Changes in neuronal activation with increasing attention demand in healthy volunteers: an fMRI study.

Several lines of evidence suggest that structures involved in mediating attention differentially respond to increasing processing demand. Investigation of differences in neuronal activation, however, has been complicated by methodological inconsistencies and concomitant discrepancies in degree of difficulty and subject effort between disparate tasks. In this study, we utilized fMRI to compare neural activation patterns associated with two related attention tasks associated with different degrees of processing load while controlling for degree of performance difficulty. Healthy volunteers performed two continuous performance tasks, utilizing an identical pairs paradigm (CPT-IP) and a matched simple number recognition paradigm with degraded stimuli (CPT-DS) during a single fMRI scan. Degree of stimulus resolution degradation in the latter CPT was designed to equalize degree of performance difficulty between the two tasks. CPT-IP and CPT-DS were both associated with activation of frontal, limbic, subcortical, and sensory integratory structures. CPT-IP administration was associated with significantly greater activation of left dorsolateral prefrontal cortex, bilateral posterior temporal cortex, bilateral putamen, and thalamus. This study demonstrates both that differing attention tasks are associated with a high degree of functional overlap and that increasing processing demand is associated with increased activation of specific portions of attentional networks.

Reaction time measures of sustained attention differentiate bipolar disorder from schizophrenia.

Although continuous performance tasks (CPTs) are becoming more common in psychiatric research, it remains unclear which performance measures best differentiate psychiatric patient groups and along which psychological dimensions. To address this the authors examined sustained attention decrements in patients with bipolar disorder and schizophrenia using CPT measures of perceptual sensitivity, response bias, and psychomotor processing speed. Patients with bipolar disorder with psychotic features (N=20), schizophrenia (N=20), and healthy controls (N=20) were evaluated using structured clinical interviews. These patients were rated with the Scale for the Assessment of Positive Symptoms and the Young Mania Rating Scale before completing a degraded-stimulus version of the CPT. Psychomotor processing speed was the only measure that reliably differentiated the groups across the entire vigilance period and was the strongest predictor of group membership. These findings suggest that reaction time measures may be sensitive to differences in the sustained attention abilities of patients with bipolar disorder and schizophrenia. By incorporating reaction time measures into CPT assessments, discriminant ability may be enhanced.

Behavioral sensitization in humans.

Behavioral sensitization is the process whereby repeated, intermittent stimulant administration produces a progressively greater and enduring behavioral response. For over two decades, behavioral sensitization has been reliably demonstrated in a number of different animal species and has been proposed as a model for the development of stimulant dependence. However, the application of this model to humans is limited since there have been relatively few studies of sensitization in human subjects. Nonetheless, results from these studies suggest that, similar to animal studies, enhanced behavioral responses do occur following repeated stimulant administration that resemble sensitization. Further research is necessary to examine characteristics of sensitization in humans, including the neurobiological systems involved.

Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance.

Previously, we reported progressively greater behavioral responses to repeated d-amphetamine in human subjects that represented a potential model of behavioral sensitization. To extend this work, 59 healthy volunteers were randomly assigned to one of three protocols: (1) placebo administered on days 1, 3, and 5 (PPP); (2) placebo administered on days 1 and 3, and d-amphetamine (0.25 mg/kg) on day 5 (PPA); and (3) d-amphetamine administered on days 1, 3, and 5 (AAA). Comparisons were made among the three groups to determine whether repeated d-amphetamine produced an increased behavioral response. Subjective ratings of vigor and euphoria exhibited the greatest response following the third dose of the AAA group, as hypothesized. In contrast, drug liking was greatest following a single or first d-amphetamine dose. These effects were greater in women. Progressive changes in subjective responses following repeated d-amphetamine administration may occur in healthy human subjects, although this effect may be greater for women.

Persistent attentional dysfunction in remitted bipolar disorder.

OBJECTIVES: Although previous research has shown that attentional dysfunction is common during acute mood episodes in individuals with bipolar disorder (BPD), few studies have examined whether attentional deficits are evident during periods of symptom stability. The goal of this study was to determine whether clinically stable individuals with BPD would have attentional disturbances relative to healthy subjects. METHODS: Fourteen patients with BPD and 12 healthy comparison subjects participated in the study, and were administered the Degraded Stimulus Continuous Performance Test (DSCPT), Digit Span Distractibility Test (DSDT) and Grooved Pegboard Test (GPT). Psychiatric symptoms were assessed with the Young Mania Rating Scale and the Scale for the Assessment of Positive Symptoms. Medication side effects were measured with the Simpson Rating Scale. RESULTS: The patient group responded significantly more slowly than the control group on the DSCPT (z = -2.52, p = 0.01) and the GPT (z = -3.37, p = 0.001). There was a trend towards the BPD patients demonstrating impaired perceptual sensitivity on the DSCPT (z = 1.68, p = 0.09). The two groups did not differ on the DSDT (z = -1.06, p = 0.3). Poor performance on the GPT and DSCPT target reaction time were not associated with symptom ratings or medications. CONCLUSION: The findings suggest that impairments in fine motor skills and reaction time may be present in clinically stable patients with BPD, even after accounting for psychiatric symptoms and medication effects. Performance decrements on attentional tasks may be in part reflective of motor impairments in patients with BPD.

Is impaired outcome following a first manic episode due to mood-incongruent psychosis?

BACKGROUND: Mood-incongruent psychosis during the course of bipolar disorder has been associated with poor outcome. However, it remains unknown whether this is secondary to persistent affective or psychotic symptoms or both. METHOD: Fifty patients with bipolar disorder between the ages of 16 and 45 years were recruited during their first psychiatric hospitalization for mania. These patients were evaluated using structured and semi-structured clinical instruments then followed longitudinally. Outcomes during the first eight months of follow-up were compared between patients with mood-incongruent psychosis and those without (i.e., patients with mood-congruent psychosis or no psychosis) during the index manic episode. Specifically, ratings of the percent of weeks during follow-up with psychosis and affective syndromes and symptoms, as well as ratings of global outcome (GAF), were compared. RESULTS: Patients with mood-incongruent psychosis at the index hospitalization exhibited significantly more weeks during follow-up with both mood-incongruent and mood-congruent psychotic symptoms than patients without mood-incongruent psychosis. Mood-incongruent psychosis was also associated with poorer overall functioning during the outcome interval. The groups did not differ in the percent of weeks with affective syndromes or symptoms. Treatment during follow-up did not differ between groups and was not associated with outcome variables in general. CONCLUSION: Mood-incongruent psychosis that occurs during the first manic episode appears to predict an increased likelihood of persistent psychotic symptoms during the subsequent eight months. This persistence of psychosis is associated with a worse overall course of illness as compared to patients without mood-incongruent psychosis. LIMITATIONS: These results apply to a relatively short outcome period and are from a single center.

fMRI of neuronal activation with symptom provocation in unmedicated patients with obsessive compulsive disorder.

BACKGROUND: Previous studies suggest that a neural circuit involving over-activation of cortical, paralimbic, limbic, and striatal structures may underlie OCD symptomatology, but results may have been limited by medication use in those studies. To address this, we examined the effects of symptom induction on fMRI neural activation in medication-free patients with OCD. METHODS: Seven outpatients with OCD were exposed to individually tailored provocative and innocuous stimuli during fMRI scans. Self-ratings of OCD symptoms were performed prior to each scan and after exposure to stimuli. Images were analyzed as composite data sets and individually. RESULTS: Stimulus presentation was associated with significant increases in OCD self-ratings. Significant activation was demonstrated in several regions of the frontal cortex (orbitofrontal, superior frontal, and the dorsolateral prefrontal); the anterior, medial and lateral temporal cortex; and the right anterior cingulate. Right superior frontal activation inversely correlated with baseline compulsion symptomatology and left orbitofrontal cortical activation was inversely associated with changes in OCD self-ratings following provocative stimuli. CONCLUSIONS: These results in unmedicated patients are consistent with those from previous studies with medicated patients and suggest that OCD symptomatology is mediated by multiple brain regions including the anterior cingulate as well as frontal and temporal brain regions.

Twelve-month outcome in bipolar patients with and without personality disorders.

BACKGROUND: We studied the 12-month course of illness after hospitalization for patients with a DSM-III-R diagnosis of bipolar disorder, manic or mixed episode, to identify the impact of a co-occurring personality disorder on measures of outcome. METHOD: Fifty-nine patients with bipolar disorder hospitalized for the treatment of a manic or mixed episode were recruited. Diagnostic, symptomatic, and functional evaluations were obtained at the index hospitalization. Personality disorders were assessed using the Structured Clinical Interview for DSM-III-R, personality disorders version (SCID-II). Patients were then reevaluated at 2, 6, and 12 months after discharge to assess syndromic, symptomatic, and functional recovery. Factors associated with outcome were identified using multivariate analyses. RESULTS: Survival analyses showed that in the 12-month follow-up period, subjects with bipolar disorder and co-occurring personality disorder were significantly less likely to achieve recovery. Logistic regression analyses indicated that both a diagnosis of personality disorder and noncompliance with treatment were significantly associated with lack of syndromic recovery. CONCLUSION: Co-occurring personality disorders in patients with bipolar disorder are associated with poor outcome after hospitalization for mania.

Neuroimaging in bipolar disorder.

OBJECTIVE: The authors reviewed neuroimaging studies of bipolar disorder in order to evaluate how this literature contributes to the current understanding of the neurophysiology of the illness. METHOD: Papers were reviewed as identified, using the NIMH PubMed literature search systems that reported results of neuroimaging studies involving a minimum of five bipolar disorder patients compared with healthy comparison subjects. RESULTS: Structural neuroimaging studies report mixed results for lateral and third ventriculomegaly. Recent studies suggest subcortical structural abnormalities in the striatum and amygdala, as well as the prefrontal cortex. Proton spectroscopic studies suggest that abnormalities in choline metabolism exist in bipolar disorder, particularly in the basal ganglia. Additionally, phosphorous MRS suggests that there may be abnormalities in frontal phospholipid metabolism in bipolar disorder. Functional studies have identified affective state-related changes in cerebral glucose metabolism and blood flow, particularly in the prefrontal cortex during depression, but no clear abnormalities specific to bipolar disorder have been consistently observed. CONCLUSIONS: The current literature examining the neurophysiology of bipolar disorder using neuroimaging is limited. Nonetheless, abnormalities in specific frontal-subcortical brain circuits seem likely. Additional targeted studies are needed to capitalize on this burgeoning technology to advance our understanding of the neurophysiology of bipolar disorder.

MRI analysis of the cerebellum in bipolar disorder: a pilot study.

Since qualitative CT studies have suggested decreased cerebellar size in patients with bipolar disorder, we performed a quantitative analysis of the cerebellum in patients with bipolar disorder to determine whether high-resolution, thin slice magnetic resonance imaging (MRI) morphometry would reveal similar results. Bipolar patients hospitalized for a first manic episode (n = 16), bipolar patients with prior manic episodes hospitalized for a manic episode (n = 14), and normal volunteers (n = 15) matched for age, sex, race, and education were recruited and anatomic brain scans were acquired using a Picker 1.5 Tesla MRI scanner. Right and left cerebellar hemisphere volumes and vermal areas V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were measured. ANCOVA comparing each ROI, adjusting for race, sex, age, total cerebral volume, and substance abuse duration, revealed a significant group effect for vermal V3 area. Specifically, V3 area was significantly smaller in multiple-episode patients than in first-episode patients or healthy volunteers. Number of previous episodes of depression may contribute to this finding. These results suggest that cerebellar vermal atrophy may be a later neurodegenerative event in patients with bipolar disorder who have had multiple affective episodes. The confounding effects of medications are considered.

Brain magnetic resonance imaging of structural abnormalities in bipolar disorder.

BACKGROUND: The neuropathogenesis of bipolar disorder remains poorly described. Previous work suggests that patients with bipolar disorder may have abnormalities in neural pathways that are hypothesized to modulate human mood states. We examined differences in brain structural volumes associated with these pathways between patients with bipolar disorder hospitalized with mania and healthy community volunteers. METHODS: Twenty-four patients with bipolar disorder and mania were recruited from hospital admission records. Twenty-two healthy volunteers were recruited from the community who were similar to the patients in age, sex, race, height, handedness, and education. All subjects were scanned using a 3-dimensional radio-frequency-spoiled Fourier acquired steady state acquisition sequence on a 1.5-T magnetic resonance imaging scanner. Scans were analyzed using commercial software. Prefrontal, thalamic, hippocampal, amygdala, pallidal, and striatal volumetric measurements were compared between the 2 groups. RESULTS: Patients with bipolar disorder demonstrated a significant (A = 0.64; F6,37 = 3.4; P = .009) overall difference in structural volumes in these regions compared with controls. In particular, the amygdala was enlarged in the patients. Brain structural volumes were not significantly associated with duration of illness, prior medication exposure, number of previous hospital admissions, or duration of substance abuse. Separating patients into first-episode (n = 12) and multiple-episode (n = 12) subgroups revealed no significant differences in any structure (P>.10). CONCLUSION: Patients with bipolar disorder exhibit structural abnormalities in neural pathways thought to modulate human mood.

Twelve-month outcome of patients with DSM-III-R schizoaffective disorder: comparisons to matched patients with bipolar disorder.

Schizoaffective disorder is a relatively common illness with an uncertain relationship with bipolar disorder. The publication of DSM-III-R in 1987 operationalized the diagnosis of schizoaffective disorder, separating it from psychotic bipolar disorder by the presence of persistent psychosis in the absence of affective symptoms. Since that time, there have been few prospective outcome studies comparing schizoaffective and bipolar disorders. The authors recruited 27 hospitalized patients with schizoaffective disorder and compared their 12-month outcome to 27 sex-, age-, socioeconomic status- and race-matched hospitalized bipolar patients. The schizoaffective patients were significantly less likely to achieve syndromic recovery than the bipolar patients, although neither group achieved high rates of symptomatic or functional recovery. As expected, the schizoaffective patients were more likely to exhibit persistent psychosis, with or without affective symptoms, throughout the follow-up interval. These data provide clinical support of the predictive value of the DSM-III-R criteria for schizoaffective disorder in a naturalistic outcome setting.

Frontosubcortical neuroanatomy and the continuous performance test in mania.

OBJECTIVE: The authors examined whether Continuous Performance Test scores correlate with frontosubcortical volumes in bipolar disorder. METHOD: The subjects were 17 patients hospitalized for an acute manic episode and 12 group-matched comparison subjects. They underwent magnetic resonance imaging and completed the Continuous Performance Test. RESULTS: The patients performed worse on the Continuous Performance Test and had smaller prefrontal cortical volumes than the comparison subjects. Within the patient group, Continuous Performance Test performance significantly correlated with prefrontal and hippocampal volumes. CONCLUSIONS: These results suggest that certain neuroanatomic structures may be associated with attentional dysfunction in mania.

Familial rates of affective and substance use disorders in patients with first-episode mania.

BACKGROUND: One explanation for the high co-occurrence between bipolar and substance use disorders is that substance abuse may precipitate affective symptoms in patients who otherwise may have not had the genetic risk for developing an affective illness. Previous studies comparing familial rates of affective illness between bipolar patients with and without alcohol use have provided conflicting results. We hypothesized that patients with bipolar disorder and antecedent alcohol abuse would have lower familial rates of affective illness than bipolar patients without antecedent alcohol abuse. METHODS: Family history data were obtained on 275 first-degree relatives of 51 patients hospitalized for a first manic episode using the Family History Research Diagnostic Criteria. RESULTS: Patients with bipolar disorder and antecedent alcohol abuse had lower familial rates of affective illness than patients with bipolar disorder without antecedent alcohol abuse (two-tailed Fisher's exact, P = 0.003). There was no statistically significant difference in the familial rates of affective illness between bipolar patients with and without antecedent drug abuse (other than alcohol). Patients with bipolar disorder and antecedent alcohol abuse had a significantly older age of onset of affective illness (27.6 years) than patients with bipolar disorder without antecedent alcohol abuse (20.6 years, z = 3.3, df = 1, P = 0.0009). There was no statistical difference in age of onset of affective illness between the patients with antecedent drug abuse and the patients without antecedent drug abuse. LIMITATIONS: Future studies with a larger number of bipolar patients, direct structured interviews of family members and better differentiation between substance abuse and dependence syndromes are needed to extend and replicate this pilot study. CONCLUSIONS: Our study suggests that there may be a subset of bipolar patients who have antecedent alcohol abuse and a subset who develop alcohol abuse after the onset of bipolar disorder. We further speculate that alcohol abuse may precipitate mania in some patients with bipolar disorder.

Traumatic brain injury in individuals convicted of sexual offenses with and without bipolar disorder.

The authors examined the occurrence of traumatic brain injury (TBI) in individuals convicted of sexual offenses with and without bipolar disorder and a comparison group of patients with bipolar disorder without a history of sexual offending behaviors. Individuals convicted of sexual offenses and diagnosed with bipolar disorder had greater rates of brain injury resulting from head trauma than individuals convicted of sexual offenses without bipolar disorder and comparison patients with bipolar disorder. TBI predated the first sexual offense and/or the onset of bipolar disorder in most subjects.

Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans.

BACKGROUND: Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressive behavioral response. Although animal models of sensitization are well established, the phenomenon has been relatively little studied in humans. In a previous study, we reported enhanced responses following a second as compared to a first amphetamine dose in eye-blink rate and ratings of increased motor activity/energy, increased speech, and elevated mood in normal human volunteers. This current study extends those findings in a new sample of normal volunteers. METHODS: Eleven normal human volunteers were administered three single oral doses of d-amphetamine (0.25 mg/kg) at 48-hour intervals, alternating with matched placebo in a randomized, double-blind trial. Hourly behavioral ratings included eye-blink rate, symptoms (elevated mood, increased speech, increased motor activity/energy), and subjective drug effects. RESULTS: Eye-blink rate and increased motor activity/energy ratings progressively increased following each challenge with the third amphetamine dose response significantly greater than all other conditions 4 hours postadministration. Similar, although less pronounced, responses were observed for elevated mood and subjective drug effect. CONCLUSIONS: These results provide further evidence for sensitization of some amphetamine-induced behaviors in human subjects.

Enhanced behavioral response to repeated d-amphetamine and personality traits in humans.

BACKGROUND: This study examined whether the magnitude of the behavioral response to repeated d-amphetamine administration previously demonstrated in a double-blind study in humans was associated with certain personality characteristics. METHODS: Eleven normal volunteers completed the Tridimensional Personality Questionnaire (TPQ) prior to being administered three doses of d-amphetamine (0.25 mg/kg) alternating with three doses of placebo over 6 consecutive days. Behavioral measures included eye-blink rates as well as ratings of elevated mood, increased motor activity/energy, and increased speech. These variables were assessed once prior to dosing, then hourly for 5 hours. RESULTS: A greater magnitude of change in elevated mood over the three amphetamine doses significantly correlated with ratings of the Novelty Seeking on the TPQ. CONCLUSIONS: These results suggest that similar to findings in animal models, there are certain intrinsic behavioral characteristics that are associated with amphetamine sensitivity in humans.

Symptom correlates of attentional improvement following hospitalization for a first episode of affective psychosis.

BACKGROUND: This study examined patients with a first-episode of affective psychosis during acute and compensated states in order to determine whether changes in attentional functioning over time were accompanied by changes in the severity of psychotic or affective symptoms. METHODS: Attentional performance was measured in patients (n = 27) using the degraded-stimulus continuous Performance Test (CPT) and symptoms were assessed at the time of index hospitalization, and 2 months after discharge. A comparison group of normal volunteers (n = 31) also performed the CPT two months apart. RESULTS: Patients performed significantly worse than controls at the initial testing but not at follow-up. The improvement in attentional performance significantly correlated with decreased severity of manic symptoms. CONCLUSIONS: Results suggest attentional dysfunction is a state-dependent characteristic of mania, and may provide an additional measure of clinical improvement following treatment.

Course of psychiatric and substance abuse syndromes co-occurring with bipolar disorder after a first psychiatric hospitalization.

BACKGROUND: Patients with bipolar disorder frequently meet criteria for other psychiatric and substance abuse diagnoses. To clarify relationships among these disorders, the authors examined the course of syndromes co-occurring with bipolar disorder for 12 months after a first hospitalization. METHOD: Seventy-seven patients were recruited from consecutive inpatient admissions who met DSM-III-R criteria for bipolar disorder, manic or mixed with psychosis. The 12-month syndromal course of co-occurring DSM-III-R alcohol and drug abuse disorders, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and other anxiety disorders were longitudinally recorded. RESULTS: The rates of all syndromes, except other anxiety disorders, were elevated. OCD demonstrated an interval course that frequently mirrored the course of the bipolar disorder. The courses of PTSD and substance abuse syndromes were separate from that of the bipolar disorder in many of those with both syndromes. Alcohol and drug abuse syndromes were strongly correlated. CONCLUSION: The obsessive-compulsive syndrome may represent an alternative expression of bipolar disorder in some patients. In contrast, PTSD appears to represent a truly separate disorder, which is possibly more prevalent in bipolar patients due to a shared risk factor. Substance abuse does not appear to simply result from attempts at self-medication or from the impulsivity of mania. These results suggest that future studies examining the course of syndromes co-occurring with bipolar disorder are warranted.

Attentional improvement following quetiapine fumarate treatment in schizophrenia.

This study examined changes in attentional performance in patients with schizophrenia during the 2 months after initiating treatment with quetiapine fumarate. Prior to treatment, attentional performance in patients with schizophrenia (n = 10) was significantly (p < 0.01) worse than in matched controls (n = 12). During treatment with quetiapine, performance in patients with schizophrenia improved, and by 2 months, did not differ significantly from that of the controls. These results suggest that quetiapine produces a significant improvement in attentional functioning in patients with schizophrenia.