Kenji W. Sax

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.

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.

Enhanced response to repeated d-amphetamine challenge: Evidence for behavioral sensitization in humans

Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressively more robust behavioral response. This process serves as an important model of neural plasticity and has also been proposed as a model for a variety of psychiatric syndromes; however, there are no published controlled studies of behavioral sensitization in human subjects. The authors report results from a double-blind, placebo-controlled study of repeated d-amphetamine challenges in a sample of normal human volunteers. Eleven consecutively recruited normal volunteers participated in this 4-day protocol. Each subject received two daily doses of d-amphetamine (0.25 mg/kg) separated by 48 hours that alternated with two daily doses of matched placebo. Symptoms (activity/energy level, mood, rate, and amount of speech) and eye-blink rates were measured hourly for 5 hours following drug administration. All four measures demonstrated significantly enhanced increases following the second amphetamine dose as compared to the first amphetamine dose and both placebo conditions. These findings suggest that behavioral sensitization is measurable in human 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.

Attention and formal thought disorder in mixed and pure mania

The Continuous Performance Test (CPT) (Rosvold et al 1956) is a quantitative measure of sustained attention (or vigilance) that has been used primarily in studies examining cognitive deficits in schizophrenia (Cornblatt et al 1989; Nuechterlein et al 1984; Orzack and Kornetsky 1966; Wohlberg and Kornetsky 1973). Although it has been used less frequently in manic-depressive samples, results indicate that patients with mania are also significantly impaired on this measure (Nuechterlein et al 1991; Rund et al 1992). One question that has not been addressed, however, is whether this deficit differs among subtypes of mania. Since the issue of heterogeneity has been a potential source of variability in studies of schizophrenia, it is important to determine whether performance differs among various subtypes of mania. A number of studies suggest that mixed and pure mania represent distinct affective states with different clinical and phenomenological profiles (McElroy et al 1992). Mixed states of mania are concurrent or cyclical manic and depressive syndromes which appear to be associated with a more chronic course of illness relative to pure mania (McElroy et al 1992, 1993). In contrast to studies examining clinical and phenomenological factors, there is limited information about differences in cognitive functioning between the two groups. Efforts to identify symptom correlates of impaired CPT performance in schizophrenia have resulted in a possible association with formal thought disorder (Neuchterlein et al 1986; Pandurangi et al 1994). One prominent feature of formal thought disorder is

Behavioral sensitization in humans.

Abstract 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.

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.

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.

Lack of Enhanced Response to Repeated d-Amphetamine Challenge in First-Episode Psychosis: Implications for a Sensitization Model of Psychosis in Humans

Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressively more robust behavioral response. This process serves as a model for the development of psychosis, but has been little studied in humans. The authors report results from a double-blind, placebo-controlled study of repeated d-amphetamine challenges in 13 patients with first-episode manic or schizophrenic psychosis. Each patient received two daily doses of d-amphetamine (0.25 mg/kg) separated by 48 hours that alternated with two daily doses of matched placebo. Symptoms (activity/energy level, mood, rate and amount of speech, and severity of psychosis) and eye-blink rates were measured hourly for 5 hours following drug administration. In contrast to results from previous work in normal volunteers, none of the measures demonstrated the progressive increase following the second amphetamine dose as compared to the first dose that characterizes sensitization. These results suggest that patients with psychosis are already maximally sensitized, so cannot exhibit progressive behavioral enhancement following repeated stimulant challenges, or that patients with psychosis do not sensitize.

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.