Pathophysiology and Neurocognition of Bipolar Disorder

Bipolar disorder is a chronic condition characterized by recurrent episodes of mania and depression. These symptoms have clear and obvious impacts on cognition which in turn can severely impact relationships, yet the disorder itself is difficult to pin a diagnosis on. Patients frequently present their symptoms first to primary care, but the range of symptoms and the diversity in the potential causes for these symptoms lead to misdiagnosis in many patients in addition to bipolar disorder being able to co-occur with other psychiatric conditions.

Where mania includes distractibility, inappropriate speech and behaviors, uncharacteristic goal-oriented actions, and impulsive decision making that results in negative consequences, depressive episodes demonstrate themselves in the opposite fashion. A depressive state could include difficulty making decisions, slow motor processes, cognitive changes, and alterations in memory.

Bipolar disorder can be divided into bipolar I ad bipolar II disorder. Specifically, both disorders have similar degrees of depressive episodes, but bipolar I disorder has more impairing manic episodes. Still, psychologists and psychiatrists consider both illnesses to be equally severe as both are equally likely to present suicidal thoughts or result in suicide. This drastic range of symptoms makes bipolar disorder, especially when a patient presents on one end of the spectrum more than the other is what makes accurate diagnosis difficult. Bipolar disorder is commonly misdiagnosed as major depressive disorder because manic episodes can be perceived as productive or a remissive state in comparison to depressive states or may appear less frequently to be a concern or noticeable.

Detecting alterations in the brain that accompany the multiple states of bipolar disorder could spare patients significant amounts of psychological stress. Accurate diagnostics are important to provide effective therapy and medication regimes rather than patients only receiving correct care for one portion of their diathesis.

Characterizing the profile of brain dysfunction in bipolar patients can also help improve pharmacological treatment and allow for individuals to be tested for neurochemical markers in patients at risk of having or developing bipolar disorder. Trait markers in diagnosing bipolar disorder implies that these cognitive variables may be representative of genetic factors influencing internal phenotypes where protein synthesis, transportation, and cell signaling in the brain that impacts how different structures communicate with each other. Understanding the biochemistry can also allow for better assessment of progressive changes or of need for acute intervention. 

Research and investigation of the causes of the associated symptoms with bipolar disorder has been difficult, especially in evaluating its significance. Firstly, because it is a paired-state illness comprised of episodes varying in severity and symptoms. Secondly, its periods of remission in one state can be accompanied by an ongoing presence of the other state. Meaning both states can be present and functional at the same time.

This contrasts with the original concept of bipolar disorder, the Kraepelinian concept, because there is no period of recovery in between episodes. This complicates the way bipolar disorder is profiled in the medical field. Because the cognitive function is disrupted in both episodes to opposite extremes, they may be affected differently by either the same or different variables at the same or different time. This makes genetic studies drastically more complex because opposite symptoms can be caused by similar proteins or ligands but by correcting for those mutations in protein synthesis, other symptoms associated with bipolar disorder may become more severe.

By understanding these symptoms, researchers deduced that bipolar disorder, or some aspects of it, come from an abnormality in the limbic system, made up of the amygdala, the hippocampus, the hypothalamus, and other surrounding complex structures, the frontal lobe, and the basal ganglia because these structures influence the functions of bipolar disorder. 

Regulation of neurocognition, such as attention, executive function, and emotional function is widely impaired in manic episodes of bipolar disorder compared to depressive episodes. Changes in attentional function were analyzed by the patient’s ability to be flexible and selective in how they process information. While both groups had a deficit compared to the control group, research showed sustained attention can be impaired more than depressive patients.

Studied with continuous cognitive performance tests, bipolar subjects tended to do worse in detecting targets and progressing in their tasks while also demonstrating the highest amounts of false alarms. This data remained consistent when manic patients were in a euthymic state. This could be attributed to impulsivity and a lack of cognitive inhibition symptomatic of mania.

Behavior and behavioral habits, such as planning, strategy, and control are enabled by executive functions and higher-level processing. The executive function of planning and strategy is a “cold” process linked to the dorsal and lateral prefrontal cortex. Processes considered “hot”, risk-reward behavior and impulse control, are regulated by the orbital prefrontal cortex, and when this region is damaged patients show uncharacteristic reward-driven and impulsive behavior.

The integrity of the frontal lobe, or lack of, could impact someone’s functional capacities and quality of life. This impaired function is consistent between manic and depressed states but is sensitive to which mood state and symptoms in presenting severity because, in remission phases, patients can still experience physical trait related symptoms while there is no evidence of neurochemical symptoms. In determining these differences between manic and depressed states, there is a significant variation in performance.

Depressed patients tended to text better on error margins but answered questions slower. Patients in remission states consistently scored higher. These conclusions are definitive of bipolar disorder having a state-changing profile, but because of the limited testing, it is unsure of whether hot processing impairment is unique to manic episodes.

Though neuroimaging is indirect, it is a valid measure in research that is inexpensive and readily available in a hospital setting to provide an efficient diagnosis. Current neurophysical testing measures brain activity based on neuroimaging to provide indirect measurements in how bipolar disorder impacts brain function. Determining the profile of brain dysfunction in bipolar disorder, in general, has been delayed by certain factors.

Earlier neurobiological research in bipolar disorder has consistently failed to control for substance use or affective symptoms like insomnia. They also did not differentiate between state-related differences. Relatively, the functions disrupted in different cognitive domains affected by bipolar disorder like attention, executive processing, and emotional processing are influenced by the varying states and displayed traits of bipolar disorder.

Brain imaging of structural components active in the functional markers for bipolar disorder supports studies of neurocognition in the prefrontal cortex, like those mentioned above. Classic studies performed on patients with abnormal mood and personality disturbances, like depression consequential of a stroke or tumor, reported damage to the left frontal cortex and the left basal ganglia. Other patients with damage to their basal ganglia, like Parkinson’s disease, are more prone and have more severe levels of depression compared to other patients matched for level of disability; the only difference being basal ganglia damage.

Cases of mania are less common poststroke but report damage to the right areas of the same structures. This demonstrates the connectivity of the frontal cortex and basal ganglia. Therefore, the frontostriatal circuitry, which connects the two structures electrically, is thought to attribute executive and emotional functions. Structural MRIs have confirmed structural abnormalities in the prefrontal cortex of the brain in patients with bipolar disorder postmortem. In both episode states and euthymic states, euthymic meaning asymptomatic, MRI scans pick up abnormal brain function. The grey matter in the anterior subgenual portion was visibly smaller in patients who had bipolar disorder and a family history of mental illness.

Functional imaging studies in bipolar patients during manic episodes, and patients with mania, had indicated a dysfunctional orbitofrontal cortex with reduced blood flow and metabolism. These studies are important to patients with bipolar disorder, and other patients with similar affective disorders, because it means that these disorders have neurophysical cause outside of psychological triggers.

However, these studies in neuroimaging were performed while patients were at rest, so it isn’t possible to control for what the patients were thinking. For example, more activity could be related to impulsive or intrusive thoughts in manic states. In response, recent work has turned to scanning patients during tasks that require neuropsychological processes to analyze the related brain activity, like decision making. In a study performed by Dr. Judy Rubinsztein, manic patients were scanned while performing a gambling task and matched to a control task. 

In Rubinsztein’s study, manic patients had fewer areas of their brain active during decision making, and depressive brains had less electrical activity during decision making. In a similar task manic patient matched with a healthy control group demonstrated significantly less activation of a region thought to be critical for inhibitory control, the orbitofrontal cortex, along with reduced activity in the ventrolateral prefrontal cortex.

This implicates that manic patients demonstrated less nonemotional control in their impulsivity control. They also showed increased activity in the medial orbitofrontal cortex with the presence of positive distractors, like being ignored, which is a control structure in impulsive control. This conglomerate of data indicates the pathophysiology of manic episodes in bipolar disorder is less of an inactive impulsivity control and, more accurately, a dysfunction in emotional processing. 

Other studies using emotional tasks reported unusually high limbic activity in patients with bipolar disorder when asked to analyze facial expression. High limbic activity was also reported in studies where performance in a task requiring sustained attention was tested. The results of these tests suggest that patients with bipolar disorder use emotional systems when processing information that is otherwise emotionally neutral.

These results were also significantly similar in patients who used were currently mood stabilizers at the time of testing. These highlighted similarities in subcortical activity are consistent with patients who were tested in remission, or resting phases, and therefore, can be used to differentiate patients who have bipolar disorder and major depressive disorder. Still, there is a need for further studies in comparing neural activity between bipolar states and depressive disorders. 

Conglomerate evidence from this array of neurocognitive testing is indicative of neuropsychological and neurochemical impairment in patients with bipolar disorder. Complimentary studies in brain imaging reliably demonstrate that cognitive deficits may be attributed to pathophysiology in neural networks between the frontal lobe and subcortical limbic regions, yet the challenge remains in identifying objective markers making definite diagnosis elusive

 Promising findings have determined neuroimaging measures that aid in differentiating between bipolar and unipolar disorders as well as identifying neural circuit patterns that can potentially classify the severity of a patient’s bipolar disorder. Genetic research is imperative in moving forward in identifying and treating bipolar disorder because it ultimately has the most potential in making uniquely target treatments feasible for all affective disorders.

References

Clark, L., & Sahakian, B. J. (2008). Cognitive neuroscience and brain imaging in bipolar disorder. Dialogues in clinical neuroscience, 10(2), 153–163.

Culpepper L. (2014). The diagnosis and treatment of bipolar disorder: decision-making in primary care. The primary care companion for CNS disorders, 16(3), PCC.13r01609. doi:10.4088/PCC.13r01609

Manji, H. K., Quiroz, J. A., Payne, J. L., Singh, J., Lopes, B. P., Viegas, J. S., & Zarate, C. A. (2003). The underlying neurobiology of bipolar disorder. World psychiatry: official journal of the World Psychiatric Association (WPA), 2(3), 136–146.

Phillips, M. L., & Kupfer, D. J. (2013). Bipolar disorder diagnosis: challenges and future directions. Lancet (London, England), 381(9878), 1663–1671. doi:10.1016/S0140-6736(13)60989-7

Singh, T., & Rajput, M. (2006). Misdiagnosis of bipolar disorder. Psychiatry (Edgmont (Pa.: Township)), 3(10), 57–63.