Delving within: the new science of the unconscious.

What exactly is the relationship between conscious awareness and the unconscious mind? How, for example, does the brain classify and sort its different functions into conscious or unconscious processes? How has the history of human conceptualizations about the unconscious influenced current theories? Steve Paulson, executive producer of To the Best of Our Knowledge, moderated a discussion among neuroscientist Heather Berlin, psychologist Efrat Ginot, and psychiatrist George Makari to shed light on the history of the mind and the latest insights into the still emerging science of the unconscious.

Altered olfactory processing and increased insula activity in patients with obsessive-compulsive disorder: An fMRI study.

Obsessive-compulsive disorder (OCD) patients show increased insula activation to disgust-inducing images compared to healthy controls (HC). We explored whether this disgust reactivity was also present in the olfactory domain by conducting the first fMRI study of olfaction in OCD. Neural activation in response to pleasant and unpleasant odors (vs. unscented air) was investigated in 15 OCD and 15 HC participants using fMRI. OCD participants (vs. HC) had increased left anterior insula activation to unpleasant odors (vs. unscented air), which positively correlated with their disgust sensitivity and ratings of the unpleasantness and intensity of those odors. OCD participants (vs. HC) showed increased activation of caudate nucleus and left anterior and posterior insula to pleasant odors (vs. unscented air), which positively correlated with their OCD symptom severity, trait anxiety, frequency of feeling disgust, and odor intensity ratings. OCD participants had increased anterior insula activation to both pleasant and unpleasant odors, which correlated with their OCD symptoms, anxiety, disgust sensitivity, and frequency of feeling disgust. OCD patients might have a negative cognitive bias and experience all stimuli, regardless of valence, as being more unpleasant than healthy people. These findings further elucidate the neural underpinnings of OCD and may contribute to more effective treatments.

The moral animal: virtue, vice, and human nature.

In Leo Tolstoy's famous novella, The Death of Ivan Ilyich, a rich and meaningful inner life is sacrificed in pursuit of material rewards and social status. How can we cultivate something intrinsic that transcends our worldly accomplishments? Assuming that a basic model or map of human nature is needed to navigate the road to the good life, what desires, tendencies, and aversions constitute our core nature? How has our evolutionary history shaped our moral impulses? Are we inherently good or fundamentally flawed? Steve Paulson, executive producer and host of To the Best of Our Knowledge, moderated a discussion with philosopher Christian Miller, neuroscientist Heather Berlin, and historian of science Michael Shermer to examine our moral ecology and its influence on our underlying assumptions about human nature.

Communicating Science: Lessons from Film.

Films engage us visually, aurally, viscerally, and emotionally. Incorporating science themes into films has the potential to open up new audiences to scientific ideas, pique their interests, and inspire them to engage in a broader discussion of the science itself. Here, I discuss several narrative techniques and strategies employed in film to effectively engage the audience around science themes, which may be useful tools for scientists looking to become better communicators.

Neural correlates of emotional response inhibition in obsessive-compulsive disorder: A preliminary study.

Failure to inhibit recurrent anxiety-provoking thoughts is a central symptom of obsessive-compulsive disorder (OCD). Neuroimaging studies suggest inhibitory control and disgust processing abnormalities in patients with OCD. However, the emotional modulation of response inhibition deficits in OCD and their neural correlates remain to be elucidated. For this preliminary study we administered an adapted affective response inhibition paradigm, an emotional go/no-go task, during fMRI to characterize the neural systems underlying disgust-related and fear-related inhibition in nine adults with contamination-type OCD compared to ten matched healthy controls. Participants with OCD had significantly greater anterior insula cortex activation when inhibiting responses to both disgusting (bilateral), and fearful (right-sided) images, compared to healthy controls. They also had increased activation in several frontal, temporal, and parietal regions, but there was no evidence of amygdala activation in OCD or healthy participants and no significant between-group differences in performance on the emotion go/no-go task. The anterior insula appears to play a central role in the emotional modulation of response inhibition in contamination-type OCD to both fearful and disgusting images. The insula may serve as a potential treatment target for contamination-type OCD.

Neuromodulation for obsessive-compulsive disorder.

Neuromodulation shows increasing promise in the treatment of psychiatric disorders, particularly obsessive-compulsive disorder (OCD). Development of tools and techniques including deep brain stimulation, transcranial magnetic stimulation, and electroconvulsive therapy may yield additional options for patients who fail to respond to standard treatments. This article reviews the motivation for and use of these treatments in OCD. We begin with a brief description of the illness followed by discussion of the circuit models thought to underlie the disorder. These circuits provide targets for intervention. Basal ganglia and talamocortical pathophysiology, including cortico-striato-thalamo-cortical loops is a focus of this discussion. Neuroimaging findings and historical treatments that led to the use of neuromodulation for OCD are presented. We then present evidence from neuromodulation studies using deep brain stimulation, electroconvulsive therapy, and transcranial magnetic stimulation, with targets including nucleus accumbens, subthalamic nucleus inferior thalamic peduncle, dorsolateral prefrontal cortex, supplementary motor area, and orbitofrontal cortex. Finally, we explore potential future neuromodulation approaches that may further refine and improve treatment.

The influence of age of onset and acute anabolic steroid exposure on cognitive performance, impulsivity, and aggression in men.

The name of author Heather Berlin omitted a middle initial in the byline and author note and should appear as Heather A. Berlin.] A growing translational literature suggests that adolescent exposure to anabolic-androgenic steroids (AASs) leads to increased aggression and impulsivity. However, little is known about the cognitive effects of AASs among AAS users or the differences between adolescent- and adult-onset users. This study provides a test of the effects of acute naturalistic AAS use and age of onset (adolescent vs. adult) on measures of inhibitory control, planning and attention, and decision making. Seventy-one active adult male AAS users completed self-report measures of impulsivity and aggression, and a subsample (11 adolescent onset vs. 11 adult onset) matched on current age were administered 4 computerized tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Cambridge Cognition, 2002) and the Iowa Gambling Task (Stanton, Liening, & Schultheiss, 2011). Multiple regression analyses and a series of 2 (adolescent vs. adult) × 2 (on-cycle vs. off-cycle) analyses of variance (ANOVAs) were used to examine the differential effects of age of onset and acute drug use on cognition and behavior. Regression analyses revealed larger on-cycle effects for adolescent users than adult users. Subsample analyses indicated that on-cycle users performed less well on cognitive measures of inhibitory control and attention, but not on tests of planning or decision making. Adolescent onset was associated with greater impulsivity and more acute sensitivity to AAS effects on attention. These preliminary findings suggest the possibility that acute AAS use is associated with some differences in inhibitory control and impulsivity and to a lesser degree, aggression. These effects may be more potent for those initiating AAS use in adolescence.

A double-blind, placebo-controlled trial of topiramate for pathological gambling.

OBJECTIVES: Pathological gambling (PG) is an impulse control disorder characterized by recurrent gambling thoughts and behaviours that impair social functioning. Earlier studies suggested that topiramate may be effective in treating some impulse control disorders. We conducted the first randomized, controlled trial of topiramate in PG. METHODS: PG patients were randomized to topiramate (N = 20) or placebo (N = 22) in this 14-week, double-blind, placebo-controlled, parallel-group trial. The primary outcome measure was change in the obsessions subscale of the Yale-Brown Obsessive-Compulsive Scale Modified for Pathological Gambling. RESULTS: Mixed regression models (time [weeks] × treatment) revealed no significant treatment effect of topiramate on the primary or secondary outcome measures. The most statistically robust findings involved reducing the Barratt Impulsiveness Scale (BIS) total score and Motor and Non-Planning subscale scores, for which topiramate outperformed placebo at merely a trend level (P < 0.1). CONCLUSIONS: The observed trend in BIS score reductions may warrant further investigation to study whether topiramate reduces clinically important impulsivity in PG. Treatment studies with larger samples and less stringent exclusion criteria are needed to produce results that can be generalized to pathological gamblers in the community.

Implicit self-esteem in borderline personality and depersonalization disorder.

Self-perception is disrupted in people with borderline personality disorder (BPD) and depersonalization disorder (DPD), fluctuating with sudden shifts in affect in BPD and experienced as detached in DPD. Measures of implicit self-esteem (ISE), free from conscious control and presentation biases, may highlight how such disruptions of self-concept differentially affect these two populations on an unconscious level. We examined ISE using the Implicit Association Test, along with measures of emotion, behavior, and temperament, in BPD (n = 18), DPD (n = 18), and healthy control (n = 35) participants. DPD participants had significantly higher ISE and were more harm avoidant than BPD and control participants, while BPD participants had more "frontal" behaviors and impulsivity and less self-directedness and cooperativeness than DPD and control participants. Thus, while BPD and DPD commonly overlap in terms of dissociative symptoms and emotional irregularities, differences in self-esteem, behavior, and temperament can help identify where they diverge in terms of their cognition, behavior, and ultimately underlying neurobiology.

Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive-compulsive disorder.

BACKGROUND: From 40% to 60% of obsessive-compulsive disorder (OCD) patients fail to tolerate or respond to selective serotonin reuptake inhibitors (SSRIs). Preclinical and neuroimaging studies have shown abnormally high glutamatergic concentrations in OCD patients and an association between decreased caudate glutamatergic concentrations and reduced OCD symptom severity after SSRI treatment. Topiramate inhibits glutamatergic conduction. METHOD: Thirty-six adult patients with DSM-IV-defined OCD were randomly assigned to topiramate (n = 18) and placebo (n = 18) groups in this 12-week, double-blind, placebo-controlled, parallel-groups trial. Subjects were taking the maximum SSRI dose they could tolerate for at least 12 weeks and their current dose for at least 6 weeks, which was maintained throughout the study. Primary outcome measures were changes in the Yale-Brown Obsessive Compulsive Scale (YBOCS) total score and compulsions and obsessions subscores. Patients were recruited and followed up between April 1, 2003, and April 13, 2006. RESULTS: Using mixed regression models (time [weeks] × treatment), we found a significant treatment effect on the YBOCS compulsions (P = .014) subscale, but not the obsessions (P = .99) subscale or the total score (P = .11). Over the 12-week trial, the topiramate group (mean endpoint dose = 177.8 ± 134.2 mg/d; range, 50-400 mg/d) showed an average linear decrease of 5.38 points on the compulsions subscale compared to 0.6 points in the placebo group. Thirteen topiramate and 14 placebo subjects completed the study. Topiramate was not well tolerated in this trial: 28% (5/18) of the subjects discontinued the drug for adverse effects, and 39% (7/18) had a dose reduction for this reason. CONCLUSIONS: The results of this first double-blind, placebo-controlled trial of topiramate augmentation for treatment-resistant OCD suggest that topiramate may be beneficial for compulsions, but not obsessions. Modifications in glutamatergic function may be responsible, at least in part, for the improved response in compulsions seen with topiramate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00211744.

Dorso- and ventro-lateral prefrontal volume and spatial working memory in schizotypal personality disorder.

Schizotypal personality disorder (SPD) individuals and borderline personality disorder (BPD) individuals have been reported to show neuropsychological impairments and abnormalities in brain structure. However, relationships between neuropsychological function and brain structure in these groups are not well understood. This study compared visual-spatial working memory (SWM) and its associations with dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) gray matter volume in 18 unmedicated SPD patients with no BPD traits, 18 unmedicated BPD patients with no SPD traits, and 16 healthy controls (HC). Results showed impaired SWM in SPD but not BPD, compared with HC. Moreover, among the HC group, but not SPD patients, better SWM performance was associated with larger VLPFC (BA44/45) gray matter volume (Fisher's Z p-values <0.05). Findings suggest spatial working memory impairments may be a core neuropsychological deficit specific to SPD patients and highlight the role of VLPFC subcomponents in normal and dysfunctional memory performance.

Neuropsychobiological aspects, comorbidity patterns and dimensional models in borderline personality disorder.

Borderline personality disorder (BPD) is a comorbid and disabling condition with high prevalence in psychiatric settings. The pathogenesis of BPD involves complex interactions among genetic, neurobiological and environmental factors, resulting in multiple core symptom domains such as emotional dysregulation, impulse dyscontrol, aggression, cognitive dysfunctions and dissociative states. Neurobiological studies show that symptoms and behaviors of BPD are partly associated with alterations in glutamatergic, dopaminergic and serotonergic systems. In addition, neuroimaging studies in BPD patients indicate differences in the volume and activity of specific brain regions related to emotion and impulse control, such as the prefrontal and cingulate cortex, amygdala and hippocampus. Neurobiological alterations are related to cognitive disturbances in patients with BPD and neuropsychological tests have shown abnormalities of memory, attention, language, and executive functions. The aim of the present review is to provide an updated overview of the main neuropsychobiological aspects of BPD and their relation to clinical symptoms, comorbidity patterns and dimensional models.

Duration of untreated illness and suicide in bipolar disorder: a naturalistic study.

The aim of this naturalistic study was to evaluate the potential influence of the duration of untreated illness (DUI)--defined as the time elapsed between the occurrence of the first mood episode and the first adequate pharmacological treatment with mood stabilizers--on the clinical course of bipolar disorder (BD). Three hundred and twenty outpatients (n = 320) with a DSM-IV diagnosis of BD--either Type I or Type II--were interviewed; their clinical features were collected and they were naturalistically followed-up for 5 years. At the end of the follow-up observation, the sample was subdivided into two groups: one group with a DUI < or =2 years (n = 65) and another group with a DUI >2 years (n = 255). The main demographic and clinical variables were analyzed and compared between the two subgroups of patients using chi-square tests for dichotomous variables or Mann-Whitney U tests for continuous variables. Patients with a longer DUI showed a higher frequency of suicide attempts (Z = -2.11, P = 0.035), a higher number of suicide attempters (chi(2) = 4.13, df = 1, P = 0.04), and a longer duration of illness (Z = -6.79, P < 0.0001) when compared to patients with a shorter DUI. Moreover, patients with a longer DUI had a depressive first episode more frequently than patients with a shorter DUI (chi(2) = 11.28, df = 2, P = 0.004). A further analysis performed dividing the total sample into two subgroups on the basis of a DUI of 6 years (corresponding to the median value of the DUI in the study sample) confirmed prior findings. Results indicate a potential association between a longer DUI and a worse outcome in BD, particularly in terms of suicidality, and confirm the clinical relevance of early diagnosis and pharmacological intervention with mood stabilizers in BD.

Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review.

Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.

FDG-PET study in pathological gamblers. 1. Lithium increases orbitofrontal, dorsolateral and cingulate metabolism.

BACKGROUND: Pathological gambling affects 1-3% of the adult population, and has high comorbidity. Although mood stabilizers and serotonin reuptake inhibitors have shown some efficacy in the treatment of this condition, there is little known about how these pharmacological interventions work. METHODS: Twenty-one patients with pathological gambling, who met lifetime comorbid bipolar spectrum diagnoses, received baseline PET scans. Sixteen of these patients were entered into a randomized double-blind placebo-controlled parallel group design trial of lithium, and received follow-up PET scans at 10 weeks. A comparison group of 32 age- and sex-matched controls was also available. Anatomical MRIs were obtained as a structural template. RESULTS: In patients with pathological gambling, relative glucose metabolic rates (rGMR) in the orbitofrontal cortex and medial frontal cortex were significantly increased at baseline compared to normal controls. Lithium increased rGMR further in the orbitofrontal cortex, heightening normal/patient differences, but it also increased the rGMR of the posterior cingulate and the dorsolateral frontal cortex normalizing the metabolic rate in these regions. CONCLUSION: Cortical areas implicated in impulse control disorders show increased rGMR in pathological gambling at baseline. Lithium treatment, while alleviating the symptoms, further increases rGMR in these areas.

Experimental therapeutics for refractory obsessive-compulsive disorder: translational approaches and new somatic developments.

Significant advances over the past 20 years in our understanding of the phenomenology and pathophysiology of obsessive-compulsive disorder, made in part from structural and functional neuroimaging and genetics research, can guide treatments that target brain regions, circuits, and neurotransmitter systems specific to obsessive-compulsive disorder, the disruption of which may alleviate obsessive-compulsive disorder symptoms. We discuss here our current understanding of the underlying neurobiology and heritability of obsessive-compulsive disorder and integrate that understanding with a review of the current pharmacological, neurosurgical, and brain stimulation treatments of refractory obsessive-compulsive disorder. Expanding on these studies, we hope that new pharmacological and psychological treatment strategies and research-driven targets for lesioning, stimulation, or other types of focal neuromodulation can be identified that could lead to future research directions. Cross-species translational research and neuroimaging of the physiological and anatomical pathways implicated in the pathophysiology and treatment response in obsessive-compulsive disorder will advance our understanding of the neural basis of obsessive-compulsive disorder and lead to more targeted and effective treatment options.

Antiepileptic drugs for the treatment of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a disruptive, chronic, and relatively common disorder that is often difficult to treat. Many patients with PTSD are unresponsive, have only moderate or marginal responses, or have troubling side effects to first-line serotonin reuptake inhibitor treatment. Studies suggest that antiepileptic drugs (AEDs) may be an effective treatment alternative or adjunctive treatment for the symptoms of PTSD. Recent results from case reports and open and controlled studies on the efficacy and tolerability of AEDs in PTSD are reviewed here, and their methodological limitations are discussed when relevant. AEDs shown to be effective in double-blind, placebo-controlled trials of PTSD include lamotrigine, topiramate, and tiagabine. Other AEDs that appear promising in open-label trials of PTSD include carbamazepine, valproate, gabapentin, vigabatrin, phenytoin, and levetiracetam. Stress-activated limbic kindling may be involved in the pathogenesis of PTSD. The possibility that AEDs may be effective in the treatment of PTSD due to their antikindling effect is discussed, and suggestions for future research are made.

Borderline personality disorder, impulsivity, and the orbitofrontal cortex.

OBJECTIVE: Orbitofrontal cortex lesions produce disinhibited or socially inappropriate behavior and emotional irregularities. Characteristics of borderline personality disorder include impulsivity and affective instability. The authors investigated whether aspects of borderline personality disorder, in particular impulsivity, are associated with orbitofrontal cortex dysfunction. METHOD: Measures of personality, emotion, impulsivity, time perception, sensitivity to reinforcers, and spatial working memory were administered to patients with borderline personality disorder (N=19), patients with orbitofrontal cortex lesions (N=23), patients with lesions in the prefrontal cortex but not in the orbitofrontal cortex (N=20), and healthy comparison subjects (N=39). RESULTS: The patients with orbitofrontal cortex lesions and the patients with borderline personality disorder performed similarly on several measures. Both groups were more impulsive and reported more inappropriate behaviors, borderline personality disorder characteristics, and anger and less happiness than the two comparison groups, and both groups were less open to experience and had a faster perception of time (underproduced time) than the healthy comparison subjects. The patients with orbitofrontal cortex lesions and the borderline personality disorder patients performed differently on other measures. The borderline personality disorder patients were less extraverted and conscientious and more neurotic and emotional than all other groups. Patients with orbitofrontal cortex lesions had deficits in reversing stimulus-reinforcer associations and a faster perception of time (overestimated time) than the healthy comparison subjects. CONCLUSIONS: Orbitofrontal cortex dysfunction may contribute to some core characteristics of borderline personality disorder, in particular impulsivity. Other characteristics of borderline personality disorder, such as high levels of emotionality and personality irregularities, do not appear to be related to the type of dysfunction produced by orbitofrontal cortex damage. The similarities and differences found between the borderline personality disorder patients and the patients with orbitofrontal cortex lesions may lead to a better understanding of the etiology of borderline personality disorder and the functions of the orbitofrontal cortex.

Time perception, impulsivity, emotionality, and personality in self-harming borderline personality disorder patients.

To investigate how time perception may contribute to the symptoms of self-harming Borderline Personality Disorder (BPD) patients, 19 self-harming BPD inpatients and 39 normal controls were given measures of time perception, impulsivity, personality, emotion, and BPD characteristics. A test sensitive to orbitofrontal cortex (OFC) function ("Frontal" Behavior Questionnaire) was also administered, as the OFC has been associated with impulsivity and time perception. BPD patients produced less time than controls, and this correlated with impulsiveness and other characteristics commonly associated with BPD. BPD patients were also less conscientious, extraverted, and open to experience, as well as more impulsive (self-report and behaviorally), emotional, neurotic, and reported more BPD characteristics, compared to controls. The results suggest that some of these core characteristics of BPD may be on a continuum with the normal population and, impulsivity in particular, may be related to time perception deficits (i.e., a faster subjective sense of time). Finally, BPD patients scored higher on the Frontal Behavior Questionnaire, suggesting that some symptoms of the BPD syndrome may be related to problems associated with the OFC. A control spatial working memory task (SWM) revealed that SWM deficits could not explain any of the BPD patients' poor performance. While impulsivity was correlated with time perception across all participants, emotionality, introversion, and lack of openness to experience were not. This suggests that different symptoms of the borderline personality syndrome may be separable, and therefore, related to different cognitive deficits, and potentially to different brain systems. This may have important implications for treatment strategies for BPD.