Steven D. Forman

Dissociating working memory from task difficulty in human prefrontal cortex

A functional magnetic resonance imaging (fMRI) study was conducted to determine whether prefrontal cortex (PFC) increases activity in working memory (WM) tasks as a specific result of the demands placed on WM, or to other processes affected by the greater difficulty of such tasks. Increased activity in dorsolateral PFC (DLPFC) was observed during task conditions that placed demands on active maintenance (long retention interval) relative to control conditions matched for difficulty. Furthermore, the activity was sustained over the entire retention interval and did not increase when task difficulty was manipulated independently of WM requirements. This contrasted with the transient increases in activity observed in the anterior cingulate, and other regions of frontal cortex, in response to increased task difficulty but not WM demands. Thus, this study established a double-dissociation between regions responsive to WM versus task difficulty, indicating a specific involvement of DLPFC and related structures in WM function.

Activation of the prefrontal cortex in a nonspatial working memory task with functional MRI

Functional magnetic resonance imaging (fMRI) was used to examine the pattern of activity of the prefrontal cortex during performance of subjects in a nonspatial working memory task. Subjects observed sequences of letters and responded whenever a letter repeated with exactly one nonidentical letter intervening. In a comparison task, subjects monitored similar sequences of letters for any occurrence of a single, prespecified target letter. Functional scanning was performed using a newly developed spiral scan image acquisition technique that provides high‐resolution, multislice scanning at approximately five times the rate usually possible on conventional equipment (an average of one image per second). Using these methods, activation of the middle and inferior frontal gyri was reliably observed within individual subjects during performance of the working memory task relative to the comparison task. Effect sizes (2–4%) closely approximated those that have been observed within primary sensory and motor cortices using similar fMRI techniques. Furthermore, activation increased and decreased with a time course that was highly consistent with the task manipulations. These findings corroborate the results of positron emission tomography studies, which suggest that the prefrontal cortex is engaged by tasks that rely on working memory. Furthermore, they demonstrate the applicability of newly developed fMRI techniques using conventional scanners to study the associative cortex in individual subjects.

Opiate Addicts Lack Error-Dependent Activation of Rostral Anterior Cingulate

BACKGROUND Healthy individuals performing response suppression tasks activate anterior cingulate cortex with occurrence of false alarm error responses to nontargets. Fundamental questions include whether this error-related activation provides a signal contributing to behavioral control and, given generally poorer performance on such tasks by addicts, whether this signal is disrupted in addiction. METHODS We used rapid, event-related functional magnetic resonance imaging to study 13 individuals with opiate dependence and 26 healthy control individuals performing a Go/NoGo task. RESULTS Compared with controls, opiate addicts exhibited an attenuated anterior cingulate cortex error signal and significantly poorer task performance. In controls, the individual level of event-related anterior cingulate cortex activation accompanying false alarm error positively predicted task performance, particularly sensitivity in discriminating targets from nontargets. CONCLUSIONS The attenuation of this error signal in anterior cingulate cortex may play a role in loss of control in addiction and other forms of impulsive behavior.

Sensitivity of prefrontal cortex to changes in target probability: A functional MRI study

Electrophysiological studies suggest sensitivity of the prefrontal cortex to changes in the probability of an event. The purpose of this study was to determine if subregions of the prefrontal cortex respond differentially to changes in target probabilities using functional magnetic resonance imaging (fMRI). Ten right‐handed adults were scanned using a gradient‐echo, echo planar imaging sequence during performance of an oddball paradigm. Subjects were instructed to respond to any letter but “X”. The frequency of targets (i.e., any letter but X) varied across trials. The results showed that dorsal prefrontal regions were active during infrequent events and ventral prefrontal regions were active during frequent events. Further, we observed an inverse relation between the dorsal and ventral prefrontal regions such that when activity in dorsal prefrontal regions increased, activity in ventral prefrontal regions decreased, and vice versa. This finding may index competing cognitive processes or capacity limitations. Most importantly, these findings taken as a whole suggest that any simple theory of prefrontal cortex function must take into account the sensitivity of this region to changes in target probability. Hum. Brain Mapping 13:26–33, 2001.

Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans.

OBJECTIVE Pharmacological and cognitive-behavioral treatments targeting insomnia and nightmares have been shown to be effective in the treatment of military veterans with sleep complaints comorbid with symptoms of stress-related disorders, including Post-Traumatic Stress Disorder (PTSD), but the two approaches have not been directly compared. This randomized controlled trial compared the effects of prazosin vs. a behavioral sleep intervention (BSI), targeting nightmares and insomnia against a placebo pill control condition on sleep and daytime symptoms. METHODS Fifty United States military veterans (mean age 40.9years, SD=13.2years) with chronic sleep disturbances were randomized to prazosin (n=18), BSI (n=17), or placebo (n=15). Each intervention lasted 8weeks. Participants completed self-report measures of insomnia severity, sleep quality, and sleep disturbances. All kept a sleep diary throughout the intervention period. Polysomnographic studies were conducted pre- and post-intervention. RESULTS Both active treatment groups showed greater reductions in insomnia severity and daytime PTSD symptom severity. Sleep improvements were found in 61.9% of those who completed the active treatments and 25% of those randomized to placebo. CONCLUSION BSI and prazosin were both associated with significant sleep improvements and reductions in daytime PTSD symptoms in this sample of military veterans. Sleep-focused treatments may enhance the benefits of first-line PTSD treatments.

Lethal Forethought: Delayed Reward Discounting Differentiates High- and Low-Lethality Suicide Attempts in Old Age

BACKGROUND The decision to commit suicide may be impulsive, but lethal suicidal acts often involve planning and forethought. People who attempt suicide make disadvantageous decisions in other contexts, but nothing is known about the way they decide about the future. Can the willingness to postpone future gratification differentiate between individuals prone to serious, premeditated and less serious, unplanned suicidal acts? METHODS Four groups of depressed participants aged 60 and older made choices between smaller immediate and larger delayed monetary rewards: 15 who had made high-lethality suicide attempts, 14 who had made low-lethality suicide attempts, 12 who seriously contemplated suicide, and 42 people with depression, but no history of suicidal thoughts. The reference group was 31 psychiatrically healthy elders. RESULTS Individuals who had made low-lethality attempts displayed an exaggerated preference for immediate rewards compared with nonsuicidal depressed and healthy control subjects. Those who had carried out high-lethality suicide attempts were more willing to delay future rewards, compared with low-lethality attempters. Better planned suicide attempts were also associated with willingness to wait for larger rewards. These effects were unchanged after accounting for education, global cognitive function, substance use disorders, psychotropic medications, and possible brain injury from attempts. Discount rates were correlated with having debt, but were not significantly associated with income, hopelessness, depressive severity, premorbid IQ, age at first attempt, or choice of violent means. CONCLUSIONS Although clinicians often focus on impulsivity in patients at risk for suicide, these data suggest that identifying biological characteristics and treatments for nonimpulsive suicidal older people may be even more important.

Factor structure of neurologic examination abnormalities in unmedicated schizophrenia.

The heterogeneity and uncertain significance of neurologic exam abnormalities in schizophrenia prompted us to evaluate their factor structure. We administered a modified version of the Neurological Evaluation Scale (NES) to 103 unmedicated patients with schizophrenia. Data were distilled by combining right- and left-side scores, and by eliminating superfluous, rarely abnormal and unreliable items from the analysis. Exploratory principal components analysis yielded four factors: repetitive motor tasks (fist-ring, fist-edge-palm, alternating fist-palm, dysdiadochokinesis); cognitive-perceptual tasks (memory, audiovisual integration, right-left orientation, face-hand test, rhythm tapping reproduction); balancing tasks (Romberg, tandem gait); and the palmomental reflex. Evaluation of the relationship between these factors and clinical and demographic variables revealed a robust correlation between the cognitive-perceptual factor and full-scale IQ score. This analysis is a step toward developing empirical subscales of a modified NES, which may provide insights into the nature of neurologic impairment in schizophrenia and may prove clinically useful.

Inter-rater reliability of the neurological examination in schizophrenia.

Neurological Examination Abnormalities (NEA) are prevalent in schizophrenia, but the significance of this is obscured by methodological problems. The Neurological Evaluation Scale (NES), the most widely used structured neurological examination in schizophrenia research, has had limited study of its inter-rater reliability (IRR). An augmented version of the NES was jointly administered (one examiner-rater and one observer-rater) by three pairs of psychiatrists to two populations of patients with idiopathic psychotic disorders. In addition to the ordinal and categorical data yielded by the original NES, continuous data were recorded in one of the series. Reliability analyses of our populations and a previously published study, reveal consistently adequate IRR in 12 of the 26 items assessed, and inconsistently adequate IRR in an additional 11. Consistent with studies using other NEA schedules, IRR was unacceptably low for some items that rely on subjective severity ratings. Certain rare abnormalities, which posed difficulties for the estimation of IRR, are probably not generally useful in the study of schizophrenia. Reliability estimates of continuous, ordinal and dichotomous data were comparable in most cases. We recommend that certain items from the NES be deleted, and that other studies of NEA in psychiatry follow similar procedures before undertaking further analyses.

Cerebrospinal fluid corticotropin-releasing factor increases following haloperidol withdrawal in chronic schizophrenia

Corticotropin-releasing factor (CRF), an endogenous neuropeptide, has been shown to coordinate endocrine, behavioral and autonomic responses to stress. However, while previous studies of cerebrospinal fluid (CSF) CRF in schizophrenia have not demonstrated significant differences compared to control groups, these studies have not examined the effects of symptom severity or antipsychotic medication. CSF CRF concentrations increased in 18 of 21 male schizophrenic (DSM-III-R) patients after maintenance haloperidol was replaced by placebo (P < 0.0001); there was also a trend for relatively greater increases in relapsers. CRF concentrations were not significantly related to severity of psychosis, depression, anxiety or negative symptoms. During haloperidol treatment, but not after medication withdrawal, worse childhood premorbid adjustment was associated with higher CSF CRF levels. Finally, in contrast to the positive correlation between CSF CRF and norepinephrine concentrations reported in depression, a negative trend was seen in this schizophrenic sample.

Simultaneous Glutamate and Perfusion fMRI Responses to Regional Brain Stimulation

Functional magnetic resonance imaging (fMRI) rests on the assumption that regional brain activity is closely coupled to regional cerebral blood flow (rCBF) in vivo. To test the degree of coupling, cortical brain activity was locally stimulated in rats by reversed microdialysis infusion of picrotoxinin, a γ-aminobutyric acid-A antagonist. Before and during the first 30 minutes of infusion, simultaneous fMRI (rCBF) and neurochemical (interstitial glutamate concentration) measures of brain activity were highly correlated (r = 0.83). After 30 minutes of picrotoxinin-induced stimulation, glutamate levels decreased but rCBF remained elevated, suggesting that additional factors modulate the relationship between neuronal neurotransmitters and hemodynamics at these later stages.