A preliminary controlled trial of divalproex in posttraumatic stress disorder.

BACKGROUND: Case reports and open trials have reported beneficial effects of divalproex in the treatment of posttraumatic stress disorder (PTSD). The objective of this study was to conduct a placebo-controlled study of the efficacy and tolerability of divalproex in chronic PTSD patients. METHODS: Patients were randomized to receive placebo or divalproex. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS). RESULTS: Of 29 patients randomized, 16 received divalproex and 13 placebo. There were no significant differences between groups in mean change from baseline to end point (last observation carried forward) on the CAPS total score or subscales except for a significant decrease in avoidance/numbing scores with placebo. The only significant difference in secondary outcomes was a greater improvement in Clinical Global Impression Scale-Severity favoring placebo. CONCLUSIONS: Divalproex was not superior to placebo in this study. This could be due to lack of efficacy of divalproex in this population, inadequate sample size to detect differences, or other factors. Further study of divalproex is needed to better clarify the role of this agent in PTSD.

Brain basis of early parent-infant interactions: psychology, physiology, and in vivo functional neuroimaging studies.

Parenting behavior critically shapes human infants' current and future behavior. The parent-infant relationship provides infants with their first social experiences, forming templates of what they can expect from others and how to best meet others' expectations. In this review, we focus on the neurobiology of parenting behavior, including our own functional magnetic resonance imaging (fMRI) brain imaging experiments of parents. We begin with a discussion of background, perspectives and caveats for considering the neurobiology of parent-infant relationships. Then, we discuss aspects of the psychology of parenting that are significantly motivating some of the more basic neuroscience research. Following that, we discuss some of the neurohormones that are important for the regulation of social bonding, and the dysregulation of parenting with cocaine abuse. Then, we review the brain circuitry underlying parenting, proceeding from relevant rodent and nonhuman primate research to human work. Finally, we focus on a study-by-study review of functional neuroimaging studies in humans. Taken together, this research suggests that networks of highly conserved hypothalamic-midbrain-limbic-paralimbic-cortical circuits act in concert to support aspects of parent response to infants, including the emotion, attention, motivation, empathy, decision-making and other thinking that are required to navigate the complexities of parenting. Specifically, infant stimuli activate basal forebrain regions, which regulate brain circuits that handle specific nurturing and caregiving responses and activate the brain's more general circuitry for handling emotions, motivation, attention, and empathy--all of which are crucial for effective parenting. We argue that an integrated understanding of the brain basis of parenting has profound implications for mental health.

Open-label trial of escitalopram in the treatment of posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly prevalent, disabling illness. Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication treatment, with sertraline, paroxetine, and fluoxetine being the most studied. More limited but favorable data suggest that citalopram, an SSRI, may also have a role in the treatment of PTSD. Its S-enantiomer escitalopram, which may have faster onset and greater magnitude of effect than citalopram in other conditions, has not yet been investigated in PTSD. OBJECTIVE: To assess the efficacy, safety, and tolerability of escitalopram in the treatment of PTSD. METHOD: A 12-week, prospective, open-label trial of escitalopram was conducted from January 2003 through August 2004 in military veterans with PTSD. Escitalopram was initiated at 10 mg daily for 4 weeks, then increased to 20 mg daily for the remainder of the study. Concomitant psychiatric medications were discontinued at least 2 weeks prior to enrollment. The primary outcome variable was the change from baseline to endpoint in global Clinician-Administered PTSD Scale-Symptom version (CAPS-SX) score. Secondary efficacy measures included the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales, the Hamilton Rating Scale for Depression (HAM-D), and the Davidson Trauma Scale (DTS). Posttraumatic stress disorder and comorbid diagnoses were established using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. RESULTS: Twenty-four of 25 patients were evaluated for efficacy. The mean global CAPS-SX score decreased from 79.4 (SD = 15.7) at baseline to 61.2 (SD = 24.7) at the end of the study (p = .0002). The CAPS-C avoidance/numbing and CAPS-D hyper-arousal subscale scores decreased significantly from baseline to endpoint (CAPS-C, p = .0171; CAPS-D, p = .0001), with trend-level reductions observed in CAPS-B reexperiencing subscale scores (p = .0593). Forty-five percent of patients (9/20) were much or very much improved at the end of the study (CGI-I of 1 or 2). The HAM-D and DTS also significantly improved (p = .0063 and p = .0004, respectively). Mild to moderate gastrointestinal disturbances were the most common side effects. Only 4 patients discontinued early because of adverse effects. CONCLUSIONS: This preliminary open-label study suggests that escitalopram is both efficacious and well tolerated in PTSD patients. However, randomized controlled studies are needed to confirm these results and to further define its potential role in the treatment of PTSD.

Regional brain activity in women grieving a romantic relationship breakup.

OBJECTIVE: Separation from loved ones commonly leads to grief reactions. In some individuals, grief can evolve into a major depressive episode. The brain regions involved in grief have not been specifically studied. The authors studied brain activity in women actively grieving a recent romantic relationship breakup. It was hypothesized that while remembering their ex-partner, subjects would have altered brain activity in regions identified in sadness imaging studies: the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex. METHOD: Nine right-handed women whose romantic relationship ended within the preceding 4 months were studied. Subjects were scanned using blood-oxygen-level-dependent functional magnetic resonance imaging while they alternated between recalling a sad, ruminative thought about their loved one (grief state) and a neutral thought about a different person they knew an equally long time. RESULTS: Acute grief (grief minus neutral state) was associated with increased group activity in posterior brain regions, including the cerebellum, posterior brainstem, and posterior temporoparietal and occipital brain regions. Decreased activity was more prominent anteriorly and on the left and included the anterior brainstem, thalamus, striatum, temporal cortex, insula, and dorsal and ventral anterior cingulate/prefrontal cortex. When a more lenient statistical threshold for regions of interest was used, additional increases were found in the lateral temporal cortex, supragenual anterior cingulate/medial prefrontal cortex, and right inferomedial dorsolateral prefrontal cortex, all of which were adjacent to spatially more prominent decreases. In nearly all brain regions showing brain activity decreases with acute grief, activity decreases were greater in women reporting higher grief levels over the past 2 weeks. CONCLUSIONS: During acute grief, subjects showed brain activity changes in the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex, consistent with the hypothesis. Subjects with greater baseline grief showed greater decreases in all these regions except for the cerebellum. Further imaging studies are needed to understand the relationship between normal sadness, grief, and depression.

Neural correlates of speech anticipatory anxiety in generalized social phobia.

Patients with generalized social phobia fear embarrassment in most social situations. Little is known about its functional neuroanatomy. We studied BOLD-fMRI brain activity while generalized social phobics and healthy controls anticipated making public speeches. With anticipation minus rest, 8 phobics compared to 6 controls showed greater subcortical, limbic, and lateral paralimbic activity (pons, striatum, amygdala/uncus/anterior parahippocampus, insula, temporal pole)--regions important in automatic emotional processing--and less cortical activity (dorsal anterior cingulate/prefrontal cortex)--regions important in cognitive processing. Phobics may become so anxious, they cannot think clearly or vice versa.

A pilot study of functional magnetic resonance imaging brain correlates of deception in healthy young men.

We hypothesized that specific brain regions would activate during deception, and these areas would correlate with changes in electrodermal activity (EDA). Eight men were asked to find money hidden under various objects. While functional MRI images were acquired and EDA was recorded, the subjects gave both truthful and deceptive answers regarding the money's location. The group analysis revealed significant activation during deception in the orbitofrontal cortex (OFCx) and anterior cingulate (AC), but individual results were not consistent. Individually and as a group, EDA correlated with blood flow changes in the OFCx and AC. Specific brain regions were activated during deception, but the present technique lacks good predictive power for individuals.

A review of functional neuroimaging studies of vagus nerve stimulation (VNS).

Vagus nerve stimulation (VNS) is a new method for preventing and treating seizures, and shows promise as a potential new antidepressant. The mechanisms of action of VNS are still unknown, although the afferent direct and secondary connections of the vagus nerve are well established and are the most likely route of VNS brain effects. Over the past several years, many groups have used functional brain imaging to better understand VNS effects on the brain. Since these studies differ somewhat in their methodologies, findings and conclusions, at first glance, this literature may appear inconsistent. Although disagreement exists regarding the specific locations and the direction of brain activation, the differences across studies are largely due to different methods, and the results are not entirely inconsistent. We provide an overview of these functional imaging studies of VNS. PET (positron emission tomography) and SPECT (single photon emission computed tomography) studies have implicated several brain areas affected by VNS, without being able to define the key structures consistently and immediately activated by VNS. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging), with its relatively high spatio-temporal resolution, performed during VNS, can reveal the location and level of the brain's immediate response to VNS. As a whole, these studies demonstrate that VNS causes immediate and longer-term changes in brain regions with vagus innervations and which have been implicated in neuropsychiatric disorders. These include the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla. Functional neuroimaging studies have the potential to provide greater insight into the brain circuitry behind the activity of VNS.

Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study.

Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.

BOLD-fMRI response vs. transcranial magnetic stimulation (TMS) pulse-train length: testing for linearity.

PURPOSE: To measure motor and auditory cortex blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to impulse-like transcranial magnetic stimulation (TMS) pulses as a function of train length. MATERIALS AND METHODS: Interleaved with fMRI at 1.5 T, TMS pulses 0.3-msec long were applied at 1 Hz to the motor cortex area for thumb. Six subjects were studied in a TR = 1 second session administering trains of 1, 2, 4, 8, and 16 pulses, and a TR = 3 seconds session administering trains of 1, 2, 4, 8, 16, and 24 pulses. A simple hemodynamic model with finite recovery and saturation was used to quantitatively characterize the BOLD-fMRI response as a function of train length. RESULTS: In both the activations directly induced in motor cortex by TMS and the indirect activations in auditory cortex caused by the sound of the TMS coil firing, the BOLD-fMRI responses to multiple pulses were well described by a summation of single-pulse impulse functions. CONCLUSION: Up to 24 discrete pulses, BOLD-fMRI response to 1 Hz TMS in both motor cortex and auditory cortex were consistent with a linear increase in amplitude and length with train length, possibly suggesting that stimuli of 1 to 2 seconds may be too long to represent impulses.

Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy.

In this 6-week, open-label trial, combat veterans meeting DSM-IV criteria for posttraumatic stress disorder (PTSD) were treated with the atypical antipsychotic quetiapine. The starting dose was 25 mg at bedtime with subsequent titration based on tolerability and clinical response. Primary outcome was measured using the Clinician Administered PTSD Scale (CAPS). Secondary assessments of efficacy included the Positive and Negative Symptom Scale (PANSS), the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Safety and tolerability evaluations included neurologic ratings, vital signs, and assessment of treatment-emergent side effects. Eighteen of 20 patients enrolled in the study completed 6 weeks of open-label treatment. The dose range of quetiapine was 25 to 300 mg daily, with an average of 100+/-70 mg/d. There was significant improvement in CAPS scores, from 89.8+/-15.7 to 67.5+/-21.0 (t=4.863, df=18, <0.005), and composite PANSS ratings from baseline to endpoint. General psychopathology (PANSS) and depressive symptoms (HRSD) were also reduced at the 6-week end point. There were no serious adverse events and no clinically significant changes in vital signs or neurologic ratings. This preliminary open trial suggests that quetiapine is well tolerated and may have efficacy in reducing PTSD symptoms in patients who have not had an adequate response other medications. Studies utilizing a randomized, controlled trial design and larger sample sizes are needed to better define the potential role of quetiapine and other atypical antipsychotics in the treatment of PTSD.

A potential role for thalamocingulate circuitry in human maternal behavior.

BACKGROUND: Little is known about the regional brain basis of human maternal behavior. To understand this better, we have been examining brain activity in mothers listening to infant cries. METHODS: We measured functional Magnetic Resonance Imaging brain activity in healthy, breastfeeding first-time mothers with young infants while they listened to infant cries, white noise control sounds, and a rest condition. Based on the thalamocingulate theory of maternal behavior and pilot work, we hypothesized that the cingulate, medial thalamus, medial prefrontal cortex, and right orbitofrontal cortex would display more activity with infant cries than with white noise (comparison 1) and would uniquely activate with the cries, meaning that these regions would display activity with cry minus rest but not with white noise minus rest (comparison 2). RESULTS: In hypothesized regions, the group displayed more activity in the medial thalamus, medial prefrontal and right orbitofrontal cortices with both comparisons. The anterior and posterior cingulate cortex displayed more activity only with comparison 1. In non-hypothesized brain regions, several other structures thought important in rodent maternal behavior displayed activity with both comparisons including the midbrain, hypothalamus, dorsal and ventral striatum, and vicinity of the lateral septal region. CONCLUSIONS: Our results partially support our hypotheses and are generally consistent with neuroanatomical studies of rodent maternal behavior.

Are there really no evolutionarily stable strategies in the iterated prisoner's dilemma?

The evolutionary form of the iterated prisoner's dilemma (IPD) is a repeated game where players strategically choose whether to cooperate with or exploit opponents and reproduce in proportion to game success. It has been widely used to study the evolution of cooperation among selfish agents. In the past 15 years, researchers proved over a series of papers that there is no evolutionarily stable strategy (ESS) in the IPD when players maintain long-term relationships. This makes it difficult to make predictions about what strategies can actually persist as prevalent in a population over time. Here, we show that this no ESS finding may be a mathematical technicality, relying on implausible players who are "too perfect" in that their probability of cooperating on any move is arbitrarily close to either 0 or 1. Specifically, in the no ESS proof, all strategies were allowed, meaning that after a strategy X experiences any history H, X cooperates with an unrestricted probability p (X, H) where 0< or =p (X, H)< or =1. Here, we restrict strategies to the set S in which X is a member of S [corrected] if after any H, X cooperates with a restricted probability p (X, H) where e< or =p (X, H)< or =1-e and 0