Competing Motivations: Proactive Response Inhibition Toward Addiction-Related Stimuli in Quitting-Motivated Individuals.

We examined whether addiction-related cues impact proactive inhibition (the restraint of actions in preparation for stopping) in individuals who are motivated to quit gambling or cannabis use. In Study 1, treatment-seeking individuals with cannabis use disorder and matched controls performed a stop-signal task that required them to inhibit categorizing cannabis or neutral pictures, and within varying levels of stop-signal probability. In Study 2, two groups of individuals, who applied to a voluntary self-exclusion program toward gambling, performed the stop-task following relaxation or gambling craving induction, with results compared to non-gamblers. Study 1 showed that despite being less efficient in proactive inhibition, individuals with cannabis use disorder exhibited heightened proactive inhibition toward cannabis cues. In Study 2, proactive inhibition toward gambling cues was heightened in gamblers after craving, but the degree of proactive adjustment decreased as a function of induced changes in gambling-related motivation. Present findings demonstrate that exposure to addiction-related cues can modulate proactive inhibition in individuals who are motivated to restrict their addictive behaviors.

Changes in functional connectivity of the amygdala during cognitive reappraisal predict symptom reduction during trauma-focused cognitive-behavioral therapy among adolescent girls with post-traumatic stress disorder.

BACKGROUND: While trauma-focused cognitive-behavioral therapy (TF-CBT) is the 'gold standard' treatment for pediatric post-traumatic stress disorder (PTSD), little is known about the neural mechanisms by which TF-CBT produces clinical benefit. Here, we test the hypothesis that PTSD symptom reduction during TF-CBT among adolescent girls with PTSD is associated with changes in patterns of brain functional connectivity (FC) with the amygdala during cognitive reappraisal. METHOD: Adolescent girls with PTSD related to physical or sexual assault (n = 34) were enrolled in TF-CBT, delivered in an approximately 12-session format, in an open trial. Before and after treatment, they were engaged in a cognitive reappraisal task, probing neural mechanisms of explicit emotion regulation, during 3 T functional magnetic resonance imaging. RESULTS: Among adolescent girls completing TF-CBT with usable pre- and post-treatment scans (n = 20), improvements in self-reported emotion from pre- to post-treatment were positively related to improvements in PTSD symptoms. Adolescent girls with greater post-treatment symptom reduction were also able to suppress amygdala-insula FC while re-appraising, which was not evident in girls with less symptom reduction. Pre- to post-treatment changes in right amygdala to left insula FC that scaled with PTSD symptom reduction also scaled with improvements in emotion regulation. CONCLUSIONS: These preliminary results suggest the neurocircuitry mechanisms through which TF-CBT produces clinical outcomes, providing putative brain targets for augmenting TF-CBT response.

Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress.

BACKGROUND: Early life stress (ELS) is a significant risk factor for depression. The effects of ELS exposure on neural network organization have not been differentiated from the effect of depression. Furthermore, many individuals exposed to ELS do not develop depression, yet the network organization patterns differentiating resiliency versus susceptibility to the depressogenic effects of ELS are not clear. METHOD: Women aged 18-44 years with either a history of ELS and no history of depression (n = 7), a history of ELS and current or past depression (n = 19), or a history of neither ELS nor depression (n = 12) underwent a resting-state 3-T functional magnetic resonance imaging (fMRI) scan. An emotion regulation brain network consisting of 21 nodes was described using graph analyses and compared between groups. RESULTS: Group differences in network topology involved decreased global connectivity and hub-like properties for the right ventrolateral prefrontal cortex (vlPFC) and decreased local network connectivity for the dorsal anterior cingulate cortex (dACC) among resilient individuals. Decreased local connectivity and increased hub-like properties of the left amygdala, decreased hub-like properties of the dACC and decreased local connectivity of the left vlPFC were observed among susceptible individuals. Regression analyses suggested that the severity of ELS (measured by self-report) correlated negatively with global connectivity and hub-like qualities for the left dorsolateral PFC (dlPFC). CONCLUSIONS: These preliminary results suggest functional neural connectivity patterns specific to ELS exposure and resiliency versus susceptibility to the depressogenic effects of ELS exposure.

Clinical milestones predict symptom remission over 6-month and choice of treatment of patients with major depressive disorder (MDD).

BACKGROUND: It is uncertain as to what short-term outcomes predict long-term treatment compliance and outcomes in patients with MDD. AIMS: To determine what treatment milestones predict symptom remission with long-term treatment with antidepressant medication. METHOD: Pooled analysis of four randomised, double-blind, active comparator, 6-month trials in MDD. RESULTS: Patients received double-blind treatment with escitalopram (N=699) or a comparator (citalopram, duloxetine, or paroxetine) (N=699). Onset of effect at week 2 was correlated with response at week 8, and response at week 8 with completion of 6-month treatment. Week 8 response was associated with a greater probability of achieving later remission. Week 24 remission (MADRS>or=10) was significantly (p<0.01) higher for patients treated with escitalopram (70.7%) than for the pooled comparators (64.7%). Week 24 complete remission (MADRS

Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.

The possibility that hypersecretion of corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal axis observed in patients with major depression was investigated by measuring the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia, or dementia. When compared to the controls and the other diagnostic groups, the patients with major depression showed significantly increased cerebrospinal fluid concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients this immunoreactivity was greater than the highest value in the normal controls. These findings are concordant with the hypothesis that CRF hypersecretion is, at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal axis characteristic of major depression.

Erythrosine (Red No. 3) and its nonspecific biochemical actions: what relation to behavioral changes?

Biochemical studies have shown that the ability of erythrosine to inhibit dopamine uptake into brain synaptosomal preparations is dependent on the concentration of tissue present in the assay mixture. Thus, the finding that erythrosine inhibits dopamine uptake (which, if true, would provide a plausible explanation of the Feingold hypothesis of childhood hyperactivity) may simply be an artifact that results from nonspecific interactions with brain membranes. In addition, although erythrosine given parenterally (50 milligrams per kilogram) did not alter locomotor activity of control of 6-hydroxydopamine-treated rats, erythrosine (50 to 300 milligrams per kilogram) attenuated the effect of punishment in a "conflict" paradigm.

Amygdala activity related to enhanced memory for pleasant and aversive stimuli.

Pleasant or aversive events are better remembered than neutral events. Emotional enhancement of episodic memory has been linked to the amygdala in animal and neuropsychological studies. Using positron emission tomography, we show that bilateral amygdala activity during memory encoding is correlated with enhanced episodic recognition memory for both pleasant and aversive visual stimuli relative to neutral stimuli, and that this relationship is specific to emotional stimuli. Furthermore, data suggest that the amygdala enhances episodic memory in part through modulation of hippocampal activity. The human amygdala seems to modulate the strength of conscious memory for events according to emotional importance, regardless of whether the emotion is pleasant or aversive.

Neural activity during attentional conflict predicts reduction in tinnitus perception following rTMS.

BACKGROUND: Subjective idiopathic tinnitus is an intrusive, distracting, and potentially disabling disorder characterized by phantom perception of sounds. Although tinnitus has no approved pharmacologic treatment, recent evidence supports the use of repetitive transcranial magnetic stimulation (rTMS) to alleviate tinnitus symptoms. OBJECTIVE/HYPOTHESIS: Repetitive TMS delivered over the middle superior temporal gyrus (STG) may alter ratings of tinnitus awareness and annoyance more than loudness due to change in attentional processing. STG has reciprocal connections to regions of the prefrontal cortex that mediate attention. To probe the hypothesized influence of STG stimulation on attention, a subset of patients with tinnitus enrolled in an rTMS clinical trial [n = 12, 9 male, mean (sd) age = 49 (15) years] underwent an attentional conflict task before and after rTMS treatment in a repeated-measures functional magnetic resonance imaging (fMRI) study. METHODS: The Multi-Source Interference Task (MSIT), a Stroop-based visual attentional conflict fMRI task, was used to map participants' neural processing of attentional conflict prior to rTMS intervention (Baseline) and after three rTMS intervention arms: Sham, 1 Hz, and 10 Hz (four sessions per arm, 1800 pulses per session, delivered @110% of the motor threshold over the posterior superior temporal gyrus). RESULTS: All measures of tinnitus severity (awareness, loudness, and annoyance) improved with 1 Hz rTMS intervention; however, the greatest and most robust changes were observed for ratings of tinnitus awareness (mean 16% reduction in severity from Baseline, p < 0.01). The MSIT elicited a similar pattern of neural activation among tinnitus participants at Baseline compared to an independent sample of 43 healthy comparison adults (r = 0.801, p = 0.001). Linear regression with bootstrap resampling showed that greater recruitment of bilateral prefrontal and bilateral parietal regions by MSIT at Baseline corresponded with poorer treatment response. Individual regions' activities explained 37-67% variance in participant treatment response, with left dorsolateral prefrontal cortex's MSIT activity at Baseline explaining the greatest reduction in tinnitus awareness following 1 Hz stimulation. Although left dorsolateral prefrontal cortex activity at Baseline also predicted reduction in tinnitus loudness and annoyance (∼50% variance explained), these symptoms were more strongly predicted by right middle occipital cortex (∼70% variance explained) - suggesting that the neural predictors of symptom-specific treatment outcomes may be dissociable. CONCLUSION: These candidate neural reactivity markers of treatment response have potential clinical value in identifying tinnitus sufferers who would or would not therapeutically benefit from rTMS intervention.

Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Obsessive-compulsive disorder. A double-blind trial of clomipramine and clorgyline.

Patients with obsessive-compulsive disorder who met DSM-III criteria and who had been ill for at least one year were studied in a double-blind, randomized, crossover comparison of the tricyclic antidepressant clomipramine hydrochloride and the monoamine oxidase inhibitor clorgyline hydrochloride. No significant improvement was evident after four weeks of treatment with placebo prior to the crossover study. Treatment with clomipramine was associated with significant improvement after both four and six weeks in measures of obsessions, anxiety, and depression. Antiobsessional responses to clomipramine did not depend on presence of depression. Improvement was correlated with plasma concentrations of clomipramine, but not with the plasma concentrations of any of its metabolites. No significant improvement was evident for the entire group with clorgyline treatment, although the conditions of individual patients did respond to the drug.

Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study.

Nineteen children (mean [+/- SD] age, 14.5 +/- 2.3 years) with severe, primary obsessive-compulsive disorder completed a ten-week, double-blind, controlled trial of clomipramine hydrochloride (mean dosage, 141 mg/day) or placebo, each of which was administered for five weeks. Half of the subjects had not responded to previous treatment with other tricyclic antidepressants. There was a significant improvement in observed and self-reported obsessions and compulsions that was independent of the presence of depressive symptoms at baseline. Improvement in obsessive-compulsive symptoms did not correlate significantly with plasma concentrations of the drug or its metabolites. Clomipramine appears to be effective in the treatment of children with obsessive-compulsive disorder and the treatment seems to be independent of an antidepressant effect.

Neural activity related to drug craving in cocaine addiction.

BACKGROUND: Crack cocaine dependence and addiction is typically associated with frequent and intense drug wanting or craving triggered by internal or environmental cues associated with past drug use. METHODS: Water O 15 positron emission tomography (PET) studies were used to localize alterations in synaptic activity related to cue-induced drug craving in 8 crack cocaine-dependent African American men. In a novel approach, script-guided imagery of autobiographical memories were used as individualized cues to internally generate a cocaine craving state and 2 control (ie, anger and neutral episodic memory recall) states during PET image acquisition. RESULTS: The mental imagery of personalized drug use and anger-related scripts was associated with self-ratings of robust drug craving or anger, and comparable alterations in heart rate. Compared with the neutral imagery control condition, imagery-induced drug craving was associated with bilateral (right hemisphere amygdala activation greater than left) activation of the amygdala, the left insula and anterior cingulate gyrus, and the right subcallosal gyrus and nucleus accumbens area. Compared with the anger control condition, internally generated drug craving was associated with bilateral activation of the insula and subcallosal cortex, left hippocampus, and anterior cingulate cortex and brainstem. A brain-wide pixel-by-pixel search indicated significant positive and negative correlations between imagery-induced cocaine craving and regional cerebral blood flow (rCBF) in distributed sites. CONCLUSIONS: The collected findings suggest the craving-related activation of a network of limbic, paralimbic, and striatal brain regions, including structures involved in stimulus-reward association (amygdala), incentive motivation (subcallosal gyrus/nucleus accumbens), and anticipation (anterior cingulate cortex).

The changing roles and targets for animal models of schizophrenia.

Unlike disorders of other fields of medicine (eg., diabetes, heart disease), schizophrenia has been only marginally impacted by the study of animal models. This gap reflects the incomplete understanding of the causes and mechanisms of schizophrenia and the resulting lack of defined targets for model development. However, prior attempts at modeling in animals the complex symptoms of schizophrenia have given way to more promising component models. This review will address the evolving field of animal models of schizophrenia with a focus on models of errors in neurotransmission, and of psychophysiological deficits, with a concluding discussion of the present and future promise of genetic-based models. Evolving models based on the long-held conceptualization of schizophrenia as being based on errors in neurotransmission are discussed as regards the integration of newer findings implicating alterations in dopamine, glutamate and neurotensin function in the pathophysiology and pharmacotherapy of schizophrenia. The case for the more recent conceptualization of schizophrenia as a core deficit in information processing and stimulus filtering is discussed. Animal behavioral paradigms that model psychophysiologic constructs of stimulus processing deficits related to schizophrenia include prepulse inhibition (PPI), a model of sensorimotor gating, or latent inhibition (LI), a model of salience learning. These models represent both better supported associations with schizophrenia and more productive targets and are providing important new information regarding the psychopharmacology of schizophrenia. Genetic models of schizophrenia are based on the demonstrated heritability of the disorder and more recent pharmacogenetic findings for antipsychotic medications. Genetic-based animal models use behavioral or molecular genetic techniques to manipulate behaviors related to schizophrenia by altering the frequencies of related genes. The future development of increasingly informative animal models of schizophrenia will be dependent on a more complete understanding of schizophrenia, an integration of findings across animal models and refinements in the criteria used to assess model "validity" that better reflect the changing nature and roles of animal models of schizophrenia.

Preliminary studies of 6 beta-hydroxydexamethasone and its importance in the DST.

The role of the metabolites of dexamethasone (DEX) in the dexamethasone suppression test (DST) has never been fully elucidated. We report here our preliminary studies of 6 beta-hydroxydexamethasone (6 OH-Dex), a known metabolite of DEX, on the hypothalamic-pituitary-adrenal (HPA) axis of the rat; its activity in the most commonly used radioimmunoassay for plasma DEX; and its plasma concentrations in a normal human subject during the standard 1.0 mg DST. Six OH-Dex administered subcutaneously to rats at a dose of 1 mg/kg was able to completely suppress corticosterone production for at least 3 hr. In the IgG Corp. radioimmunoassay for plasma DEX, 6 OH-Dex was moderately cross-reactive yielding a 50% cross-reactivity of 10%. Gas chromatographic coupled mass spectroscopic analysis of human plasma samples, obtained 12 to 20 hr after the oral ingestion of 1.0 mg DEX, demonstrated similar plasma concentrations for both the parent compound and the 6-hydroxyl metabolite. The relevance of these findings, particularly to pharmacokinetic studies of the DST, is discussed.

Neural correlates of maternal separation in rhesus monkeys.

BACKGROUND: The neurobiological basis of stress and anxiety in primates remains poorly understood. In this study, we examined the neural response to a naturalistic social stressor: maternal separation. We used rhesus monkeys as an animal model because of their close phylogenetic affinity with humans. METHODS: Six juvenile rhesus monkeys received [(18)F]-fluorodeoxyglucose positron emission tomography scans following 1) a period together with their mothers and again after separation from their mothers 2) with or 3) without visual contact. Image subtraction revealed brain regions that exhibited altered activity during separation. In addition, plasma cortisol concentrations obtained following each condition were tested for correlations with regional brain activity. RESULTS: Maternal separation activated the right dorsolateral prefrontal cortex and the right ventral temporal/occipital lobe. There was also decreased activity in left dorsolateral prefrontal cortex associated with separation stress. Correlational analyses demonstrated these activated and deactivated regions to be positively and negatively correlated with cortisol, respectively. Additionally, correlational analyses revealed cortisol-related activation in brainstem areas previously implicated in stress and anxiety. CONCLUSIONS: In juvenile rhesus monkeys, the stress of maternal separation is associated with activation in the right dorsolateral prefrontal cortex and ventral temporal/occipital lobes and decreased activity in the left dorsolateral prefrontal cortex.

Thioridazine and the neuroleptic radioreceptor assay.

When the neuroleptic radioreceptor assay (NRRA) has been used to monitor total neuroleptic-like activity (NLA) in the blood of patients taking thioridazine, the NLA values obtained from the NRRA are much lower than values calculated in the same sample by measuring the actual concentrations of parent drug and active metabolites and multiplying these values by the relative potency of each compound. The present report demonstrates that in the NRRA for thioridazine or its active metabolites, the normal displacement of [3H]-spiperone from striatal membranes by thioridazine is altered in the presence of sera. The inclusion of serum (50 microliter/ml) distorts the sigmoidal displacement curves, such the resulting log-logit (or Hill) slope is markedly decreased. Similar serum-induced changes in the log-logit slope are seen for two active metabolites of thioridazine, but not for chlorpromazine or haloperidol. As a consequence, when one of these latter drugs is used as a standard, the NRRA substantially underestimates the actual NLA (chlorpromazine equivalents) values for patients treated with thioridazine. Moreover, because of differences in the magnitude of the effect with serum from different individuals, it is not possible to control completely for this effect. Thus, these data reconcile discrepancies that have been reported for data from the NRRA versus that from direct analytical measurements, and demonstrate that the use of the NRRA as a quantitative tool in the clinical pharmacology of thioridazine may lead to erroneous estimations of active drug and metabolites in the blood.

Plasma steady-state concentrations of hydroxylated metabolites of clomipramine.

Plasma clomipramine, desmethylclomipramine, 8-hydroxyclomipramine, and 8-hydroxydesmethylclomipramine concentrations were measured in nine obsessive-compulsive outpatients. The mean dose of clomipramine at steady state was 237.5 +/- 51.8 (SD) mg/24 hr. The mean concentrations at steady state were: clomipramine, 147.5 +/- 57.5; desmethylclomipramine, 313.0 +/- 170.0; 8-hydroxyclomipramine, 56.1 +/- 20.9; and 8-hydroxydesmethylclomipramine, 152.7 +/- 83.2 ng/ml. In vitro, the hydroxymetabolites of clomipramine and desmethylclomipramine exhibited serotonin reuptake potency of the same order as that of the parent compounds.

Platelet MAO activity in posttraumatic stress disorder.

Platelet monoamine oxidase (MAO) activity was assessed in 23 patients with posttraumatic stress disorder and 19 age-matched male control subjects. An overall significantly lower MAO activity was observed in the posttraumatic stress disorder group. When the group was divided into those with and those without a history of alcohol abuse, only the former group differed significantly from control subjects. The heuristic importance of these findings is discussed.

Sertraline and desmethylsertraline in human breast milk and nursing infants.

OBJECTIVE: The purpose of this study was to determine the concentrations of sertraline and desmethylsertraline in both human breast milk and infant serum. METHOD: Breast milk samples from 12 women were collected at specific time intervals after oral doses of sertraline (25-200 mg once daily). For 11 mother-infant pairs, maternal serum levels 24 hours after a dose and their infants' serum levels 2-4 hours after nursing were ascertained by high-performance liquid chromatography. RESULTS: Sertraline and desmethylsertraline were present in all breast milk samples, with a gradient from "fore" milk to "hind" milk. The highest concentrations of sertraline were observed in hind milk 7-10 hours after maternal dose. Increasing the maternal dose of sertraline resulted in increased breast milk concentrations of both sertraline and desmethylsertraline. Detectable concentrations of sertraline were found in three nursing infants and desmethylsertraline in six. No adverse effects of exposure were observed in any infant. CONCLUSIONS: Sertraline and desmethylsertraline were present in the breast milk of nursing women treated with sertraline. Concentrations were affected by aliquot of milk sampled, time after maternal dose, and maternal daily dose. The infants' serum concentrations detected were below the detection limit of most commercial laboratories. The presence of desmethylsertraline in six infants' samples underscores the importance of metabolite monitoring in determining infant exposure. Estimates of daily infant exposure can be determined after analysis of sertraline and desmethylsertraline concentrations from one full breast at maternal serum steady state. Future studies of breast milk and infant serum samples should address these issues.

Alterations in the functional anatomy of working memory in adult attention deficit hyperactivity disorder.

OBJECTIVE: The authors used a functional neuroimaging study with a working memory probe to investigate the pathophysiology of attention deficit hyperactivity disorder (ADHD). Their goal was to compare regional cerebral blood flow (rCBF) changes related to working memory in adults with and without ADHD. METHOD: Using [(15)O]H(2)O positron emission tomography (PET) studies, the authors compared the sites of neural activation related to working memory in six adult men diagnosed with ADHD and six healthy men without ADHD who were matched in age and general intelligence. RESULTS: Task-related changes in rCBF in the men without ADHD were more prominent in the frontal and temporal regions, but rCBF changes in men with ADHD were more widespread and primarily located in the occipital regions. CONCLUSIONS: These data suggest the use of compensatory mental and neural strategies by subjects with ADHD in response to a disrupted ability to inhibit attention to nonrelevant stimuli and the use of internalized speech to guide behavior.