References

 

Schizophrenia

Snyder, M. A., & Gao, W.-J. (2013). NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Frontiers in Cellular Neuroscience7, 31. http://doi.org/10.3389/fncel.2013.00031

 

Nakazawa, K., Jeevakumar, V., and Nakao, K. (2017). Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia. Npj Schizophrenia, 3(1), 1. Doi:10.1038/s41537-016-0003-3

 

Sekar, A., Bialas, A. R., de Rivera, H., Davis, A., Hammond, T. R., Kamitaki, N., McCarroll, S. A. (2016). Schizophrenia risk from complex variation of complement component 4. Nature530(7589), 177–183. http://doi.org/10.1038/nature16549

 

Rompala, G. R., Zsiros, V., Zhang, S., Kolata, S. M., & Nakazawa, K. (2013). Contribution of NMDA Receptor Hypofunction in Prefrontal and Cortical Excitatory Neurons to Schizophrenia-Like Phenotypes. PLoS ONE8(4), e61278. http://doi.org/10.1371/journal.pone.0061278

 

Schizophrenia (2017). Mind. [Online] Accessed from: https://www.mind.org.uk/information-support/types-of-mental-health-problems/schizophrenia/#.WdpCXxNSzOQ

 

 

OCD UK. http://www.ocduk.org/ocd

 

Froukje E. de Vries, Stell J. de Wit, Odile A. van den Heuvel, Dick J. Veltman, Danielle C. Cath, Anton J. L. M. van Balkom and Ysbrand D. van der Werf (2017). Cognitive control networks in OCD: A resting-state connectivity study in unmediated patients with obsessive-compulsive disorder and their unaffected relatives. The World Journal of Biological Psychiatry. http://dx.doi.org/10.1080/15622975.2017.1353132

Nutt D, and Malizia A (2006). Anxiety and OCD – the chicken or the egg? Journal of Psychopharmacology, 20(6). 729-731.

Imaged sourced from: https://dynamicyou.org/obsessive-compulsive-disorder-ocd-cycle-despair/

 

MDD

Aan het Rot, M., Mathew, S. J., & Charney, D. S. (2009). Neurobiological mechanisms in major depressive disorder. CMAJ : Canadian Medical Association Journal, 180(3), pp. 305–313.

 

Hyde, C., Nagle, M.W., Tian, C. et al. (2016). Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nature genetics. 48(2016), pp. 1031-1036.

 

Bipolar disorder

 

HH Gardner, NL Kleinman, RA Brook, K Rajagopalan, TJ Brizee, JE Smeeding

The economic impact of bipolar disorder in an employed population from an employer perspective. J Clin Psychiatry, 67 (2006), pp. 1209-1218

A Schaffer, ET Isometsä, L Tondo, et al. International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder. Bipolar Disord, 17 (2015), pp. 1-16.

 

K Martinowich, RJ Schloesser, HK Manji. Bipolar disorder: from genes to behavior pathways

J Clin Invest, 119 (2009), pp. 726-736.

M Berk, F Kapczinski, AC Andreazza, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev, 35 (2011), pp. 804-817.

 

GT Konopaske, N Lange, JT Coyle, FM Benes. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry, 71 (2014), pp. 1323-1331

 

 

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s