Emotional dysregulation and impaired stress response, other important features of bipolar disorder , may be caused by disturbances in corticotropin metabolism and dysfunction in the hypothalamic–pituitary–adrenal axis . Interestingly, a recent rat model study demonstrated significant long-term loss, shrinkage of cell soma size, and axonal degeneration of corticotropin-releasing factor-positive neurons in the amygdala following neonatal hypoxia–ischaemia . These changes were associated with increased locomotor activity and exploratory behaviour , behavioural abnormalities that are also observed in patients with bipolar disorder . Moreover, increased anxiety has been reported following perinatal asphyxia and is associated with dopamine-innervated neurocircuitries in the amygdala, among other structures . Dopaminergic pathways are particularly vulnerable to perinatal asphyxia , and are also involved in the pathophysiology of psychotic disorders . Taken together, it seems biologically plausible that perinatal asphyxia is associated with long-term alterations in the structure of the amygdala, as our results suggest. Such alterations may be functionally associated with the distinct behavioural abnormalities observed in bipolar disorder. Instead of confirming our initial hypothesis that the associations between perinatal asphyxia/severe OCs would be stronger in patients with psychotic than non-psychotic bipolar disorder, the results indicate different patterns of associations in psychotic versus non-psychotic bipolar disorder. Within a psychosis continuum, psychotic bipolar disorder would be considered to be closer than non-psychotic bipolar disorder to schizophrenia. In schizophrenia, smaller hippocampal volumes have been associated with preand perinatal trauma . Surprisingly, we found no associations between severe OCs or perinatal asphyxia and smaller hippocampal volume in patients with psychotic bipolar disorder,agriculture vertical farming but we did find such associations in patients with non-psychotic bipolar disorder.
The biological validity of this association is, nevertheless, supported by the literature. First, animal models have demonstrated the pyramidal neurons within the hippocampus to be sensitive to prenatal hypoxia . Second, in the human neonate, hippocampal neurocircuitries are reported to be particularly vulnerable to hypoxia , and, third, healthy adolescents who have suffered perinatal asphyxia exhibit reduced hippocampal volumes . Based on these findings, one could expect to find associations between perinatal hypoxia or severe OCs and hippocampal volume in the healthy controls as well, as we did in a previous study of schizophrenia patients and healthy controls . The hippocampus is, however, one of the brain regions in which neurogenesis occurs , and the number of hippocampal neurons , as well as the hippocampal volume as measured by MRI , might increase in response to different training tasks. On the other hand, hippocampal volume may be reduced in alcohol dependence and heavy cannabis use , as well as in several mental disorders including schizophrenia , unipolar depression and bipolar disorder , although we did not confirm the latter in this study. As such, a variety of factors may confound and interfere with putative associations between pre- and perinatal trauma and adult hippocampal volume. The number of possible known and unknown confounders not accounted for constitute one limitation in the current study. Although we did control for current lithium use, which is known to affect hippocampal and amygdala volumes in bipolar disorder, we did not have reliable data on cumulative medication use. Another possible limitation to the generalizability of the current study is the inclusion of patients across mood states, i.e. depression, mania/hypomania, and euthymia, since it has been suggested that amygdala volume may fluctuate across mood states . Third, the subject groups were relatively small when the bipolar disorder group was split into psychotic and non-psychotic subgroups, which may have caused type II errors within the statistical analyses. Finally, by studying severe OCs, and comparing subjects with them versus all other subjects , we placed high demands on the strength of the relationship, and may have missed possible associations between brain structure and less severe OCs.
Strengths of the current study include the use of unbiased birth registry data, thorough clinical characterization of participating subjects, and the use of one MRI scanner with no upgrades during the study period. In summary, we report perinatal asphyxia to be related to smaller amygdala volume in patients with bipolar disorder. This suggests a neurodevelopmental component in the brain morphology of bipolar disorder. The different associations between preand perinatal complications and brain morphology observed in patients with psychotic and non-psychotic bipolar disorder, as well as their possible functional consequences, warrant further investigation.Treatments for bipolar disorder have been very limited and no novel therapeutics specifically for BD have been developed in a long time. Treatments that target the neural circuitry specifically affected in BD patients are urgently required in order to ameliorate the symptoms of this disorder.It is characterized by episodes of mania and depression, with periods of absence of symptoms that meet diagnostic criteria for mania or depression in-between . The symptomatology of BD is heavily dependent on the state in which patients present. Mania includes long periods of euphoria, reduced sleep, hypersexuality, extreme irritability, racing thoughts, aggression, hedonic behavior, and hyperactivity, which is a conspicuous feature during acute manic states . Indeed, the latest edition of the Diagnostic and Statistical Manual of Mental Disorders states that changes in activity and energy are required for diagnosis of a manic episode in addition to an ‘increase in goal-directed activity’ or ‘psychomotor agitation’ . Symptoms of depression are largely the opposite and consist of long periods of dysphoria, reduced libido, increased sleep, feeling tired or ‘slowed down’, anhedonia, and greater risk of suicide. Bipolar depression is differentiated from unipolar depression or major depressive disorder diagnostically by the requirement of at least one manic or hypomanic episode for BD diagnosis . In addition to mood and behavioral changes, patients with BD also suffer from a variety of neurocognitive deficits in domains such as executive functioning, vigilance, impulsivity, and decision-making .
Although BD has typically been described as a mood disorder, these cognitive impairments are irrefutably important since they correlate closely with a patient’s functional outcome . Hence, by understanding and improving cognitive function, the patient’s quality of life will likely improve. Untreated or poorly maintained BD can be devastating to the quality of life of patients and their families. Treatments that are commonly used include the mood stabilizer lithium, anticonvulsants such as valproate and lamotrigine, and several antipsychotics . None of these treatments completely stabilize behavior nor improve cognitive functioning. In fact, current treatments, particularly lithium, can worsen cognitive functioning and ingenuity . Hence, increased creativity and individuality felt by many people with BD are eroded by these treatments, limiting adherence compliance . Instead of using generic ‘band aid’ treatments for subduing behavior, developing targeted treatments for problematic symptoms experienced by BD patients would likely generate better treatment outcomes and adherence. Indeed, none of the currently approved treatments were developed with BD as a target, but were in fact discovered serendipitously . Together with the symptoms suffered by patients, these poor treatment options contribute to an increased suicide mortality rate ; recent estimates indicate that one in three BD patients attempt suicide . Novel therapies based on the underlying mechanisms of abnormal behavior in BD patients are urgently required to improve quality of patient care. Both in vitro and in vivo preclinical studies play essential roles in the discovery of novel targets to develop useful therapeutic outcomes. Modeling the abnormal behaviors present in people with BD across different species remains a challenging task . The complexity of the abnormal behaviors in patients both within and between bipolar states makes modeling BD extremely difficult. Even targeting a single behavioral abnormality can be challenging; for example,china vertical farming racing thoughts or hopelessness is measured using questionnaires in humans, which would be impossible to mimic in rodent studies. The limitations of mimicking psychiatric illnesses in non-human mammals has resulted in the frequent simplistic use of increased motor activity as a primary measure of animal models of BD mania . Besides activity, other relevant BD behaviors modeled in animals include aggression, hypersexuality, hedonia-like behavior, inattention, and risk-taking or decision-making . The use of a comprehensive sequence of tests assessing different BD-like behaviors – instead of focusing on one aspect of the illness – can aid the identification of global mechanisms underlying symptoms as well as treatments . Combining this approach with the reverse-translational behavioral tasks that characterize behaviors from patients to rodents and vice versa would likely yield more relevant information . The majority of approaches used in the field still tend to focus on the assessment of relative basic behaviors in rodents. The observations of simple behaviors in rodents have limited validity with regards to modeling human behaviors often interpreted from self-report measures . More elaborate tasks provide a high-quality method to quantify behaviors exhibited by BD patients in a laboratory setting and subsequently assess such behaviors in rodents. Therefore in this review, we will describe models of BD that specifically utilize translationally relevant tasks. While the use of basic tests with little specific relevance to abnormal patient behavior can be useful as a first pass in the screening of rodent models for BD, our focus will be placed on tasks that exist in both humans and animals from which direct comparisons of behavior performance can be made. Several lines of research have begun to utilize this methodology, resulting in promising behavioral paradigms in humans and rodents. Indeed, this translational approach is being used in other disorders as well, such as HIV and methamphetamine dependence , schizophrenia , and other substance use disorders . Here, the quantification of abnormal behavior in BD and attempts to recreate these behaviors in etiologically relevant models will be discussed. This review provides an invited summary of research presented as a Keynote Lecture at the International Behavioral Neuroscience Society in 2014, highlighting our laboratory’s approach toward delineating the neural mechanisms underlying BD. Mechanisms underlying the complex umbrella of symptoms in BD are as yet unresolved, complicating targeted treatment development. Nevertheless, several mechanisms have been elucidated that likely mediate both states of mania and depression in BD. The catecholaminergic-cholinergic balance hypothesis of BD states that functional levels of catecholamines are increased during manic states, whereas increased cholinergic functioning is more relevant to depression .
Among the catecholamines, dysfunctional dopamine neurotransmission is recognized to be a central factor in the pathophysiology of BD . The DA transporter is the primary reuptake mechanism of extracellular DA by which homeostasis is maintained . Polymorphisms in the gene encoding for DAT have been associated with BD , although these results have not been replicated in every genome wide association study . SNPs can reduce cell surface migration of DAT , down-regulating its functional expression. Subsequently, reduced striatal DAT levels have been observed in drug-free depressed and euthymic BD patients and in the postmortem tissue of BD patients . On the other hand, higher DAT binding has also been observed in the striatum of medicated depressed and unmedicated euthymic BD patients. Another symptom associated with BD is an abnormal circadian rhythm . For instance, altered rhythms in physiological parameters such as body temperature, plasma cortisol, and melatonin have been observed in patients with depression and BD , who also often experience altered sleep-wake cycles. Altered circadian rhythms can influence the release, synthesis, and levels of neurotransmitters such as DA . Taken together, these mechanistic findings provide targets which can be used to aid the development of animal models as well as treatments for BD.Previously, we described how increased motor activity and exploratory behavior described in patients with BD could be characterized using a multivariate translational approach called the human behavioral pattern monitor . In brief, the human BPM consists of a room that is novel to the test subjects and contains furniture and several items placed around the room to encourage exploration . Subjects are asked to wait in the room with no specification of the duration, unaware of simultaneously being tested on several ambulatory parameters. By measuring exploratory behavior of patients in this novel environment, a unique pattern of activity and exploration of manic and euthymic BD patients was identified. This abnormal exploratory pattern exhibited by BD patients included hyperactivity, increased specific exploration, and more linear patterns of movement, which importantly differed from control subjects , adult attention deficit hyperactivity subjects , and patients with schizophrenia . Because the human BPM was developed using a “reverse-translational” approach based on the BPM originally designed for testing rats or mice , it has been possible to examine mechanisms that underlie this specific pattern of exploration using the same manner of assessment of locomotor exploration in rodents. In brief, the BPM for rodents consists of a Plexiglas arena containing both floor and wall holes .