Depression and Bipolar Disorder (BD) are both disabling psychiatric mood disorders with one having states of mania and depression and depression being unipolar (Brady Jr. et al., 2016 and 2017, Young et al., 2017). This paper is a review of current literature about the neuropathology of the two in an attempt to show some of the similarities and differences in their abnormal functioning with an emphasis on the amygdala, (a structure in the brain that research suggests is critical to emotional processing and responses (Young et al. 2017)) as well as the possible innovative treatments these studies could support.
Though it is most well-known for its role in emotional processing, the amygdala is involved in many functions such as fear/reward learning, aggressive behaviors, sexual behaviors, maternal behaviors, feeding behaviors, attention, and perception, as well as encoding emotional memories (Hybouski et al., 2016). It is a complex, heterogenous structure that consist of 13 distinct nuclei that are consistently grouped into basolateral and centrocorticomedial subdivisions, with the basolateral consisting of the lateral, basal, and accessory basal nuclei and the centrocorticomedial consisting of the medial, cortical, and central nuclei (Hybouski et al., 2016). In animal studies, it has been found that the central nucleus connects to part of the hypothalamus and is involved in regulating autonomic responses (Hybouski et al. 2016). It also connects to the ventral tegmental area, locus coeruleus, and basal forebrain, possibly playing a part in vigilance and attention, as well as to the periaqueductal gray and cranial nerve for a possible role in freezing and escape actions (Hybouski et al. 2016). It has also been shown that the basal nucleus receives information from the lateral nucleus and the orbitofrontal cortex and sends information to the central nucleus and the striatum, where it is used to modulate emotional processing as context (Hybouski et al. 2016).
For the following study the amygdala was divided into three subuclei groups with the central and medial nuclei creating the centromedial group, the cortical, basal, and accessory basal creating the basal group, and the lateral nucleus being the final group. In an attempt to better understand how each nuclei of the amygdala contributes to emotional processing, Stainslau Hybouski, Arash Aghamohammadi-Sereshki, Christopher R. Madan, Andrea T. Shaffer, Corey A. Baron, Peter Seres, Christian Beaulieu, Fraser Olsen, and Nikolai V. Malykhin showed 28 healthy patients pictures from the International Affective Picture System based on valence and arousal in an fMRI study. They found that the amygdala was significantly more responsive to negative stimuli than neutral, and that the subnuclei groups responded to negative stimuli differently (2016). The centromedial group was the most responsive to negative stimuli, followed by the basal, with both having significantly more activity in response to negative stimuli than neutral (Hybouski et al., 2016). It was also found that the activity in the centromedial group was much more accurate when trying to predict the emotional reaction to a picture, suggesting that it may have the larger role (Hybouski et al. 2016). The centromedial group also showed more connectivity to the basal group than it did to the lateral group, though it was shown that all groups interacted with each other (Hybouski et al. 2016). This finding supports previously done animal studies.
The amygdala has been found to be doubly dissociated in depressed patients, meaning that it responds less than in healthy people to positive stimuli and more than in healthy people to negative stimuli (Young et al. 2017). This reaction to positive stimuli is found to be related to symptom severity in these patients (Young et al. 2017). In an fMRI study of individuals with unmedicated current and remitted depression, individuals with high risk of depression due to family history, and healthy individuals, Kymberly D. Young (Ph.D), Greg J. Siegle (Ph.D), Jerzy Bodurka (Ph.D), and Wayne C. Drevets (M.D) examined the amygdala reactivity and connectivity via fMRI while the participants engaged in a autobiographical memory recall task (2015). The task, specifically, was to recall a memory for 12 seconds in response to an emotionally valenced or neutral word, and then rate the memory on specificity and valence based on the definitions of standard memory categories they were instructed on. To insure they could accurately do this, they were asked to provide and classify examples of each type of memory before the scanning was started. These scans showed a significant decrease in activity in the left amygdala in depressed participants during positive specific memory recollection relative to all other groups (Young et al. 2015). It was also found that the healthy control group had decreased activity in the left amygdala during negative specific memory recall compared to all other groups (Young et al. 2015). For the right amygdala, it was found that the control group had significantly more activity when recalling positive specific memories than the depressed group (Young et al., 2015). When observing connectivity to other areas of the brain during positive memory recall, it was found that amygdala connectivity with the right dorsal anterior cingulate cortex (ACC) and the left and right posterior cingulate cortex (PCC) was significantly less, but higher with the left and right medial frontal polar cortex, as well as the left superior temporal gyrus in the depressed group compared to the other groups (Young et al., 2015). During negative memory recall amygdala connectivity with the left dorsal ACC, superior temporal gyrus and insula, left and right dorsolateral prefrontal cortex, PCC, thalamus, middle temporal gyrus, right precunceus, inferior temporal gyrus was increased, but was decreased in connectivity with the left medial frontal polar cortex in the depressed group (Young et al. 2015). The areas of greatest connectivity in the depressed group were the areas of lowest connectivity in the healthy groups, with the remitted group showing lower amygdala connectivity than the depressed group, but greater connectivity than the healthy groups (Young et al. 2015). These findings show an abnormality in the connectivity of the amygdala in depressed and remitted individuals that may explain the difficulty depressed patients have in recalling positive memories due to the amygdala’s critical role in determining the processing and response of emotional stimuli, with greater activity meaning greater salience or attention to said stimuli (Young et al. 2015).
Bipolar disorder is characterized by episodes of emotional dysregulation causing mania or depression (Brady Jr. et al. 2016). Therefore, patients experience depression as well as mania, whereas patients with depression do not experience periods of mania. Roscoe O. Brady Jr., Grace A. Masters, Ian T. Mathew, Allison Margolis, Bruce M. Cohen, Dost ?–ng??r, and Matcheri Keshavan studied bipolar patients in both a manic and euthymic(stable) state, as well as healthy participants in an effort to find the neurological differences in the two states in an article published in 2016. They found a significant decrease in connectivity between the amygdala and the pregenual ACC in mania when compared to stable bipolar patients, with greater loss in the right amygdala (Brady Jr. et al. 2016). There was also a significant increase in connectivity between the amygdala and the bilateral supplemental motor area of the frontal cortex in manic patients as opposed to euthymic (Brady Jr. et al. 2016). Brady Jr. et al. also found that there was a significant loss of connectivity between the amygdala and ACC in manic patients that is present in euthymic and healthy patients (2016). The healthy group scores were in between the euthymic patients and manic patients as expected (Brady Jr. et al. 2016). These results are consistent with findings that the right amygdala is more important for emotional regulation than the left amygdala, as the differences between groups were more significant in the right than the left amygdala (Brady Jr. et al. 2016). These findings are further supported in a longitudinal study by Brady Jr. et al. (with the loss of Ian T. Mathew and Bruce M. Cohen from the group) in 2017.
In 2017, a study by Ambrosi et al., differences between bipolar depression and unipolar depression were investigated through the resting fMRI examination of patients with bipolar depression, unipolar depression, and healthy participants as determined by DSM-IV criteria. It was found that the bipolar patients had even lower functional connectivity between the left insula, and the right frontopolar prefrontal cortex, but higher connectivity between the right amygdala and the left anterior hippocampus than patients with unipolar depression (Ambrosi et al. 2017). There was also lower connectivity between the right frontopolar prefrontal cortex and the bilateral dorsal anterior insula and posterior insula in bipolar depression (Ambrosi et al. 2017). Between the left anterior hippocampus, right laterobasal and centromedial amygdala, and dorsal anterior insula there was a significantly higher connectivity in patients with bipolar depression than in unipolar depression (Ambrosi et al. 2017). In comparisons with healthy patients, there was lower connectivity between the left mid-dorsolateral prefrontal cortex and posterior insula, as well as between the right frontopolar prefrontal cortex and the left posterior insula and right dorsal anterior insula in bipolar patients (Ambrosi et al. 2017). However, in unipolar patients, there was lower connectivity between the left anterior hippocampus and the right centromedial and laterobasal amygdala (Ambrosi et al. 2017).
When taken into account, all the cited research suggests that the neurological basis of depression is the amygdala functioning abnormally, responding more to negative stimuli than to neutral or positive stimuli. However, the basis for bipolar depression seems to also involve the insula and other areas of the brain more than unipolar depression. This research could help with more accurate diagnosis of bipolar disorder for patients that are experiencing bipolar depression that have not yet had a manic episode, as 69% are first given a diagnosis of unipolar depression (Ambrosi et al. 2017). This would mean that effective treatment could be received sooner and improve the outcome for the patient (Ambrosi et al. 2017).
The double dissociative property of the amygdala in a depressed patient is found to be related to symptom severity (Young et al. 2017). With an estimated two-thirds of people with depression not responding to treatment fully, new treatments are in need (Young et al. 2017). With the findings stated above, fMRI interventions have been created and investigated. In the 2015 study by Young et al. the participants that they scanned were clinically assessed with the 21-item Hamilton Depression Rating Scale (HAM-D), State-Trait Anxiety Inventory (STAI), and the Profile Mood of States (POMS). In these initial assessments, Young et al. found the currently depressed group had significantly higher scores than the other groups on all measures, the patients with remitted depression had significantly higher scores on the HAM-D, STAI anxiety ratings, and POMS measures than the healthy control group while remaining in the healthy range, and the high-risk group did not differ significantly from the healthy control group (2015). The POMS and STAI were also given immediately before and after the autobiographical memory task. It was found that no rating in the healthy or high-risk group changed significantly without any significance of scores between groups, but the POMS and STAI scores decreased significantly in the currently depressed and remitted participants, also with no significant difference in scores between the two groups (Young et al., 2015).
In a later, similar study, Young et al, with the addition of Vadim Zotev (Ph.D), Raquel Phillips (BS), Masaya Misaki (Ph.D), and Han Yuan (Ph.D) examined the effectiveness of real-time fMRI neurofeedback (rtfMRI-nf) intervention for patients with depression (2017). The participants completed four visits. At the first visit, patients were given the Beck Depression Inventory-II, the Snaith-Hamilton Pleasure Scale, the Montgomery-Asberg Depression Rating Scale, The 21-item HAM-D, and the autobiographical memory test (must recall a specific memory for each cue word given) (Young et al. 2016). During visit two, they completed their first rtfMRI-nf session, and given the same assessments, at visits 3 and 4 they were given another session and same set of assessments (Young et al. 2016). Some participants received neurofeedback for the left amygdala, others from an area not associated with emotion in a double-blind selection (Young et al. 2016). There was significant decrease in scores on the assessments in the experimental group in regard to depression assessment measures from visit one (Young et al. 2016). The scores between groups were significantly different at visit three and four, with the experimental group having lower scores (Young et al. 2016). In the experimental group, there was significant increase in amygdala activity when compared with the control group, and increased intraparietal activity in the control group when compared to the experimental group, meaning that the neurofeedback component was effective in recruiting the specific areas (Young et al. 2016). All differences became significant at visit three and continued to be at visit four (Young et al. 2016). At the end of the study 32% of participants met criteria for remission (Young et al. 2016). This shows that the rtfMRI-nf therapeutic treatment with positive autobiographical memory recall is effective with multiple sessions, though the duration of the effects after treatment ceases still need to be investigated (Young et al. 2016).
The aim of this paper was to examine the differences between two mood disorders that both involve depression: bipolar disorder and depression itself, as well as explore the possible implications on treatment these differences have. When considered together, all the cited research suggests that the neurological basis of depression is the amygdala functioning abnormally, responding more to negative stimuli than to neutral or positive stimuli. However, the basis for bipolar depression seems to also involve the insula and other areas of the brain more than unipolar depression. The differences between manic, euthymic, and depressive states in bipolar disorder also suggest more involvement of other parts of the brain in addition to the amygdala. These differences and noted neurological abnormalities can be used to discover new treatments, as the 2016 Young et al. study shows, as well as improve speed of diagnosis for those with severe or non-respondent illness due to wrong diagnosis. This means hope for patients that struggle everyday with non-respondent depression or undiagnosed bipolar disorder.
Ambrosi, E., Arciniegas, D. B., Madan, A., Curtis, K. N., Patriquin M. A., Jorge, R. E.,& Sala, R. (Jul 2017). Insula and amygdala resting-state functional connectivity differentiate bipolar from unipolar depression. Acta Psychiatrica Scandinavica, 136(1), 129-139. https://doi.org/10.1111/acps.12724
Brady Jr., R. O. Masters, G. A., Mathew, I. T., Margolis, A., Cohen, B. M., ?–ng??r D., Keshavan, M. (Sep 2016). State dependent cortico-amygdala circuit dysfunction in bipolar disorder. Journal of Affective Disorders, 201, 79-87. https://doi.org/10.1016/j.jad.2016.04.052
Brady Jr., R. O., Margolis, A., Masters, G. A., Keshavan, M., & ?–ng??r, D. (Aug 2017). Bipolar mood state reflected in cortico-amygdala resting state connectivity: A cohort and longitudinal study. Journal of Affective Disorders, 217, 205-209. https://doi.org/10.1016/j.jad.2017.03.043
Hrybouski, S., Aghamohammadi-Sereshki, A., Madan, C. R., Shafer, A. T., Baron, C. A., Seres, P.,Malykhin, N. V. (Jun 2016) Amygdala subnuclei response and connectivity during emotional processing. NeuroImage, 133, 98-110. https://doi.org/10.1016/j.neuroimage.2016.02.056
Young, K. D., Siegle, G. J., Bodurka, J., & Drevets, W. C. (Nov 2015). Amygdala Activity During Autobiographical Memory Recall in Depressed and Vulnerable Individuals: Association With Symptom Severity and Autobiographical Overgenerality. The American Journal of Psychiatry, 173(1), 78-89. https://doi.org/10.1176/appi.ajp.2015.15010119
Young, K. D., Siegle, G. J., Zotev, V., Phillips, R., Misaki, M., Yuan, H.,& Bodurka, J. (Apr 2017). Randomized Clinical Trial of Realt-Time fMRI Amygdala Neurofeedback for Major Depressive Disorder: Effects on Symptoms and Autobiographical Memory Recall. The American Journal of Psychiatry, 174(8), 748-755. https://doi.org/10.1176/appi.ajp.2017.16060637
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