Manic Depression: The Neuroscience behind Bipolar Disorders
|✅ Paper Type: Free Essay||✅ Subject: Psychology|
|✅ Wordcount: 4443 words||✅ Published: 8th Feb 2020|
Bipolar Disorder (BD), otherwise known as Manic Depression, is a psychiatric illness that causes shifts from depressive to manic states, both of which can present psychotic features. The two main types of bipolar disorder known (Bipolar I Disorder and Bipolar II Disorder) differ by their defined pattern between depressive and manic episodes. Bipolar I Disorder is defined by manic symptoms of increased energy with heightened mood and activity levels, followed by extremely low and depressive symptoms. Bipolar II Disorder is defined more so by hypomanic episodes, which do not cause as severe symptoms as full-blown manic episodes seen in Bipolar I. Bipolar patients may also experience mixed or euthymic episodes, but are generally deemed as non-neurotic, extroverted and impulsive. Manic depression is often linked to schizophrenia (SZ) and major depressive disorder (MDD) as the symptomologies are similar, causing diagnostic dilemmas. SZ and MDD are characterized anatomically by cellular alterations of the dorsolateral prefrontal cortex, whereas the neuropathology of BD is still undergoing research (Anderson 2007). There have been multiple theories as to how BD manifests itself, some of those involving neuroanatomic structure differences, whether though defects in immune activation, enzyme activity, or the variation in catecholaminergic systems. BD is treated with mood stabilizers such as Lithium to help reduce symptoms, and the way in which the body responds to these mood stabilizers could help distinguish which pathways are at fault and potentially help future drug development.
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As BD is defined by disordered emotional experiences and responses, the brain’s amygdala structure is often put to question as emotional functioning is associated with the amygdaloidal complex. Multiple neuroimaging studies show that amygdala activity varies with emotional information processing correlated with emotional experience. The amygdala takes on the role of evaluating emotional experience within feedback projections. However, there is evidence that patients with amygdala lesions do not manifest disordered emotional experiences (Anderson and Phelps 2000; Anderson and Phelps 2002). Abnormalities of the prefrontal cortex, the striatum and amygdala, found through structural magnetic resonance imaging (MRI) studies, exist already early on in the development of the illness, therefore may not be related to illness onset. Other abnormalities found in the cerebellar vermis appear to worsen with repeated episodes, and therefore may only represent the effects of illness progression.
The symptoms of BD include affective instability, impulsivity and psychosis, which suggests that anterior limbic brain network structures which control behaviour, such as the amygdala involving prefrontal-striatal-thalamic circuits, are dysfunctional. Studies have shown that differences in brain volumes have been observed in the prefrontal cortex, subcortical and medial temporal structures, in bipolar patients compared to healthy controls. Investigations of both grey and white matter compartments within the five subregions (superior, middle, inferior, orbital and cingulate) of the prefrontal cortex suggested that bipolar patients had smaller grey matter volumes in the left superior, middle and right subregions (Lopez-Larson et al. 2002). In addition to this, a study involving middle-aged bipolar patients showed that with illness progression and recurrent affective episodes, there was increased grey matter volume loss within the inferior prefrontal cortex (Brambilla et al. 2001). Investigations into cortical thickness have further suggested that predictions can be made for future affective lability in adolescents at risk of developing bipolar disorder. Patients who have been predicted to have future manic/mixed symptoms were those with lower bilateral parietal cortical thickness, lower right transverse temporal cortex thickness, and greater left ventrolateral prefrontal cortex thickness (Bertocci et al., 2018). It is recognized that prefrontal cortical volumes are inversely correlated with performance on a measure of attention, and that distinct subregions project to corresponding regions in the striatum to initiate the prefrontal-striatal-thalamic loops that modulate human emotional and social behaviour. Therefore it is hypothesized these differences in brain volumes may be the cause of the abnormal behaviours and affective lability seen in bipolar patients.
The reduction in regional brain volumes was not only investigated for grey matter, but also for neuronal and glial density. A study which suggested the decrease in neuronal and glial density in post-mortem bipolar patient brains, observed using a 3D morphometric method, was similar to the reductions in cell density found in MDD (Selemon et al., 2001), which can explain the disordered depressive episodes of bipolar patients and perhaps why patients are often wrongly diagnosed.
It has been said that euthymic bipolar patients experience relatively stable yet residual emotional symptoms, where they are neither manic nor depressed. However, even though a euthymic phase is characterized by more tranquil and normal mood symptoms, studies have shown that euthymic bipolar patients differ in emotional response to positive stimuli compared to healthy controls. Using an emotional induced method with emotional pictures from the International Affective Picture System (IAPS), physiological measures of emotional response were assessed by measuring pupil size. It was found that upon viewing positive pictures, pupil dilation was significantly lower in euthymic patients than in healthy controls (Lemaire et al., 2014). This finding was independent of sleep duration, life events, and emotional regulation strategies, yet variables such as sleep quality and anxiety may have impacted the data obtained. Euthymic patients also have reportedly increased subjective emotional response (Henry et al., 2008). Decreased pupil dilation and subjective emotional hyperactivity may be explained by the negative bias amongst euthymic patients, as well as the imbalance in emotional response to negative and positive stimuli. Physiological components, such as pupil dilation, have proven they can be used as possible endophenotypes to highlight disordered emotional response in BD. The argument that emotional processing is more responsive to metal imagery than verbal thought, where bipolar patients were found to have greater mental imagery use, suggests that intrusive visual imagery may play a role in the development and maintenance of affective episodes. This would therefore be a good basis to develop early cognitive behavioural interventions for populations at risk (McCarthy-Jones et al., 2012).
Bipolar patients are known to score higher than healthy controls in emotional instability (Solomon et al. 1996). Additionally, studies have suggested that affective lability and affect intensity are also altered/increased in euthymic bipolar patients (Henry et al., 2008). It is hypothesized that as euthymic patients have higher affective intensity, meaning they feel emotions with a higher intensity than healthy controls, this contributes to their increased emotional lability. This emotional hyper-activity is a trait shared by both bipolar and borderline personality patients, which is why mood stabilizers are often prescribed to both patients. However, a study showing that affective lability may only be a temperamental trait in bipolar disorder, leading to more enduring dysphoric moods that tend towards either elation or depression rather than self-damaging impulsivity in border personality disorder (Henry et al., 2001). This suggests that mood stabilizers may not necessarily be the best treatment for bipolar patients, as the sedating effects can worsen a patient’s mood and energy during a depressive episode.
Animal models of bipolar depression are largely based on stress-induced behavioural changes due to lack of knowledge of causative genetic mutations. However, de novo mutations have proven to play a role in schizophrenia, which is partially related to BD, suggesting that identification of de novo mutations that cause BD could be identified in future genetic modelling of animals. A certain approach to studying how altered gene expression can lead to BD and other psychotic illnesses is by the use of vectors that can reside in post-mitotic cells, such as the use of herpes simplex virus (HSV) amplicon vectors. The study using the HSV amplicon vectors suggested that viral vector-mediated elevations of transcription factor CREB in the nucleus accumbens (NAc) region produced signs of depressive symptoms in animal models (Neve et al., 2018). To be able to differentiate between depressive and manic episodes, the glutamate receptor 6 (GluR6) gene has been hypothesized to be associated with BD. Researchers found that mice that were missing the GluR6 gene displayed symptoms of mania, including hyperactivity, risk-taking and aggressiveness. Administering the mice with the classic treatment of mood stabilizers, such as lithium, reduced the symptoms (Shaltiel et al., 2008). However, whether the glutamatergic system may play a role in BD is still uncertain.
The neuropathology of manic depression has shown to be associated with human immune dysfunction and activation. The upregulation of pro-inflammatory cytokines may make the brain more susceptible to stress, as well as affecting neurochemical pathways, which may lead to the onset of mood disorders. Investigators suggested that increased levels of C-reactive protein (CRP), as well as IL-6 and TNF-α cytokines in patients with manic symptoms, heightened the biological vulnerability of illness onset. Variables such as sleep are regulators of the immune system, with prolonged loss of sleep inducing the increase in CRP and cytokine level. Consequently, with manic patients showing reduced need for sleep, the onset of the symptoms may be caused by increased immune activity from sleep disturbances (Becking et al., 2013). Cytokines are also able to induce the indoleamine-2,3-dioxygenase enzyme that catalyses the degradation of tryptophan, which can consequently lower the synthesis of serotonin and causes depressive symptoms. In addition to this, multiple studies indicate that a polymorphism located on the gene phospholipase Cγ1 (PLCG1- encodes for a γ-1 isozyme of phospholipase C) is also implemented in increased immune activity and consequently in the possible onset of BD. Phospholipase C (PLC) is an enzyme that can play an important role in the inflammation pathway by catalysing the release of arachidonic acid, which can then go on into the cyclooxygenase pathway to produce prostaglandins. It was found that mice lacking PLCG1 in the forebrain exhibited hyperactive and reduced depressive-related behaviour, suggesting that the loss of PLCG1 from the forebrain results in manic-like behaviour which is present in BD (Turecki et al., 1998; Yang et al., 2017). Lithium relieved the mice of the hyperactive symptoms. Lithium, the most commonly used mood stabilizer, has shown to decrease prostaglandin activity, therefore contributing to the decrease in pro-inflammatory cytokines that may be associated with manic and depressive symptoms (Anand et al., 2016). This data upholds the hypothesis that neurophysiological pathways involved in BD may be affected by altered immunological functioning.
As previously mentioned, the loss of serotonin production may be involved in depressive episodes of bipolar patients. A study performing gain and loss-of-function experiments suggested that dorsal raphe serotonin sub-systems differed in input and output connectivity and behavioural functions, with implied anxiety-like behaviour resulting from these dorsal raphe serotonin neuronal projections (Ren et al., 2018). Serotonin transmission in the amygdala could therefore also be implemented in the understanding of disordered emotional regulation.
Along with the amygdala, a large percentage of the midbrain including the substantia nigra (SN) and the ventral tegmental area (VTA) have shown an increase in sensory connectivity in patients with manic symptoms. The SN and VTA are the brain’s primary sources of dopaminergic innervation, consequently being crucial in the brain’s reward circuitry system. Therefore it is suggested that midbrain hyperconnectivity and hyperactivation of mesocortical/mesolimbic dopamine pathways are associated with emotional hyperactivity and mania-related pursuit of pleasurable activities (Anand et al., 2016). Additionally, studies have shown that dopamine D3 receptor (DRD3) mRNA is of significantly decreased levels compared to healthy controls, supporting the hypothesis of irregularity within dopamine pathways in BD (Vogel et al., 2004).
Glycogen synthase 3 (GSK3) and inositol monophosphatase (IMPase) are both potential therapeutic targets in BD as both are inhibited by lithium. Lithium blocks IMPase and the recycling of inositol phosphates and inositol-containing phospholipids, leading to a reduction in phosphatidylinositol-4,5-bispohosphate (PIP2), and consequently a reduction in inositol-1,4,5-trispohsphate (IP3) which is needed to stimulate an increase in intracellular calcium concentration and a host of downstream signalling events. Hence, inhibiting IMPase will reduce neuronal excitability and disordered mood symptoms. This data is supported by the study observing the accumulation of inositol phosphates in the brain of mice and rats due to lithium administration (Brandish et al., 2005). GSK3 has a role in multiple intracellular signalling pathway such as glucose regulation and apoptosis. GSK3 usually works by inhibiting the activity of its downstream target. As lithium acts on GSK3, it is suggested that GSK3 activity must be abnormal in bipolar patients, with increased activity leading to hyperactive behaviour. Lithium acts on indirectly inhibiting GSK3 by triggering the phosphorylation of GSK3αSer21/βSer9, resulting in cytoprotection. Studies show that rodent models being medicated with lithium have an increase in phospho- GSK3αSer21/βSer9 levels in the frontal cortex and cerebellum, as well as indicating antidepressant-like effects and reduced hyperactive behaviour when administered with GSK3 pharmalogical inhibitors (Leng et al., 2008). In addition to this, it was shown that Trpm-2 (Transient receptor potential cation channel member 2) deficient mice showed increased anxiety as Trpm-2 is involved in the downregulation of the GSK3 phosphorylation, suggesting that possible genetic mutations lead to Trpm-2 malfunction and consequently to the dephosphorylation of GSK3 (Jang et al., 2015). Therefore, future drug development should also look into the treatment of Trpm-2 malfunction, as well as GSK3inhibition.
Studies have shown that mice with an N-ethyl-N-nitrosourea (ENU)-induced point mutation in the circadian gene Clock (Clock Δ19 mice) display manic symptoms similar to BD patients that can be treated with lithium. This mutation in the Clock gene leads to diminished cellular function and signalling within mesolimbic brain regions, such as the nucleus accumbens (NAc), which leads to the manic-like behaviour in ClockΔ19 mice. This NAc signalling can be monitored using non-invasive techniques such as magnetoencephalography, and therefore can be used as a biomarker for diagnosis of BD. The ways in which lithium operates within the mesolimbic circuit to treat the manic behaviour is not entirely known (Dzirasa et al., 2010).
There have been many suggestions as to what the principle cause of BD in humans is. However it can be concluded that perhaps multiple causes may be linked to each other in the pathology of BD. Mood stabilizers have so far been helpful in the treatment of manic and depressive-like behaviours, yet more research needs to be done to fully understand the circuits in which they act. At present, attempting to model the human disease in rodents has been seen to be questionable as it is difficult to validate the behavioural changes observed in animal models, as differences in behavioural characteristics among species must be taken into account. The nature of the illness itself is complex, with possibly multiple genetic and environmental factors working in disharmony. In addition to being difficult to correctly observe behavioural changes, most animal models of BD have not used clinical strategies and criteria, such as DMS-5 (The Diagnostic and Statistical Manual of Mental Disorders), to fully establish whether these behaviours belong to BD and not SZ or MDD. Clinical trials have suggested many theories as to what may make a patient biologically vulnerable to the onset of the illness, nevertheless discrepancies in clinical trial reports have raised questions of accuracy.
Overall, it may be said that there is a need for improved animal models which will depend on well-defined endophenotypes, downstream of gene expression and upstream of clinical symptoms to elaborately understand the neuropathology of BD, and be able to accelerate future drug development specific to BD treatment.
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