Robin E. Gross

The Neural Correlates of Social Anxiety Disorder and Response to Pharmacotherapy

This study attempted to define further the neural processing events underlying social anxiety in patients with social anxiety disorder (SAD) and their response to pharmacotherapy. Social anxiety-related changes in regional cerebral blood flow were defined by [15O]H2 positron emission tomography (PET) in medication-free individuals with generalized SAD (gSAD), and age- and sex-matched comparison subjects, and analyzed using a linear mixed effects model. PET studies were again acquired in the gSAD individuals following an 8-week, flexible dose treatment trial of nefazodone. Both script-guided mental imagery of an anxiogenic social situation and a confrontational mental arithmetic task were associated with marked increases in self-rated anxiety in both subject groups. For gSAD subjects, social anxiety induced by guided mental imagery was associated with increased activity in the left postcentral gyrus and lenticulate, and the right inferior frontal and middle temporal gyri. Social anxiety induced by the mental arithmetic task was associated with activation of the medial and left dorsolateral prefrontal cortex, cerebellum, thalamus, insula, and ventral striatum. Both tasks were associated with relative decreases in activity in the right amygdala and the hippocampus. A direct group comparison indicated that comparison subjects exhibited a differing pattern of social anxiety-related neural activations. Nefazodone treatment was associated with marked clinical improvement. Comparison of social anxiety-related neural activations prior to and after nefazodone administration indicated greater activity in the precentral gyrus, insula, midbrain/hypothalamus, and middle frontal and anterior cingulate gyrus prior to treatment, and greater activity in the left middle occipital and bilateral lingual gyri, postcentral gyrus, gyrus rectus, and hippocampus after treatment. The results of an analysis relating neural activity and treatment-related changes in symptom severity indicated differential neural responses associated with states of symptom remission vs partial response. The observed social anxiety-related changes in distributed neural activity are consistent with cognitive models of SAD and adaptive decreases in amygdala activity in response to social anxiogenics, and support the association of altered frontal cortical responses with treatment response.

Anatomy and Mechanisms of Neurotensin‐Dopamine Interactions in the Central Nervous System

The modulatory influence of NT on brain DA neuronal function is widesprcad with effects reported for retinal to hypothalamicZ DA neurons. Light microscopic autoradiographic analyses have shown a dense localization of NT receptors on DA-containing neurons in the substantia nigra zona compacta and the ventral tegmental area (VTA).3 A facilitatory effect of NT on [3H]-DA release from rat mesencephalic cells in primary culture represents a functional corollary of this receptor di~tribution.~ Several studies using 6-hydroxydopamine-induced lesions of the nigrostriatal or mesolimbic DA system in the rat have also demonstrated the presence of NT receptors on presynaptic dopaminergic innerva t i~n .~-~ Along with the dopaminergic terminals, a large percentage of NT receptors is lost in the caudate putamen, nucleus accumbens, and olfactory tubercle following 6-hydroxydopamine lesion of the median forebrain bundlc.8 As well as receptors for both NT and DA existing in the same anatomical location, the neurotransmitters themselves are colocalized within neurons originating from the ventral tegmental area and projecting to either the nucleus accumbens9 or the prefrontal cortexlo in the rat. Whether an interaction would have the same physiological relevance in man is unclear because, in contrast to the rat, NT and DA in man arc not colocalized in neurons projecting to the prefrontal cortex. The presence of NT receptors on presynaptic dopaminergic terminals in the caudate-putamen correlates well with demonstrated biochemical effects of NT on this pathway. It has been shown that NT modifies DA mctabolism in the striatumll and facilitates the in vitro releasc of DA from rat striatal slices.lz A modulatory interaction between NT and DA receptors on receptor function is also supported by accumulating evidence. In vitro findings demonstrate that NT reduces the affinity of [3H]-DA binding sites in membranes from the subcortical

Neural network activation during a stop‐signal task discriminates cocaine‐dependent from non‐drug‐abusing men

Cocaine dependence is defined by a loss of inhibitory control over drug‐use behaviors, mirrored by measurable impairments in laboratory tasks of inhibitory control. The current study tested the hypothesis that deficits in multiple subprocesses of behavioral control are associated with reliable neural‐processing alterations that define cocaine addiction. While undergoing functional magnetic resonance imaging (fMRI), 38 cocaine‐dependent men and 27 healthy control men performed a stop‐signal task of motor inhibition. An independent component analysis on fMRI time courses identified task‐related neural networks attributed to motor, visual, cognitive and affective processes. The statistical associations of these components with five different stop‐signal task conditions were selected for use in a linear discriminant analysis to define a classifier for cocaine addiction from a subsample of 26 cocaine‐dependent men and 18 controls. Leave‐one‐out cross‐validation accurately classified 89.5% (39/44; chance accuracy = 26/44 = 59.1%) of subjects with 84.6% (22/26) sensitivity and 94.4% (17/18) specificity. The remaining 12 cocaine‐dependent and 9 control men formed an independent test sample, for which accuracy of the classifier was 81.9% (17/21; chance accuracy = 12/21 = 57.1%) with 75% (9/12) sensitivity and 88.9% (8/9) specificity. The cocaine addiction classification score was significantly correlated with a measure of impulsiveness as well as the duration of cocaine use for cocaine‐dependent men. The results of this study support the ability of a pattern of multiple neural network alterations associated with inhibitory motor control to define a binary classifier for cocaine addiction.

Neurotensin induces Fos and Zif268 expression in limbic nuclei of the rat brain

The endogenous tridecapeptide neurotensin exerts a wide range of behavioral, electrophysiological and neurochemical effects when administered directly into the brain. These effects are thought to result from the activation of distinct populations of neurotensin receptors distributed throughout the central nervous system. We have mapped the sites of functional change in the rat brain associated with the central administration of neurotensin using the induction of the nuclear protein products of the immediate early genes c-fos and zif268 as markers of cellular activation. The administration of neurotensin into the lateral ventricle of rats produced an increase in the number of nuclei positive for Fos and Zif268 immunoreactivity in the central and basolateral nuclei of the amygdala and the paraventricular and supraoptic nuclei of the hypothalamus. Neurotensin also produced an increase in serum corticosterone concentration and decrease in body temperature. The intraperitoneal administration of SR48692, a non-peptide neurotensin receptor antagonist, blocked the neurotensin-induced corticosterone secretion and significantly reduced the number of neurotensin-induced Fos-positive and Zif268-positive neurons in the amygdaloid complex. A significant positive correlation was found between the number of Fos-positive nuclei in the central or basolateral nucleus of the amygdala and the serum corticosterone concentration. A significant positive correlation was also found between the number of Zif-positive cells in the paraventricular nucleus of the hypothalamus and change in body temperature following treatment. Our findings indicate that the central role of neurotensin in increasing serum corticosterone involves the induction of Fos in the central and basolateral nuclei of the amygdala. In contrast, the neurotensin-induced hypothermia, which was unaffected by pretreatment with SR48692, involves Zif induction in the paraventricular nucleus of the hypothalamus. These data support further the existence of central neurotensin receptor subtypes which may regulate distinct immediate early genes.

Toxoplasma gondii exposure affects neural processing speed as measured by acoustic startle latency in schizophrenia and controls

The prevalence of Toxoplasma gondii (TOXO) infection in schizophrenia (SCZ) is elevated compared to controls (odds ratio=2.73). TOXO infection is associated with psychomotor slowing in rodents and non-psychiatric humans. Latency of the acoustic startle response, an index of neural processing speed, is the time it takes for a startling stimulus to elicit the reflexive response through a three-synapse subcortical circuit. We report a significant slowing of latency in TOXO seropositive SCZ vs. seronegative SCZ, and in TOXO seropositive controls vs. seronegative controls. Latency was likewise slower in SCZ subjects than in controls. These findings indicate a slowing of neural processing speed with chronic TOXO infection; the slowest startle latency was seen in the TOXO seropositive SCZ group.

Clinical correlates of attentional bias to drug cues associated with cocaine dependence.

BACKGROUND AND OBJECTIVE Preoccupation (attentional bias) related to drug-related stimuli has been consistently observed for drug-dependent persons with several studies reporting an association of the magnitude of measured attentional bias with treatment outcomes. The major goal of the present study was to determine if pre-treatment attentional bias to personal drug use reminders in an addiction Stroop task predicts relapse in treatment-seeking, cocaine-dependent subjects. METHODS We sought to maximize the potential of attentional bias as a marker of risk for relapse by incorporating individualized rather than generalized drug use cues to reflect the personal conditioned associations that form the incentive motivation properties of drug cues in a sample of cocaine-dependent subjects (N = 35). RESULTS Although a significant group Stroop interference effect was present for drug versus neutral stimuli (ie, attentional bias), the level of attentional bias for cocaine-use words was not predictive of eventual relapse in this sample (d = .56). A similar lack of prediction power was observed for a non-drug counting word Stroop task as a significant interference effect was detected but did not predict relapse outcomes (d = .40). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE The results of the present study do not provide clear support for the predictive value of individual variation in drug-related attentional bias to forecast probability of relapse in cocaine-dependent men.

A controlled trial of the adjunct use of d-cycloserine to facilitate cognitive behavioral therapy outcomes in a cocaine-dependent population☆

Cocaine dependence is a chronically relapsing disorder for which its predominant behavioral therapies are associated with only partial efficacy. The goal of this study was to determine if the N-methyl-d-aspartate (NMDA) glutamate receptor partial agonist and cognitive enhancer, d-cycloserine (DCS), could boost the cocaine abstinence and treatment retention goals of cognitive behavioral therapy (CBT). This study employed a placebo-controlled, randomized double-blind trial design of 44 cocaine-dependent men enrolled in a 4-week outpatient Substance Abuse Treatment Program (SATP) at the Atlanta Veterans Administration Medical Center. Subjects received 50mg of DCS or placebo prior to four weekly sessions of a condensed version of a manual-based CBT for cocaine dependence. Cocaine abstinence and treatment retention measures represented primary outcome variables. Relative to a 12-step based treatment-as-usual, an under-dosed CBT was associated with significant improvements in drug abstinence and treatment retention at 4-weeks and for maintenance of drug abstinence after four more weeks of follow-up. The robust response to the under-dosed CBT was not enhanced by the adjunct administration of DCS at either the 4- or 8-week endpoints. This controlled clinical trial failed to demonstrate an ability of DCS to boost the relapse prevention or treatment retention goals of CBT.

Targeting memory reconsolidation to prevent the return of fear in patients with fear of flying

When a memory is recalled, it may again exist in a labile state and stored information becomes amenable to change, a psychobiological process known as reconsolidation. Exposure therapy for anxiety disorders involves accessing a fear memory and modifying it with less fearful information. A preclinical study reported that providing a reminder of a fear memory 10 min prior to extinction training in humans decreased fear up to 1 year later (Schiller et al., 2010). Methods: For this pilot clinical study, we used virtual reality exposure therapy (VRE) for fear of flying (FoF) to determine if using a cue to reactivate the memory of the feared stimulus 10 min prior to exposure sessions leads to fewer anxiety‐related behaviors and a more durable response compared to a neutral cue. FoF participants (N = 89) received four sessions of anxiety management training followed by four sessions of VRE. Participants were randomly assigned to receive an FoF cue (reactivation group) or a neutral cue (control group) prior to the VRE sessions. Heart rate (HR) and skin conductance levels (SCLs) were collected during posttreatment and 3‐month follow‐up assessments as objective markers of fear responding. Results: Treatment was effective and all clinical measures improved equally between groups at posttreatment with maintained gains through follow‐ups. Significant differences were identified with regard to HR and SCL indices. Conclusions: These results suggest that memory reactivation prior to exposure therapy did not have an impact on clinical measures but may enhance the effect of exposure therapy at the physiological level.

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.

Impaired reward responsiveness in schizophrenia

BACKGROUND Anhedonia is a core negative symptom of schizophrenia. Schizophrenia patients report largely intact pleasure in consuming rewards, but have impairments in generating motivated behavior to pursue rewards, and show reduced fMRI activation of the reward pathway during presentation of rewarded stimuli. A computer based task measuring the development of a response bias in favor of rewarded stimuli permits assessment of reward-induced motivation. We hypothesized that subjects with schizophrenia would be impaired on this task. METHODS 58 schizophrenia subjects (SCZ) and 52 healthy controls (CON) were studied with a signal detection task to assess reward responsiveness. In multiple trials over three blocks subjects were asked to correctly identify two stimuli that were paired with unequal chance of monetary reward. The critical outcome variable was response bias, the development of a greater percent correct identification of the stimulus that was rewarded more often. RESULTS An ANOVA on response bias with Block as a repeated-measures factor and Diagnosis as a between-group factor indicated that SCZ subjects achieved a lower bias to rewarded stimuli than CON subjects (F(1,105)=8.82, p=0.004, η2=0.078). Post hoc tests indicated that SCZ subjects had significantly impaired bias in Block 1 (p=0.002) and Block 2 (p=0.05), indicating that SCZ were slower to achieve normal levels of bias during the session. CONCLUSIONS SCZ subjects were slower to develop response bias to rewarded stimuli than CON subjects. This finding is consonant with the hypothesis that people with schizophrenia have a blunted capacity to modify behavior in response to reward.