Neuroscience of Mania
Bipolar Disorder has been listed as one of the leading disorders of the Global Burden of Diseases...
Yet the amount of research and funding put towards it is abysmal.
Laine and I share that during our clinical education, we were taught almost nothing about the experience of mania, diagnosing, or treating the disorders like Bipolar.
This episode share's what we know so far (from the MANY articles Laine went through to try to make sense of it) and what's happening in the brain -- referencing studies from Harrison, Gettes, Tunbridge, Clark, Sahakian, and more.
It also touches on what needs to be done to not only better support those who have experienced manic episodes or have been diagnosed, but what is required for the field of mental health to improve.
The takeaways of this episode are some of our favorites -- you can hear it in Laine's voice at the end.
Enjoy -- and as always, if you have any questions feel free to email us at info@brainblownpodcast.com.
REFERENCES
Dionisio et al. - "Cognitive flexibility impairment and reduced frontal cortex BDNF expression in the ouabain model of mania"
Dzirasa et al. - "Impaired Limbic Gamma Oscillatory Synchrony during Anxiety-Related Behavior in a Genetic Mouse Model of Bipolar Mania"
Ferrari et al. - "Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder"
Schmidta et al. - "Cerebrospinal fluid hypocretin-1 (orexin A) levels in mania compared to unipolar depression and healthy controls"
de Soussa et al. - "Lithium increases plasma brain-derived neurotrophic factor in acute bipolarmania: A preliminary 4-week study"
Paul J. Harrison, John R. Geddes, and Elizabeth M. Tunbridge1 - "The Emerging Neurobiology of Bipolar Disorder"
Luke Clark, Barbara J. Sahakian - "Cognitive neuroscience and brain imaging in bipolar disorder"
G.S. Kirshenbaum, C. R. Burgess, N. De'ry, M. Fahnestock, J. H. Peever and J C Roder - "Attenuation of mania-like behavior in na+,k+-atpase a3 mutant mice by prospective therapies for bipolar disorder: melatonin and exercise"
Emre Bora - "Neurocognitive features in clinical subgroups of bipolar disorder: A meta-analysis"
Ryan W. Logan, Ph.D. and Colleen A. McClung, Ph.D. - "Animal Models of Bipolar Mania: The Past, Present and Future"
General Outline of Episode
Loosely comparable to the socially common term “crazy”
Just because you gambled away your rent money or believe your partner might be cheating doesn’t mean you are manic.
Just like all the mental disorders we’re covering this season, there are certain criteria involved. So let’s talk about it.
This is the neuroscience of Mania.
LAINE
Prevalence - variance in reporting on multiple sources between 1% and about 4%
Mental Illness Policy - a site that states it unbiased information for poly makers and media states it 2.3 million Americans or 1 percent of the population.
The National Library of Medicine for the National Institute of Health cited an article from 2022 that states prevalence is 4%, with being found equally regardless of individuals
Almost 2/3rd of people with bipolar have a close relative with bipolar or with depression
Is argued to be underdiagnosed
mania(colloquially)
Sopranos
Tony Stark
mania(clinically) -mania
Within this category, clinicians would be looking at if this was a manic episode or a hypomanic episode.
Mania - period of abnormally and persistently elevated, expansive, or irritable mood and increased goal-directed energy - lasts at least one week - present most of the day, nearly every day
With
Inflated self-esteem
Lack of need for sleep
More talkative/pressured speech
Flight of ideas/racing thoughts
Distractibility
Increased goal-directed activity
Excessive involvement in activities with painful consequences
Sufficiently severe to cause marked impairment in life, work, or school to necessitate hospitalization to prevent harm or there are psychotic features
Hypomania- period of abnormally and persistently elevated, expansive, or irritable mood and increased activity or energy - lasts at least 4 consecutive days- present all day nearly every day
With
Inflated self-esteem
Lack of need for sleep
More talkative/pressured speech
Flight of ideas/racing thoughts
Distractibility
Increased goal-directed activity
Excessive involvement in activities with painful consequences
The episode is NOT severe enough in life or work or school to necessitate hospitalization. If psychotic features - then mania
They would be looking if there ever was a depressive episode
Would need to assess if it was Bipolar I, Bipolar II, or Cyclothymic Disorder (experiencing symptoms without meeting the full criteria for an episode) - found with a likelihood of co-morbid for ADHD
Bipolar II is more hypomanic episodes, generally depressed for longer periods of time
Bipolar I is more manic or psychotic
Both diagnoses often get confused with Borderline Personality Disorder
PART 1: Terms & Background Info (5-10 minutes)
Hanging out with Hipocaraties again - documented extreme moods - high low and high highs, specifically energized/excited.
Thought to be caused by too much yellow bile.
Aretaues of Cappadocia - the first-century Greek physician - stated that people could have a mood spectrum - with extremes on either end - and stated this was a problem with the brain.
Plato also stated this in his writing but stated the two types were either from the body or from the divine.
1850 two French doctors and two German doctors were all documenting these extremes, one Emile Kraeplin, also a Gemeran psychiatrist stated this was manic-depressive insanity.
Became an official mental health diagnosis in 1980 - then known as Manic Depressive
PART 2: What About Neuroscience (5 minutes)
Harrison, Geddes, and Tunbridge state this well by simply saying “Bipolar disorder (BD) is a leading cause of global disability. Its biological basis is unknown, and its treatment unsatisfactory.”. Sophia Frangou also agrees with this.
They go on to state that really we are treating this with therapy and psychiatry and basing as we do many things in mental health - with criteria developed two centuries ago. Mental health in general is based on a cluster of symptoms rather than anything we find in biology - ie run biological tests to confirm. Ever seen an episode of House - they have tons of theories (that they are often super confident on) that they test for that then show they are wrong. Harder to do in mental health. For bipolar we are treating with “drugs discovered serendipitously several decades ago. BD typifies this unsatisfactory state of affairs”. Its name has changed however what we see, how we diagnose, and how we treat has barely changed at all. Welcome to Season 2 of the brain-blown podcast.
Clark, and Sahakian state that part of the major importance is that “bipolar disorder continues to be frequently misdiagnosed as Major depressive disorder in individuals without a clear history of manic episodes with the consequence that patients may be maintained on a suboptimal medication regime until their bipolar diathesis is noticed.”
Logan and McClung state “The mood stabilizing therapeutic effects of lithium (a salt) and valproate (an anticonvulsant) were discovered by accident and in the absence of any significant mechanistic understanding of BD (Can et al., 2014). While current treatments are generally effective for the reversal of manic episodes and preventing future episodes, these medications have limited, if any, efficacy on their own in the acute treatment of depressive episodes. Moreover, standard antidepressant medications used either as monotherapies, or in conjunction with mood stabilizers or antipsychotics, are generally ineffective for treating depressive episodes, and may induce mood switching in a subset of patients with rapid cycling BD.”
Coupled with the fact that the medications for bipolar often have harsh side effects and the loss of the good feel of mania, makes this diagnosis the least likely for a person diagnosed with it to follow the needed treatment to manage it.
In short, what we have is a bandaid. And people with this diagnosis deserve better.
**BREAK**
PART 3: The Science (30-35 minutes)
Harrison, Geddes, and Tunbridge state “Our understanding of BD remains frustratingly limited.” Much like ADHD, we have some evidence, but it is all over the place and doesn’t appear to be often confirmed.
As we talked about in ADHD, we have some limiting factors. Now this diagnosis isn’t as recent as ADHD, and it is nowhere near the level of misdiagnosis. With ADHD the symptoms echo so many other things that can go on that it's ripe for mistakes. Bipolar is the other direction, and often completely missed. However, there is an additional complication similar to ADHD where we should be asking if we even have this right in the first place - more on that after the break.
So what we do have - to cite Harrison, Geddes, and Tunbridge we have evidence for seeing variances in both brain structure and connectivity, we also see changes chemically, changes with mitochondrial function, great variances with circadian rhythms, and some adjustment to neurotransmitters but “it remains difficult to integrate these diverse findings, and to disentangle causative changes from those that are secondary to the disorder and its treatment”.
But let's get into what has been researched.
Variance in Brainwaves
Dzirasa, McGarity, Bhattacharya, Kumar,1. Takahashi, Dunson, McClungn, and Nicolelis
Remember from ADHD where we talked about neural networks - similar thought here. We are seeing neural networks that help generate perception and behavior. There are studies looking at the outlet later of the cerebrum (topmost part of the brain) and areas deep within the brain having shared activity of neurons, such as the area impacted by scent and the area we think of for memories being activated to develop memory and then engage with the prefrontal cortex help humans determine where they are and how to find a home.
Choir - right - basses start to sing with the altos and the soprano takes over and says ‘that way”
The NAC - N-Acetyl Cysteine (something in your brain to regulates neurotransmitters) receives afferent projections from your basal amygdala and ventral tegmental area (also midbrain) midbrain equals fear and safety. If your NAC is impacting this could make modulation of decision choices hard, and they are seeing some evidence that this is lower than normal both defined by this study and an earlier study. They are specifically looking at this because of its focus on circa-dum rhythms. This potentially impacts a higher desire for drugs, decreased need to sleep, and wanting new and exciting things to happen. Can also increase hyperactivity or depression as hypothesized.
Macrophages and HPA Axis
Ferrari, et all stated that there is “Emerging evidence has shown that bipolar disorder is accompanied by the activation of immune-inflammatory pathways”. Specifically looking at macrophages which are responsible for immune response, arguing that this and microglia increase inflammation which can lead to bipolar disorder. Specifically stating that this is due to “chronic activation and desensitization of the hypothalamic-pituitary-adrenal axis (HPA), and related to the susceptibility of patients to stress”. Stress as we know is bad for you, due to the cortisol that is released which is toxic, and they are arguing that this is impacting the HPA axis, however own that their sample size is small and their patients were medicated, making this harder to research.
HCRTs
Schmidta, Brügelb, Kratzschb, Straußa, Sandera, Baumc, Thieryb, Hegerla, and Schönknechta argue that this is a loss of hypocretins (hcrt’s). Hypocretins are hypothalamic neuropeptides - important with sleep and feeling alteration. They argue this is what is throwing off the circadian rhythm clock, and state this causes a switch between states of vigilance and hyperarousal. They are also arguing this is impacted due to a key role in reward-seeking and addictive behavior.
Calcium signaling
Harrison, Geddes, and Tunbridge argue that bipolar disorder is due to “at least in part, an ion channelopathy, in which aberrant calcium signaling is important” specifically because this is impacted by lithium, which is used in the treatment of the disorder and has results that this impacts the disorder in some way. =
BDNF
Sousaa, van de Bilt a, Diniza, Ladeiraa, Portelab, Souzab, Forlenzaa, Gattaza, and Machado-Vieiraa looked at BDNF or brain-derived neurotrophic factor is a molecule found in the hippocampus, amygdala, cerebellum, and cerebral cortex. Plays a major role in neuroplasticity and strengthening the connection between neurons. They state that in bipolar disorder, lower BDNF levels were seen in both depressive and manic episodes, specifically impacting severity. An increase in BPDF showed improvement in manic symptoms, an increase in gray matter, and better cognitive function. Lithium can impact BDNF, helping to regulate this.
Amodeo, Grospe, Zang, Dwivedi, and Ragozzino are also some of the many who argue that BDNF is the thing to look at. Specifically, this study was treating this with ouabain, a toxin found in Africa used in hunting and warfare, and found BDNF levels impacted causing an impact on behavior.
Kirshenbaum, Burgess, De’Ry, Fahnestock, Peever, and Roder looked at the fact that an increase in BDNF seems to induce mania and argued that BDNF is the cause of it. They looked at this in mice, specifically looking at the positive impact of melatonin in bipolar, helping with circa-dum rhythms as well, specifically in conjunction with other therapies as a lack of sleep exacerbates symptoms while increased sleep helps decrease the symbology. They also looked at how exercise can increase BDNF in your hippocampus which is positively impacting mood.
The dorsal lateral and prefrontal cortex
Clark and Sahakian looking at bigger parts of the brain argue that your dorsolateral and ventrolateral prefrontal cortex are impacted as people with bipolar show issues with executive function. They are looking at this area as there is often an issue with attention shifting which as we remember from a few episodes this season, dorsal lateral is often a manager - helping your brain determine what to focus on. Specifically, they are focused on ‘cold executive processing’ from the dorsal lateral and ‘hot processing’ from the orbital prefrontal. Looking at emotions, decision making, and impulse control - areas we see people in manic episodes specifically struggling with. They state they see this in postmortem studies of people with bipolar. Specifically, the anterior cingulate cortex is reduced in these brains, and gray matter reduction in the prefrontal cortex. They also looked at functional imaging studies seeing a reduction in blood flow around the orbital frontal. And “blunted activation of the right lateral orbital frontal cortex” which means there is less control of a human’s inhibitions.
In bipolar depression, we see a decrease in prefrontal activity and an increase in amygdala activation.
However there is a significant lack of research data on bipolar depression.
Frangou also reports on the ventrolateral prefrontal cortex and anterior cingulate cortex, specifically looking at a connection between bipolar disorder and schizophrenia, looking at distortions in reality. Also cites dorsal lateral for executive functional issues and ‘task dependent networks’ impacted by the prefrontal cortex and amygdala activity, and that this is increased in bipolar.
Fragou also looks at neural networks but states the most evidence we have is for a neural network impacted by every neuropsychiatric condition including (but not limited to) TBI, Alzheimer's, etc. but also states “It was assumed until recently that the component mental processes of cognitive control were realized within topographically distinct regions or networks. Attempts to map these networks have generated an expansive body of evidence which, however, points to a domaingeneral, superordinate cognitive control network.” and “Substantial evidence points to the involvement of multiple large-scale neural networks and alterations in local microscale circuitry within associative and sensory cortices. Nonetheless, a fully mechanistic description of either psychotic disorder remains elusive.”
So that’s a lot. Simplified it is ‘it's complicated and we don’t really know”. As we’ve discussed, neural networks are harder for us to study at this point, which adds to it. Also, this is underdiagnosed. Also, this is a diagnosis to be taken seriously. As we discussed in the beginning we are seeing two things - either high levels of mania to the point of possible psychosis- needing to be hospitalized - that comes with a risk to self and others and/or a high risk of depression which increases suicide risk - so another major complication is how do you ethically study this without having patients who are medicated.
Bora argues that there are several limitations. There’s a lack of information on too many variables including but not limited to drugs, alcohol use, and medication impact. “It is not possible to conclude whether cognitive differences between subtypes of BD pre-existed before the first episode or emerged after the onset of illness. Also, it was not possible to investigate the subdomains of social cognition as a number of studies were not sufficient.” and argues “The use of data-driven and advanced statistical methods using clinical, neurobiological and genetic data might be necessary to distinguish true subtypes of BD.”
I would add one other complication. We have a lot of similar but not quite the same symptomology locked into a diagnosis.
Think of the way mental health diagnoses are created - unlike most other medical diagnosis
How much have we gotten wrong
If we get the dx wrong - how do we do accurate research on it
We want to learn WHY we do what we do as humans, and we’ve looked to the brain for explanations…
**BREAK**
PART 4: TAKEAWAYS (10-15 minutes)
Harrison, Geddes, and Tunbridge state bipolar disorder illustrates “how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches. These developments exemplify how genomics, neuroscience, and digital technologies are heralding a new era for psychiatry.”
Harrison, Geddes, and. Tunbridge state that the increase of technology is allowing for better, more accurate research into symptomology- helping with remote capture of both self-reported symptoms as well as with medical smart devices adding in data of heart rate, human location, activity and other things for the environment that allow for more information. This could lead us to more data-driven information which increases objectivity and allows for more personalized prediction. However, this is still coming. “Although the work is at an early stage, it is likely ultimately to alter the view of the core phenotype of BD, with a greater role for biological and quantitative data in BD diagnosis, prognosis, and management.”
Also, they argue for the need to know about more genomics to assist with earlier and more accurate diagnoses, which will also help with more accurate research, as well as better outcomes for the patient.
“Possible changes include redrawing or removing the diagnostic boundaries between BD and other disorders involving lability of mood, emotion, and behavior; the inclusion of behavioral and physiological correlates of mood and mood instability (or other symptoms) into clinical practice; a focus on identifying interventions that can stabilize mood independent of the underlying diagnosis; and new, genetically informed treatments”.
They argue a need for additional research stating “It is not always appreciated that BD causes a global health burden comparable with that of schizophrenia, yet it has attracted considerably less research funding and interest from policymakers” and state “We would argue that, for various reasons, BD currently has a greater potential for transformative advances. More generally, BD is a useful case study for illustrating how psychiatric disorders are belatedly embarking on the journey from being descriptive syndromes towards more neurobiologically grounded, quantitative, and digital phenotypes”
Frangou Argues more research on things like bipolar could help create more of an error where neuroscience is more employed to help with psychiatric disorders, but we need to go that route to get there.
