William Boshoven

Timing of extinction relative to acquisition: A parametric analysis of fear extinction in humans

Fear extinction is a reduction in conditioned fear following repeated exposure to the feared cue in the absence of any aversive event. Extinguished fear often reappears after extinction through spontaneous recovery. Animal studies suggest that spontaneous recovery can be abolished if extinction occurs within minutes of acquisition. However, a limited number of human extinction studies have shown that short interval extinction does not prevent the return of fear. For this reason, we performed an in-depth parametric analysis of human fear extinction using fear-potentiated startle. Using separate single-cue and differential conditioning paradigms, participants were fear conditioned and then underwent extinction either 10 min (Immediate) or 72 hr (Delayed) later. Testing for spontaneous recovery occurred 96 hr after acquisition. In the single cue paradigm, the Immediate and Delayed groups exhibited differences in context, but not fear, conditioning. With differential conditioning, there were no differences in context conditioning and the Immediate group displayed less spontaneous recovery. Thus, the results remain inconclusive regarding spontaneous recovery and the timing of extinction and are discussed in terms of performing translational studies of fear in humans.

An fMRI Study of the Interaction of Stress and Cocaine Cues on Cocaine Craving in Cocaine-Dependent Men

Acute stress is associated with relapse in cocaine addiction, possibly through the activation of craving-related neural circuitry. Neural responses to cocaine cues and acute stress were investigated in an fMRI study. Ten male participants mentally re-enacted personalized scripts about cocaine use and a neutral experience both with and without a stressor present (anticipation of electrical shock). Interaction analysis between script type and stress condition revealed greater activation of the posterior cingulate cortex and of the parietal lobe during the cocaine script in the presence of the stressor. These data suggest that stress may precipitate relapse in cocaine addiction by activating brain areas that mediate reward processing and the attentional and mnemonic bias for drug use reminders.

Altered engagement of attention and default networks during target detection in schizophrenia

Recent studies have implicated inappropriate engagement of functional brain networks in schizophrenia. This fMRI study examined task-induced activations and deactivations in 10 schizophrenia patients with prominent negative symptoms and 10 healthy controls during a simple target detection task. Group comparison revealed recruitment of distinct attentional networks during this task, with schizophrenia subjects activating the dorsal attention system and controls activating the executive network. Further, schizophrenia patients failed to deactivate posterior cingulate regions during the task, supporting recent studies of altered default mode processing. These findings support theories of dysfunctional recruitment of large-scale brain networks in schizophrenia.

Heritability of acoustic startle magnitude, prepulse inhibition, and startle latency in schizophrenia and control families

Prepulse inhibition (PPI) is an acoustic startle paradigm that has been used as an operational measure of sensorimotor gating. Many patients with schizophrenia have impaired PPI, and several lines of evidence suggest that PPI may represent a heritable endophenotype in this disease. We examined startle magnitude and latencies in 40 schizophrenia patients, 58 first-degree relatives of these patients, and 100 healthy controls. After removing low-startlers, we investigated PPI and startle habituation in 34 schizophrenia patients, 43 relatives, and 86 control subjects. Heritability analyses were conducted using a variance-component approach. We found significant heritability of 45% for PPI at the 60-ms interval and 67% for startle magnitude. Onset latency heritability estimates ranged between 39% and 90% across trial types, and those for peak latency ranged from 29% to 68%. Heritability of startle habituation trended toward significance at 31%. We did not detect differences between controls and either schizophrenia patients or their family members for PPI, startle magnitude, or habituation. Startle latencies were generally longer in schizophrenia patients than controls. The heritability findings give impetus to applying genetic analyses to PPI variables, and suggest that startle latency may also be a useful measure in the study of potential endophenotypes for schizophrenia.

Differences in startle reflex and prepulse inhibition in European‐Americans and African‐Americans

The acoustic startle reflex and its modulation by a prepulse are psychophysiological phenomena that are commonly studied to evaluate various aspects of information processing. Recent reports in human populations suggest that subjects from disparate racial backgrounds may have significant differences in the startle response. To determine if this pattern could be observed in our subject population and whether it extended to prepulse inhibition (PPI), we evaluated baseline startle parameters and PPI in 53 African-Americans (AA) and 38 European-Americans (EA). In AA compared to EA, mean startle magnitude and probability of blink response were lower, with no difference in habituation. PPI was greater in AA than EA when groups were matched on baseline startle magnitude. These findings support the idea of racial differences in startle response. Implications for study design are highlighted, and possible environmental and genetic influences are considered.

Lack of relationship between acoustic startle and cognitive variables in schizophrenia and control subjects

Measures of acoustic startle such as prepulse inhibition (PPI) and startle latency have been found to be impaired in schizophrenia, and are commonly thought to be related to cognitive deficits in this disease. However, findings about the relationship between startle variables and cognitive performance have been equivocal. In this study, we examined correlations between startle measures (baseline startle magnitude, latency, habituation and PPI) and cognitive performance (using the Benton Visual Retention Test, Conners Continuous Performance Test, California Verbal Learning Test, Finger Tapping Test, and Wisconsin Card Sort Test) in 107 schizophrenia patients and 94 healthy controls. Overall, there was a lack of any significant relationship between these constructs in both populations when correcting for multiple comparisons. This suggests that alterations in startle measures seen in schizophrenia may not reflect elements of information processing that cause cognitive deficits in the disease.

Declarative memory and WCST-64 performance in subjects with schizophrenia and healthy controls

The Wisconsin Card Sorting Test (WCST) is a set-switching task used extensively to study impaired executive functioning in schizophrenia. Declarative memory deficits have also been associated with schizophrenia and may affect WCST performance because continued correct responding depends on remembering the outcome of previous responses. This study examined whether performance in visual and verbal declarative memory tasks were associated with WCST performance. Subjects comprised 30 patients with schizophrenia or schizoaffective disorder (SCZ) and 30 demographically matched healthy controls (CON) who were tested on the WCST, the Benton Visual Retention Test (BVRT), the California Verbal Learning Test (CVLT), and the Continuous Performance Test (CPT). SCZ subjects showed significant correlations between visual and verbal declarative memory and performance on the WCST-64 that were in the hypothesized direction such that worse memory performance was associated with worse performance on the WCST. CON subjects did not show a significant relationship between visual or verbal memory and WCST-64 performance. Fishers r to z transformations indicated that the associations between declarative memory and WCST-64 performance in the SCZ subjects differed significantly from those of CON subjects. The findings suggest that interpretations of WCST-64 scores for subjects with schizophrenia should be considered in light of their declarative memory functioning.

The effect of antipsychotic medications on acoustic startle latency in schizophrenia

Prepulse inhibition of the acoustic startle reflex (PPI) is extensively studied as a biomarker of schizophrenia (SCZ); however, antipsychotic medication can confound the measure. Latency, the time between the startling stimulus and the reflexive eye blink, provides an index of neural processing speed and is 90% heritable. SCZ subjects have slower latency than controls (CON). This study examined the effects of antipsychotic medication on startle latency. 108 CON and 132 SCZ subjects in three medication subgroups (94 on second-generation antipsychotics (SGA), 25 on first-generation antipsychotics (FGA), 13 unmedicated (NoMed)) were tested on a standard acoustic startle paradigm designed to measure startle magnitude, PPI, and latency. Latency was slower in SCZ compared to CON subjects (p=0.005). Latency did not differ between the three SCZ medication groups. When CON were added to that model, both the NoMed subjects (p=0.04) and the SGA subjects (p=0.003) were slower than CON subjects. For PPI, CON did not differ from SCZ analyzed as a single group. When SCZ subjects were divided into medication groups, PPI was lower in NoMed subjects than the CON group (p=0.03), the SGA group (p=0.02) and the FGA group (p=0.05). SCZ subjects on any medication did not differ from CON. Thus, latency was partially normalized by antipsychotic medication, but this did not obscure the slower latency in SCZ compared to CON. Therefore latency is both trait and state related, whereas medication normalized PPI and obscured any difference between SCZ and CON.