Joel L. Steinberg

Reduced Anterior Corpus Callosum White Matter Integrity is Related to Increased Impulsivity and Reduced Discriminability in Cocaine-Dependent Subjects: Diffusion Tensor Imaging

Brain imaging studies find evidence of prefrontal cortical dysfunction in cocaine-dependent subjects. Similarly, cocaine-dependent subjects have problems with behaviors related to executive function and impulsivity. Since prefrontal cortical axonal tracts cross between hemispheres in the corpus callosum, it is possible that white matter integrity in the corpus callosum could also be diminished in cocaine-dependent subjects. The purpose of this study was to compare corpus callosum white matter integrity as measured by the fractional anisotropy (FA) on diffusion tensor imaging (DTI) between 18 cocaine-dependent subjects and 18 healthy controls. The Barratt Impulsiveness Scale (BIS-11) and a continuous performance test: the Immediate and Delayed Memory Task (IMT/DMT) were also collected. Results of the DTI showed significantly reduced FA in the genu and rostral body of the anterior corpus callosum in cocaine-dependent subjects compared to controls. Cocaine-dependent subjects also had significantly higher BIS-11 scores, greater impulsive (commission) errors, and reduced ability to discriminate target from catch stimuli (discriminability) on the IMT/DMT. Within cocaine dependent subjects there was a significant negative correlation between FA in the anterior corpus callosum and behavioral laboratory measured impulsivity, and there was a positive correlation between FA and discriminability. The finding that reduced integrity of anterior corpus callosum white matter in cocaine users is related to impaired impulse control and reduced ability to discriminate between target and catch stimuli is consistent with prior theories regarding frontal cortical involvement in impaired inhibitory control in cocaine-dependent subjects.

Increased trait-like impulsivity and course of illness in bipolar disorder

BACKGROUND Impulsivity as a trait characteristic is increased in bipolar disorder and may be a core factor of the illness. We have investigated relationships between trait-like impulsivity, measured by the Barratt Impulsiveness Scale (BIS-11), and demographic and illness-course characteristics of bipolar disorder. METHODS We studied 114 subjects with bipolar disorder and 71 healthy comparison subjects. Diagnoses were based on the Structured Clinical Interview for DSM-IV. In addition to impulsivity, we examined age, education, gender, psychiatric symptoms, and characteristics related to course of illness. We used general linear mixed model analysis to evaluate the manner in which the variables contributed to BIS-11 scores. RESULTS All BIS-11 subscale scores were higher in bipolar disorder than in comparison subjects. There were less consistent independent effects of education and age. Elevated BIS-11 scores were associated with early onset, more frequent episodes of illness, and a history of suicide attempts. These relationships persisted when age, gender, and education were taken into account. DISCUSSION These results show that, after accounting for common confounding factors, trait-like impulsivity was substantially higher in subjects with bipolar disorder than in nonbipolar comparison subjects, regardless of symptoms. Within subjects with bipolar disorder, high trait impulsivity was associated with a more severe course of illness.

P50, N100, and P200 sensory gating: Relationships with behavioral inhibition, attention, and working memory

P50, N100, and P200 auditory sensory gating could reflect mechanisms involved in protecting higher-order cognitive functions, suggesting relationships between sensory gating and cognition. This hypothesis was tested in 56 healthy adults who were administered the paired-click paradigm and two adaptations of the continuous performance test (Immediate/Delayed Memory Task, IMT/DMT). Stronger P50 gating correlated with fewer commission errors and prolonged reaction times on the DMT. Stronger N100 and P200 gating correlated with better discriminability on the DMT. Finally, prolonged P200 latency related to better discriminability on the IMT. These findings suggest that P50, N100, and P200 gating could be involved in protecting cognition by affecting response bias, behavioral inhibition, working memory, or attention.

Altered brain activation during cognitive control in patients with moderate to severe traumatic brain injury.

Background. Persistent deficits in cognitive control have been documented following traumatic brain injury (TBI) but are inconsistently related to the presence and location of focal lesions. Objective. Functional magnetic resonance imaging (fMRI) was used to examine brain activation during a cognitive control task in patients with moderate to severe TBI or orthopedic injury (OI). Methods. Fourteen TBI patients and 10 OI patients underwent fMRI at 3 months postinjury using a stimulus-response compatibility task in which response accuracy and reaction time were measured. Performance between the groups was equated by individually adjusting the amount of training. Groups did not differ in age, gender, or education. Results. Brain activation during stimulus-response incompatibility was greater in TBI patients than in OI patients within the cingulate, medial frontal, middle frontal, and superior frontal gyri. However, the positive regression of activation with response accuracy during stimulus-response incompatibility indicated a stronger relationship for OI patients than the TBI group within the anterior cingulate gyrus, medial frontal, and parietal regions, as well as deep brain structures (eg, brainstem). The number of focal lesions within either the whole brain or within prefrontal areas was not related to brain activation, but there was a relationship between activation and TBI severity. Conclusions. These findings suggest that neural networks mediating cognitive control are altered after moderate to severe TBI, possibly as a result of diffuse axonal injury, and that the typical relationship of brain activation to performance is disrupted.

Trait Impulsivity and Response Inhibition in Antisocial Personality Disorder

BACKGROUND Impulsive behavior is a prominent characteristic of antisocial personality disorder. Impulsivity is a complex construct, however, representing distinct domains of cognition and action. Leading models refer to impulsivity as an inability to evaluate a stimulus fully before responding to it (rapid-response impulsivity), and as an inability to delay responding despite a larger reward (reward-delay impulsivity). We investigated these models in terms of the diagnosis and severity of antisocial personality disorder. METHODS Thirty-four male subjects on probation/parole who met DSM-IV criteria for ASPD, and 30 male healthy comparison subjects, matched by ethnicity, were recruited from the community. The Barratt Impulsiveness Scale (BIS-11) provided an integrated measure of trait impulsivity. Rapid-response impulsivity was assessed using the Immediate Memory Task (IMT), a continuous performance test. Reward delay impulsivity was assessed using the Two-choice Impulsivity Paradigm (TCIP), where subjects had the choice of smaller-sooner or larger-delayed rewards, and the Single Key Impulsivity Paradigm (SKIP), a free-operant responding task. RESULTS Compared to controls, subjects with ASPD had higher BIS-11 scores (Effect Size (E.S.)=0.95). They had slower reaction times to IMT commission errors (E.S.=0.45). Correct detections, a measure of attention, were identical to controls. On the SKIP, they had a shorter maximum delay for reward (E.S.=0.76), but this was not significant after correction for age and education. The groups did not differ on impulsive choices on the TCIP (E.S.<0.1). On probit analysis with age and education as additional independent variables, BIS-11 score, IMT reaction time to a commission error, and IMT positive response bias contributed significantly to diagnosis of ASPD; SKIP delay for reward did not. Severity of ASPD, assessed by the number of ASPD symptoms endorsed on the SCID-II, correlated significantly with commission errors (impulsive responses) on the IMT, and with liberal IMT response bias. This relationship persisted with correction for age and education. DISCUSSION These results suggest that ASPD is characterized by increased rapid-response impulsivity. Aspects of impulsivity related to reward-delay or attention appear relatively intact.

Performance of Cocaine Dependent Individuals and Controls on a Response Inhibition Task with Varying Levels of Difficulty

An assay in which groups perform at both similar and significantly different levels within the same test session may have experimental advantages both in understanding underlying behavioral-cognitive processes and in helping to resolve neuroimaging issues regarding functional significance vs. performance confounds. Here we report behavioral data from a response inhibition (Go/No-Go) task with two levels of No-Go difficulty (easy, hard). The sample included individuals with current cocaine dependence (N = 18) and controls (N = 15). Using signal detection methodology (d′ and Beta), significant main effects were observed for group and trial type on d′. Post-hoc analyses revealed the cocaine-dependent individuals performed significantly worse than controls on difficult, but not easy, trials. Differences on d′ but not Beta, and slower reaction times in cocaine subjects, suggest that response inhibition deficits were related to disruption in visual information processing rather than inhibition of motor activity.

Diffusion tensor imaging and decision making in cocaine dependence.

Background Chronic stimulant abuse is associated with both impairment in decision making and structural abnormalities in brain gray and white matter. Recent data suggest these structural abnormalities may be related to functional impairment in important behavioral processes. Methodology/Principal Findings In 15 cocaine-dependent and 18 control subjects, we examined relationships between decision-making performance on the Iowa Gambling Task (IGT) and white matter integrity as measured by diffusion tensor imaging (DTI). Whole brain voxelwise analyses showed that, relative to controls, the cocaine group had lower fractional anisotropy (FA) and higher mean of the second and third eigenvalues (λ⊥) in frontal and parietal white matter regions and the corpus callosum. Cocaine subjects showed worse performance on the IGT, notably over the last 40 trials. Importantly, FA and λ⊥ values in these regions showed a significant relationship with IGT performance on the last 40 trials. Conclusions Compromised white matter integrity in cocaine dependence may be related to functional impairments in decision making.

Working memory fMRI activation in cocaine-dependent subjects: Association with treatment response

Functional magnetic resonance imaging (fMRI) studies of early abstinence cocaine users offer information about the state of the brain when most cocaine users seek treatment. This study examined the relationship between pretreatment brain function and subsequent treatment response in 19 treatment-seeking early abstinence cocaine-dependent (CD) subjects. These subjects and 14 non-drug-using control subjects underwent fMRI while performing a working memory task with three levels of difficulty. CD subjects were then randomized to treatment studies. Results showed CD subjects had significantly lower (random effects, corrected for multiple comparisons) brain activation in caudate, putamen, cingulate gyrus, middle and superior frontal gyri, inferior frontal gyrus pars triangularis and pars opercularis, precentral gyrus, and thalamus compared with non-drug-using controls. Within CD subjects, thalamic activation significantly correlated with treatment response. This study shows CD subjects in early abstinence have alterations of brain function in frontal, striatal, and thalamic brain regions known to be part of a circuit associated with motor control, reward, and cognition. Subjects with pretreatment thalamic deactivation showed the poorest treatment response, possibly related to thalamic involvement in mesocortical and mesolimbic dopamine projections.

Severity of bipolar disorder is associated with impairment of response inhibition

BACKGROUND Pathological impulsivity in bipolar disorder could be related to deficiencies in mechanisms involved in attention or response inhibition. We investigated these mechanisms in subjects with bipolar disorder and examined relationships to severity of course of illness, use of medication, affective state, age, education, and gender. We measured two complementary aspects of response inhibition: attention-based and reward-based. METHODS Subjects with bipolar disorder (n=112) and healthy controls (n=71) were recruited from the community. Diagnoses were rendered using the SCID for DSMIV. Impulsivity-related measures included the Immediate Memory Task (IMT), a form of the Continuous Performance Task, and the Single Key Impulsivity Paradigm (SKIP), an operant procedure measuring ability to delay responding for a reward. RESULTS Subjects with bipolar disorder had fewer correct detections (Effect Size (ES)=0.5), prolonged reaction times (ES=0.88), and decreased discriminability (ES=0.57) on the IMT compared to controls. History of frequent episodes, substance use disorders, or suicide attempts predicted faster reaction times, especially to a commission error. Subjects with bipolar disorder who also met criteria for an Axis II disorder had fewer correct detections, more commission errors relative to correct detections, and poorer discriminability on the IMT than other subjects with bipolar disorder. Subjects with bipolar disorder made more responses on the SKIP than did controls (ES=0.5), with a shorter maximum delay (ES=0.62), consistent with inability to delay reward. Probit analysis showed that faster reaction time to a commission error on the IMT was associated with history of substance use disorder, suicide attempt, or many previous episodes. Effects of medication or affective state did not account for these differences. DISCUSSION Bipolar disorder was associated with impairment in attention and response inhibition, encompassing impaired inhibition of rapid responses and an inability to delay reward, and resulting in impulsivity. Response inhibition mechanisms are impaired further in subjects with more severe complications of illness.

Citalopram Combined with Behavioral Therapy Reduces Cocaine Use: A Double-Blind, Placebo-Controlled Trial

Cocaine dependence continues to be a significant problem in the United States, without any approved pharmacotherapy. Promising findings from preclinical research on the effects of cocaine on serotonin lead to examination of selective serotonin reuptake inhibitors (SSRIs) as potential treatments for cocaine dependence with mixed results, possibly due to drug interactions or specifics of concomitant behavioral therapy. The purpose of this study was to examine whether the SSRI citalopram would reduce cocaine positive urines in a 12-week, double-blind placebo-controlled trial. Seventy-six cocaine dependent patients received either citalopram 20 mg per day or placebo along with cognitive behavioral therapy (CBT) and contingency management (CM). Citalopram treated subjects showed a significant reduction in cocaine-positive urines during treatment compared to placebo treated subjects. No differences were noted in retention between the two groups. Side effects reported for citalopram were mild, with none leading to discontinuation of study drug. Results of this study support further examination of citalopram in combination with behavioral therapy as a treatment for cocaine dependence.