Arpi Minassian

Sensorimotor gating deficits in adults with autism.

BACKGROUND Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is impaired in a family of neuropsychiatric disorders characterized by abnormalities of inhibitory function. Adults with autistic disorder (AD) exhibit clinical features of inhibitory deficits, such as restrictive and repetitive behaviors, that may be explained by deficits in sensorimotor gating. METHODS Acoustic startle reactivity, habituation, and PPI (30-, 60-, 120-msec interstimulus intervals) were assessed in 14 adult men diagnosed with AD and 16 typically developing normal comparison (NC) participants. All participants were administered measures of intelligence and frontal-executive functioning. RESULTS Adults with AD exhibited significantly less PPI in the 60-msec condition than NC participants, which was correlated with increased ratings of restricted and repetitive behaviors. The groups did not differ on measures of startle amplitude or overall habituation. There was, however, a significant group-by-block habituation effect. Furthermore, PPI was not related to intelligence but was moderately associated with performance on a measure of frontal-executive functioning. CONCLUSIONS Adults with AD have sensorimotor gating deficits similar to other neurodevelopmental disorders, implicating a failure of normal inhibitory regulation of sensory, motor, and attentional mechanisms. Thus, PPI deficits may be indirectly linked to one of the hallmark features of AD.

Adjunctive Intranasal Oxytocin Reduces Symptoms in Schizophrenia Patients

BACKGROUND Both human and animal studies suggest oxytocin may have antipsychotic properties. Therefore, we conducted a clinical trial to directly test this notion. METHODS Nineteen schizophrenia patients with residual symptoms despite being on a stable dose of at least one antipsychotic were enrolled in a randomized, double-blind, crossover study. They received 3 weeks of daily intranasal oxytocin (titrated to 40 IU twice a day) and placebo adjunctive to their antipsychotics. Order of intranasal treatment was randomly assigned and there was a 1-week washout between treatments. RESULTS Analysis of the 15 subjects who completed all the study visits revealed that oxytocin significantly reduced scores on the Positive and Negative Symptom Scale (p < .001) and Clinical Global Impression-Improvement Scale (p < .001) compared with placebo at the 3-week end point. No benefit was seen at the early time points. Oxytocin was well tolerated and produced no adverse effects based upon patient reports or laboratory analysis. CONCLUSIONS The results support the hypothesis that oxytocin has antipsychotic properties and is well tolerated. Higher doses and longer duration of treatment may produce larger benefits and should be evaluated in future studies.

Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania

BACKGROUND Deficits in sensorimotor gating as assessed by prepulse inhibition (PPI) and habituation of the human startle response have been noted in schizophrenia and other patients with known dysfunction in the brain substrates that regulate PPI. During acute mania, bipolar disorder (BD) and schizophrenia patients present with symptoms that are similar. To determine if these clinical similarities extend to neurophysiologic domains, PPI and startle habituation were assessed in BD patients with acute psychotic mania and compared with a sample of acutely psychotic schizophrenia patients and a normal comparison group. METHODS Fifteen BD patients, 16 schizophrenia patients, and 17 control subjects were assessed on PPI and startle habituation. RESULTS The BD patients had significantly lower PPI than did the control subjects in two of the three PPI conditions (60- and 120-msec interstimulus intervals) as well as less startle habituation. The BD patients did not statistically differ from the schizophrenia patients in PPI or habituation. CONCLUSIONS These findings of sensorimotor gating deficits among bipolar disorder patients are consistent with other findings using different measures of information processing and suggest that the neurobiological substrates underlying sensorimotor gating may be dysregulated during acute manic and psychotic states.

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.

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.

Adjunctive intranasal oxytocin improves verbal memory in people with schizophrenia

INTRODUCTION Cognitive deficits are a prominent, disabling component of schizophrenia and current pharmacological treatments have demonstrated limited efficacy in their amelioration. Oxytocin - though it has shown promise as a novel antipsychotic in multiple clinical trials - has as-yet poorly characterized effects on cognition, with some evidence indicating an amnestic profile. METHOD As part of a previously reported trial of chronic adjunctive oxytocin in schizophrenia, we measured its effect on two cognitive tests: the CVLT (California Verbal Learning Test) and the LNS (Letter Number Sequence). Tests were performed at baseline and after 3 weeks of treatment. RESULTS We found no evidence for an amnestic effect and, in fact, significantly better performance with oxytocin on several subtests of the CVLT; namely total Recall trials 1-5 (p=0.027), short delayed free recall (p=0.032) and total recall discrimination (p=0.020). In contrast we found no difference between placebo and oxytocin on LNS performance. CONCLUSIONS This is the first report we are aware of documenting a beneficial effect of oxytocin on cognition in schizophrenia. Though from a small sample (n=15), these data both offset past concerns about oxytocins amnestic effects, and may auger another potential benefit in addition to the already-demonstrated salutary effects on other components of the illness.

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.

The mania-like exploratory profile in genetic dopamine transporter mouse models is diminished in a familiar environment and reinstated by subthreshold psychostimulant administration

Bipolar Disorder (BD) is a neuropsychiatric disorder characterized by symptoms ranging from a hyperactive manic state to depression, with periods of relative stability, known as euthymia, in between. Although prognosis for BD sufferers remains poor, treatment development has been restricted due to a paucity of validated animal models. Moreover, most models focus on the manic state of BD with little done to characterize the longitudinal behavior of these models. We recently presented two dopamine transporter (DAT) mouse models of BD mania: genetic (DAT knockdown; KD, mice) and pharmacological (the selective DAT inhibitor GBR 12909). These models exhibit an exploratory profile consistent with the quantified exploratory profile of manic BD patients observed in the cross-species translational test, the Behavioral Pattern Monitor (BPM). To further explore the suitability of these models, we examined the effects of reduced DAT function on the behavior of mice tested after familiarization to the BPM environment. Testing with 16mg/kg GBR 12909 in familiarized mice resulted in a consistent mania-like profile. In contrast, the mania-like profile of DAT KD mice disappears in a familiar environment, with partial reinstatement elicited by the introduction of novelty. In addition, we found that a subthreshold dose of GBR 12909 (9mg/kg) reinstated the mania-like profile in DAT KD mice without affecting wildtype behavior. Thus, the mania-like exploratory profile of DAT KD mice is reduced in a familiar environment, partially reinstated with novelty, but is fully restored when administered a stimulant that is ineffective in wildtype mice. These mice may provide a model of BD from mania to euthymia and back again with stimulant treatment. Acute blockade of the DAT by GBR 12909 however, may provide a consistent model for BD mania.