Brook L. Henry

A reverse translational study of dysfunctional exploration in psychiatric disorders: from mice to men

CONTEXT Bipolar mania and schizophrenia are recognized as separate disorders but share many commonalities, which raises the question of whether they are the same disorder on different ends of a continuum. The lack of distinct endophenotypes of bipolar mania and schizophrenia has complicated the development of animal models that are specific to these disorders. Exploration is fundamental to survival and is dysregulated in these 2 disorders. Although exploratory behavior in rodents has been widely studied, surprisingly little work has examined this critical function in humans. OBJECTIVES To quantify the exploratory behavior of individuals with bipolar mania and schizophrenia and to identify distinctive phenotypes of these illnesses. DESIGN Static group comparison by the use of a novel human open field paradigm, the human Behavioral Pattern Monitor (BPM). SETTING Psychiatric hospital. PARTICIPANTS Fifteen patients with bipolar mania and 16 patients with schizophrenia were compared with 26 healthy volunteers in the human BPM. The effects of amphetamine sulfate, the selective dopamine transporter inhibitor GBR12909, and the genetic knockdown of the dopamine transporter were compared with controls in the mouse BPM. MAIN OUTCOME MEASURES The amount of motor activity, spatial patterns of activity, and exploration of novel stimuli were quantified in both the human and mouse BPMs. RESULTS Patients with bipolar mania demonstrated a unique exploratory pattern, characterized by high motor activity and increased object exploration. Patients with schizophrenia did not show the expected habituation of motor activity. Selective genetic or pharmacologic inhibition of the dopamine transporter matched the mania phenotype better than the effects of amphetamine, which has been the criterion standard for animal models of mania. CONCLUSIONS These findings validate the human open field paradigm and identify defining characteristics of bipolar mania that are distinct from those of schizophrenia. This cross-species study of exploration calls into question an accepted animal model of mania and should help to develop more accurate human and animal models, which are essential to the identification of the neurobiological underpinnings of neuropsychiatric disorders.

The Effect of Lateral Septum Corticotropin-Releasing Factor Receptor 2 Activation on Anxiety Is Modulated by Stress

Corticotropin-releasing factor (CRF), a 41 amino acid peptide, mediates endocrine, autonomic, and behavioral responses to stress. Whereas the CRF1 receptor appears to contribute to anxiety associated with stress, the role of the CRF2 receptor remains unclear and may depend on drug dose, brain location, or testing environment. Results involving treatments with selective CRF2 receptor agonists or antagonists and the behavior of CRF2 receptor knock-out mice suggest both anxiogenic and anxiolytic effects of CRF2 receptor activation. The present study tested the hypothesis that the effect of CRF2 receptor activation on anxiety depends on the stress level of the animal. The selective CRF2 receptor agonist urocortin 2 was infused into the lateral septum of mice under low- or high-stress (30 min of immobilization) testing conditions, and then behavior in the light–dark box, open-field, and novel-object tests was assessed. In the low-stress environment, 240 pmol of septal urocortin 2 increased anxiety, but lower doses (0.48, 4.8, and 48 pmol) did not have consistent effects. However, in the high-stress condition, 48 pmol of septal urocortin 2 significantly increased anxiety compared with control in wild-type but not CRF2 receptor knock-out mice in the light–dark box. Septal administration of the relatively selective CRF2 antagonist astressin-2B, but not the CRF1- selective antagonist antalarmin, blocked the anxiogenic effects of urocortin 2. Urocortin 2 infusion into the medial septum or lateral ventricle did not affect anxiety measures. These results indicate that the effect of septal CRF2 receptor activation on anxiety is dependent on stress level.

Heart rate variability in bipolar mania and schizophrenia.

BACKGROUND Autonomic nervous system (ANS) dysfunction and reduced heart rate variability (HRV) have been reported in a wide variety of psychiatric disorders, but have not been well characterized in bipolar mania. We recorded cardiac activity and assessed HRV in acutely hospitalized manic bipolar (BD) and schizophrenia (SCZ) patients compared to age- and gender-matched healthy comparison (HC) subjects. METHOD HRV was assessed using time domain, frequency domain, and nonlinear analyses in 23 manic BD, 14 SCZ, and 23 HC subjects during a 5min rest period. Psychiatric symptoms were assessed by administration of the Brief Psychiatric Rating Scale (BPRS) and the Young Mania Rating Scale (YMRS). RESULTS Manic BD patients demonstrated a significant reduction in HRV, parasympathetic activity, and cardiac entropy compared to HC subjects, while SCZ patients demonstrated a similar, but non-significant, trend towards lower HRV and entropy. Reduction in parasympathetic tone was significantly correlated with higher YMRS scores and the unusual thought content subscale on the BPRS. Decreased entropy was associated with increased aggression and diminished personal hygiene on the YMRS scale. CONCLUSION Cardiac function in manic BD individuals is characterized by decreased HRV, reduced vagal tone, and a decline in heart rate complexity as assessed by linear and nonlinear methods of analysis. Autonomic dysregulation is associated with more severe psychiatric symptoms, suggesting HRV dysfunction in this disorder may be dependent on the phase of the illness.

Predictive animal models of mania: hits, misses and future directions.

Mania has long been recognized as aberrant behaviour indicative of mental illness. Manic states include a variety of complex and multifaceted symptoms that challenge clear clinical distinctions. Symptoms include over‐activity, hypersexuality, irritability and reduced need for sleep, with cognitive deficits recently linked to functional outcome. Current treatments have arisen through serendipity or from other disorders. Hence, treatments are not efficacious for all patients, and there is an urgent need to develop targeted therapeutics. Part of the drug discovery process is the assessment of therapeutics in animal models. Here we review pharmacological, environmental and genetic manipulations developed to test the efficacy of therapeutics in animal models of mania. The merits of these models are discussed in terms of the manipulation used and the facet of mania measured. Moreover, the predictive validity of these models is discussed in the context of differentiating drugs that succeed or fail to meet criteria as approved mania treatments. The multifaceted symptomatology of mania has not been reflected in the majority of animal models, where locomotor activity remains the primary measure. This approach has resulted in numerous false positives for putative treatments. Recent work highlights the need to utilize multivariate strategies to enable comprehensive assessment of affective and cognitive dysfunction. Advances in therapeutic treatment may depend on novel models developed with an integrated approach that includes: (i) a comprehensive battery of tests for different aspects of mania, (ii) utilization of genetic information to establish aetiological validity and (iii) objective quantification of patient behaviour with translational cross‐species paradigms.

The quantitative assessment of motor activity in mania and schizophrenia

BACKGROUND Increased motor activity is a cardinal feature of the mania of Bipolar Disorder (BD), and is thought to reflect dopaminergic dysregulation. Motor activity in BD has been studied almost exclusively with self-report and observer-rated scales, limiting the ability to objectively quantify this behavior. We used an ambulatory monitoring device to quantify motor activity in BD and schizophrenia (SCZ) patients in a novel exploratory paradigm, the human Behavioral Pattern Monitor (BPM). METHOD 28 patients in the manic phase of BD, 17 SCZ patients, and 21 nonpatient (NC) subjects were tested in the BPM, an unfamiliar room containing novel objects. Motor activity was measured with a wearable ambulatory monitoring device (LifeShirt). RESULTS Manic BD patients exhibited higher levels of motor activity when exploring the novel environment than SCZ and NC groups. Motor activity showed some modest relationships with symptom ratings of mania and psychosis and was not related to smoking or body mass index. LIMITATIONS Although motor activity did not appear to be impacted significantly by antipsychotic or mood-stabilizing medications, this was a naturalistic study and medications were not controlled, thus limiting conclusions about potential medication effects on motor activity. CONCLUSION Manic BD patients exhibit a unique signature of motoric overactivity in a novel exploratory environment. The use of an objective method to quantify exploration and motor activity may help characterize the unique aspects of BD and, because it is amenable to translational research, may further the study of the biological and genetic bases of the disease.

Quantifying over-activity in bipolar and schizophrenia patients in a human open field paradigm

It has been suggested that a cardinal symptom of mania is over-activity and exaggerated goal-directed behavior. Nevertheless, few attempts have been made to quantify this behavior objectively in a laboratory environment. Having a methodology to assess over-activity reliably might be useful in distinguishing manic bipolar disorder (BD) from schizophrenia (SCZ) during highly activated states. In the current study, quantifiable measures of object interaction were assessed using a multivariate approach. Additionally, symptom correlates of over-activity were assessed. Patients admitted to an acute care psychiatric hospital for either BD with mania or SCZ (paranoid and non-paranoid subtypes) as well as non-patient comparison (NC) participants were assessed in an open field setting referred to as the human Behavioral Pattern Monitor (hBPM). Activity and interactions with novel and engaging objects were recorded for 15min via a concealed video camera and rated for exploratory behavior. Both BD and SCZ patients spent more time near the objects and exhibited more overall walking compared to NC. In contrast, BD patients exhibited greater physical contact with objects (number of object interactions and time spent with objects) relative to SCZ patients or NC participants, as well as more perseverative and socially disinhibited behaviors, indicating a unique pattern of over-activity and goal-directed behavior. Further analyses revealed a distinction between SCZ patients according to their subtype. The current study extends our methodology for quantifying exploration and over-activity in a controlled laboratory setting and aids in assessing the overlap and distinguishing characteristics of BD and SCZ.

Effect of Methamphetamine Dependence on Everyday Functional Ability

BACKGROUND Methamphetamine (METH) is an increasingly popular and highly addictive psychostimulant with a significant impact on public health. Chronic METH exposure has been associated with neurotoxic effects, profound neuropsychological deficits, and impaired quality of life, but few studies have examined the effect of the drug on the ability to carry out everyday activities. We assessed the effect of METH dependence on everyday functioning using the UCSD Performance-Based Skills Assessment (UPSA-2), a performance-based measure designed to evaluate real-life skills. METHOD UPSA-2 performance was quantified in 15 currently abstinent individuals with a history of METH dependence and 15 drug-free comparison subjects. The Positive and Negative Syndrome Scale (PANSS) and Wisconsin Card Sorting Task (WCST) were administered to assess psychopathology and executive function. RESULTS METH-dependent participants exhibited significant impairment on the UPSA-2 total score and several UPSA-2 subscales, including comprehension, finance, transportation, communication, and medication management compared to drug-free comparison subjects. Lower UPSA-2 scores were associated with impaired performance on the WCST, higher PANSS scores, and drug use at an earlier age. CONCLUSION METH dependence may be associated with decreased everyday functioning ability potentially mediated by frontal cortex dysfunction or the emergence of psychopathology related to chronic drug use.

Cross-species assessments of motor and exploratory behavior related to bipolar disorder.

Alterations in exploratory behavior are a fundamental feature of bipolar mania, typically characterized as motor hyperactivity and increased goal-directed behavior in response to environmental cues. In contrast, abnormal exploration associated with schizophrenia and depression can manifest as prominent withdrawal, limited motor activity, and inattention to the environment. While motor abnormalities are cited frequently as clinical manifestations of these disorders, relatively few empirical studies have quantified human exploratory behavior. This article reviews the literature characterizing motor and exploratory behavior associated with bipolar disorder and genetic and pharmacological animal models of the illness. Despite sophisticated assessment of exploratory behavior in rodents, objective quantification of human motor activity has been limited primarily to actigraphy studies with poor cross-species translational value. Furthermore, symptoms that reflect the cardinal features of bipolar disorder have proven difficult to establish in putative animal models of this illness. Recently, however, novel tools such as the human behavioral pattern monitor provide multivariate translational measures of motor and exploratory activity, enabling improved understanding of the neurobiology underlying psychiatric disorders.

Reduced dopamine transporter functioning induces high-reward risk-preference consistent with bipolar disorder.

Individuals with bipolar disorder (BD) exhibit deleterious decision making, negatively impacting their lives. Such aberrant decision making can be quantified using the Iowa Gambling Task (IGT), which requires choosing between advantageous and disadvantageous options based on different reward/punishment schedules. The mechanisms underlying this behavioral deficit are unknown, but may include the reduced dopamine transporter (DAT) functioning reported in BD patients. Using both human and mouse IGTs, we tested whether reduced DAT functioning would recreate patterns of deficient decision making of BD patients. We assessed the IGT performance of 16 BD subjects (7 female) and 17 healthy control (HC) subjects (12 female). We recorded standard IGT performance measures and novel post-reward and post-punishment decision-making strategies. We characterized a novel single-session mouse IGT using C57BL/6J mice (n=44). The BD and HC IGT performances were compared with the effects of chronic (genetic knockdown (KD; n=31) and wild-type (n=28) mice) and acute (C57BL/6J mice (n=89) treated with the DAT inhibitor GBR12909) reductions of DAT functioning in mice performing this novel IGT. BD patients exhibited impaired decision making compared with HC subjects. Both the good-performing DAT KD and GBR12909-treated mice exhibited poor decision making in the mouse IGT. The deficit of each population was driven by high-reward sensitivity. The single-session mouse IGT measures dynamic risk-based decision making similar to humans. Chronic and acute reductions of DAT functioning in mice impaired decision-making consistent with poor IGT performance of BD patients. Hyperdopaminergia caused by reduced DAT may impact poor decision making in BD patients, which should be confirmed in future studies.

Repeated Assessment of Exploration and Novelty Seeking in the Human Behavioral Pattern Monitor in Bipolar Disorder Patients and Healthy Individuals

Background Exploration and novelty seeking are cross-species adaptive behaviors that are dysregulated in bipolar disorder (BD) and are critical features of the illness. While these behaviors have been extensively quantified in animals, multivariate human paradigms of exploration are lacking. The human Behavioral Pattern Monitor (hBPM), a human version of the animal open field, identified a signature pattern of hyper-exploration in manic BD patients, but whether exploratory behavior changes with treatment is unknown. The objective of this study was to assess the sensitivity of the hBPM to changes in manic symptoms, a necessary step towards elucidating the neurobiology underlying BD. Methodology and Principal Findings Twelve acutely hospitalized manic BD subjects and 21 healthy volunteers were tested in the hBPM over three sessions; all subjects were retested one week after their first session and two weeks after their second session. Motor activity, spatial and entropic (degree of unpredictability) patterns of exploration, and interactions with novel objects were quantified. Manic BD patients demonstrated greater motor activity, extensive and more unpredictable patterns of exploration, and more object interactions than healthy volunteers during all three sessions. Exploration and novelty-seeking slightly decreased in manic BD subjects over the three sessions as their symptoms responded to treatment, but never to the level of healthy volunteers. Among healthy volunteers, exploration did not significantly decrease over time, and hBPM measures were highly correlated between sessions. Conclusions/Significance Manic BD patients showed a modest reduction in symptoms yet still demonstrated hyper-exploration and novelty seeking in the hBPM, suggesting that these illness features may be enduring characteristics of BD. Furthermore, behavior in the hBPM is not subject to marked habituation effects. The hBPM can be reliably used in a repeated-measures design to characterize exploration and novelty seeking and, in parallel with animal studies, can contribute to developing treatments that target neuropsychiatric disease.