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Objective:To evaluate in vivo the dynamics of endogenous dopamine (DA) neurotransmission during migraine ictus with allodynia.Methods:We examined 8 episodic migraineurs and 8 healthy controls (HC) using PET with [11C]raclopride. The uptake measure of [11C]raclopride, nondisplaceable binding potential (BPND), would increase when there was a reduction in endogenous DA release. The opposite is true for a decrease in [11C]raclopride BPND. Patients were scanned twice: one PET session was during a spontaneous migraine ictus at rest, followed by a sustained thermal pain threshold (STPT) challenge on the trigeminal region, eliciting an allodynia experience; another was during interictal phase.Results:Striatal BPND of [11C]raclopride in migraineurs did not differ from HC. We found a significant increase in [11C]raclopride BPND in the striatum region of migraineurs during both headache attack and allodynia relative to interictal phase. However, when compared to the migraine attack at rest, migraineurs during the STPT challenge had a significant sudden reduction in [11C]raclopride BPND in the insula. Such directional change was also observed in the caudate of HC relative to the interictal phase during challenge. Furthermore, ictal changes in [11C]raclopride BPND in migraineurs at rest were positively correlated with the chronicity of migraine attacks, and negatively correlated with the frequency during challenge.Conclusions:Our findings demonstrate that there is an imbalanced uptake of [11C]raclopride during the headache attack and ictal allodynia, which indicates reduction and fluctuation in ictal endogenous DA release in migraineurs. Moreover, the longer the history and recurrence of migraine attacks, the lower the ictal endogenous DA release.

Objective: To test whether black cohosh (BC) exhibits an action on the central endogenous opioid system in postmenopausal women. Design: This was a mechanistic study conducted in the same individuals of luteinizing hormone pulsatility with a saline/naloxone challenge (n = 6) and positron emission tomography with [ 11 C]carfentanil, a selective K-opioid receptor radioligand (n = 5), before and after 12 weeks of unblinded treatment with a popular BC daily supplement. Results: BC treatment for 12 weeks at a standard dose (Remifemin, 40 mg/day) had no effect on spontaneous luteinizing hormone pulsatility or estrogen concentrations. With naloxone blockade, there was an unexpected suppression of mean luteinizing hormone pulse frequency (saline vs naloxone = 9.0 T 0.6 vs 6.0 T 0.7 pulses/16 h; P = 0.056), especially during sleep when the mean interpulse interval was prolonged by approximately 90 minutes (saline night interpulse interval = 103 T 9 min vs naloxone night interpulse interval = 191 T 31 min, P = 0.03). There were significant increases in K-opioid receptor binding potential in the posterior and subgenual cingulate, temporal and orbitofrontal cortex, thalamus, and nucleus accumbens ranging from 10% to 61% across brain regions involved in emotional and cognitive function. In contrast, binding potential reductions of lesser magnitude were observed in regions known to be involved in the placebo response (anterior cingulate and anterior insular cortex). Conclusions: Using two different challenge paradigms for the examination of central opioid function, a neuropharmacologic action of BC treatment was demonstrated in postmenopausal women.

The mechanisms responsible for disordered reproductive, metabolic, appetite, and mood function in women with polycystic ovary syndrome (PCOS) are unclear. Increasing evidence suggests that changes in central opioid sensitivity in patients with PCOS contribute to the pathogenesis of the disease through mediation of insulin's neuromodulatory effects. This pilot study tested the hypothesis that interactions between central opioid activity and insulin resistance (IR) in limbic appetite and mood-regulating regions of women with PCOS may be associated with the behavioral and reproductive pathology of the disease. Central opioid activity was assessed by determining the availability of the μ-opioid receptor (μOR) for the opioid agonist β-endorphin. Positron emission tomography with a radioactive μOR-receptor selective radiotracer was used to compare receptor availability in women with IR-PCOS (n = 7) and with non-IR controls (n = 5), and also assessed the ability of the hypoglycemic agent, metformin, to restore μOR concentrations to normal levels. Before and after metformin treatment, the binding potential of the μOR was determined in IR-PCOS patients and controls. The data showed greater μOR availability in the limbic regions of IR-PCOS patients than non-IR controls. After 4 months of metformin treatment, receptor availability returned to levels found in the controls. The restoration of μOR binding capacity to control levels by metformin indicated that improved insulin sensitivity restored dysregulated opioid neurotransmission. The findings of this small pilot study suggest that insulin modulation of central opioid activity in PCOS may contribute to behavioral and reproductive pathologies of the disease.

Objective: Increases in adrenergic activity are associated with stress, anxiety, and other psychiatric, neurological, and medical disorders. To improve understanding of normal CNS adrenergic function, CBF responses to adrenergic stimulation were determined. Methods: Using PET, the CBF changes after intravenous yohimbine, an alpha2-adrenoreceptor antagonist that produces adrenergic activation, were compared with placebo in nine healthy humans. Heart rate, blood pressure, Paco2, plasma catecholamines, and symptom responses were also determined. Results: Among nonscan variables, yohimbine produced significant symptom increases (including a panic attack in one subject), a decrease in Paco2 due to hyperventilation, increases in systolic and diastolic blood pressure, and a trend toward a significant norepinephrine increase. Among scan results, yohimbine produced a significant decrease in whole-brain absolute CBF; regional decreases were greatest in cortical areas. Medial frontal cortex, thalamus, insular cortex, and cerebellum showed significant increases after normalization to whole brain. Medial frontal CBF change was correlated with increases in anxiety. A panic attack produced an increase instead of a decrease in whole-brain CBF. Factors potentially contributing to the observed CBF changes were critically reviewed. Specific regional increases were most likely due in large part to activation produced by adrenergically induced anxiety and visceral symptoms. Conclusions: This study supports the relationship of anxiety and interoceptive processes with medial frontal, insular, and thalamic activation and provides a baseline for comparison of normal yohimbine-induced CNS adrenergic activation, adrenergically-based symptoms, and other markers of adrenergic function to stress, emotion, and the adrenergic pathophysiologies of various CNS-related disorders.

We report the results of an open trial of trazodone in the treatment of severe behavioral disturbances in a sample of 22 hospitalized children previously found to be unresponsive to other treatments. Response to treatment was assessed by overall clinical criteria and improvements in individual symptom dimensions during the inpatient hospitalization. Thirteen children (67%) were found to benefit from the introduction of trazodone. Aggressive, impulsive behaviors were symptoms most frequently improved by this agent. Three of those found to be nonresponders actually worsened in symptomatology. A follow-up interview of the parents was conducted 3-14 months after discharge from the inpatient unit, for those children who initially responded to trazodone administration. The results of this interview suggest that the effect of trazodone was persistent for a prolonged period of time after the initial inpatient trial. Trazodone appears to be of value in the management of severe behavioral disturbances in children. The possible mechanism of action of trazodone is discussed.