Arousal dissociates amygdala and hippocampal fear responses: evidence from simultaneous fMRI and skin conductance recording.

The experience and appraisal of threat is essential to human and animal survival. Lesion evidence suggests that the subjective experience of fear relies upon amygdala-medial frontal activity (as well as autonomic arousal), whereas the factual context of threat stimuli depends upon hippocampal-lateral frontal activity. This amygdala-hippocampus dissociation has not previously been demonstrated in vivo. To explore this differentiation, we employed functional magnetic resonance imaging (fMRI) and simultaneous skin conductance response (SCR) measures of phasic arousal, while subjects viewed fearful versus neutral faces. fMRI activity was subaveraged according to whether or not the subject evoked an arousal SCR to each discrete face stimulus. The fMRI-with arousal and fMRI-without arousal data provided a distinct differentiation of amygdala and hippocampal networks. Amygdala-medial frontal activity was observed only with SCRs, whereas hippocampus-lateral frontal activity occurred only in the absence of SCRs. The findings provide direct evidence for a dissociation between human amygdala and hippocampus networks in the visceral experience versus declarative fact processing of fear.     

Presynaptic alpha 2-adrenoceptor and kappa-opiate receptor occupancy promotes closure of neuronal (N-type) calcium channels

Synaptosomes prepared from rat cerebral cortex by homogenization in isotonic sucrose and centrifugation on four-step discontinuous percoll density gradients were loaded with the fluorescent indicator fura-2 to allow measurement of intrasynaptosomal free calcium concentrations [( Ca2+]i). Incubation of fura-2 loaded synaptosomes with either the kappa-opiate agonist U-50,488H (0.1-100 microM) or the alpha 2-adrenoceptor agonist clonidine (0.1-100 microM), resulted in a dose-dependent reduction in [Ca2+]i and these changes were completely antagonised by prior inclusion of naloxone (20 microM) or idazoxan (RX781094) (2 microM) respectively. When the 1,4-dihydropyridine Ca2+-channel blocker nifedipine (1 microM) was incubated with synaptosomes for 1 min, there was a 17.0% decrease in [Ca2+]i and when it was combined with either U-50,488H (1 microM) or clonidine (1 microM) there was a reduction in [Ca2+]i of 35.0 and 48.1% respectively i.e. the effects were additive. The increases in the depression of [Ca2+]i produced by these drug combinations were antagonised by the inclusion of naloxone (20 microM) or idazoxan (2 microM) which resulted in decreases in free [Ca2+]i of 26.5 and 14.1% respectively. These data indicate that the effects of clonidine and U-50,488H are not mediated by L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil

Functional magnetic resonance imaging (fMRI) can be used to detect regional brain responses to changes in sensory stimuli. We have used fMRI to determine the amount of visual and auditory cortical activation in 12 normal subjects and 12 subjects with the narcoleptic syndrome, using a multiplexed visual and auditory stimulation paradigm. In both normal and narcoleptic subjects, mean cortical activation levels during the presentation of periodic visual and auditory stimulation showed no appreciable differences with either age or sex. Normal subjects showed higher levels of visual activation at 10:00 hours than 15:00 hours, with a reverse pattern in narcoleptic subjects (P = 0.007). The group differences in spatial extent of cortical activation between control and narcoleptic subjects were small and statistically insignificant. The alerting action, and imaging response, to a single oral dose of the sleep-preventing drug modafinil 400 mg were then determined and compared with placebo in both the 12 normal (8 given modafinil, 4 placebo) and 12 narcoleptic subjects (8 modafinil, 4 placebo). Modafinil caused an increase in self-reported levels of alertness in 7 of 8 narcoleptic subjects, but there was no significant difference between mean pretreatment and post-treatment activation levels as determined by fMRI for either normal or narcoleptic syndrome subjects given modafinil. However, in the modafinil-treated group of 8 normal and 8 narcoleptic subjects, there was a clock time independent correlation between the initial level of activation as determined by the pretreatment scan and the post-treatment change in activation (visual, P = 0.002; and auditory, P = 0.001). No correlation was observed in placebo-treated subjects (P = 0.99 and 0.77, respectively). Although limited by the small number of subjects, and the lack of an objective measure of alertness, the findings of this study suggest that low cortical activation levels in both normal and narcoleptic subjects are increased following the administration of modafinil. Functional magnetic resonance imaging may be a valuable addition to established studies of attention.     

Fingerspelling, signed language, text and picture processing in deaf native signers: the role of the mid-fusiform gyrus

In fingerspelling, different hand configurations are used to represent the different letters of the alphabet. Signers use this method of representing written language to fill lexical gaps in a signed language. Using fMRI, we compared cortical networks supporting the perception of fingerspelled, signed, written, and pictorial stimuli in deaf native signers of British Sign Language (BSL). In order to examine the effects of linguistic knowledge, hearing participants who knew neither fingerspelling nor a signed language were also tested. All input forms activated a left fronto-temporal network, including portions of left inferior temporal and mid-fusiform gyri, in both groups. To examine the extent to which activation in this region was influenced by orthographic structure, two contrasts of orthographic and non-orthographic stimuli were made: one using static stimuli (text vs. pictures), the other using dynamic stimuli (fingerspelling vs. signed language). Greater activation in left and right inferior temporal and mid-fusiform gyri was found for pictures than text in both deaf and hearing groups. In the fingerspelling vs. signed language contrast, a significant interaction indicated locations within the left and right mid-fusiform gyri. This showed greater activation for fingerspelling than signed language in deaf but not hearing participants. These results are discussed in light of recent proposals that the mid-fusiform gyrus may act as an integration region, mediating between visual input and higher-order stimulus properties.     

Efficacy of UK-49,858 (fluconazole) against Candida albicans experimental infections in mice.

UK-49,858 (fluconazole), a new, orally absorbed bis-triazole derivative, has been evaluated against systemic infections with Candida albicans in normal and immunosuppressed mice and against an intestinal infection with C. albicans in immunosuppressed mice. Orally administered ketoconazole was used as a comparison agent throughout, and orally administered amphotericin B was included for comparative in the experimental intestinal infection. In a 10-day dosage regimen, UK-49,858 was far more active than ketoconazole against systemic infections with C. albicans in normal and immunosuppressed mice. In normal mice, extension of UK-49,858 dosing to 30 days resulted in prolongation of survival to over 90 days, and up to 60% of treated animals had no detectable C. albicans in their kidneys. In addition, over 90% of mice with intestinal candidiasis had culture-negative feces after a 3-day treatment with UK-49,858, but only 62 and 23% of mice gave this response after amphotericin B and ketoconazole therapy, respectively. These data suggest that UK-49,858 may be of value in the treatment of systemic and gastrointestinal infections due to C. albicans in humans.     

Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women

Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.     

Misattribution of speech and impaired connectivity in patients with auditory verbal hallucinations

Several studies report that patients with schizophrenia who experience auditory verbal hallucinations (AVH) tend to misidentify their own speech as that of somebody else. We tested the hypothesis that this tendency is associated with poor functional integration within the network of regions that mediate the evaluation of speech. Using functional magnetic resonance imaging, we measured brain responses from 11 schizophrenics with AVH, 10 schizophrenics without AVH, and 10 healthy controls. Stimuli comprised prerecorded words, which varied for their source (self, alien) and acoustic quality (undistorted, distorted). Participants had to indicate whether each word was spoken in their own or another person's voice via a button press. Using dynamic causal modeling, we estimated the impact of one region over another ("effective connectivity") and how this was modulated by source and distortion. In controls and in patients without AVH, the connectivity between left superior temporal and anterior cingulate cortex was significantly greater for alien- than for self-generated speech; in contrast, the reverse trend was found in schizophrenic patients with AVH. In conclusion, when patients with AVH appraise their own speech we find impaired functional integration between left superior temporal and anterior cingulate cortex. Although this finding is based on external rather than internal speech, the same mechanism may contribute to the faulty appraisal of inner speech that putatively underlies AVH.     

Infused therapy and survival in older patients diagnosed with metastatic breast cancer who received trastuzumab

We used Surveillance, Epidemiology, and End Results-Medicare data (2000-2006) to describe treatment and survival in women diagnosed with metastatic breast cancer (MBC) who received trastuzumab. There were 610 patients with a mean age of 74 years. Overall, 32% received trastuzumab alone and 47% received trastuzumab plus a taxane. In multivariate analysis, trastuzumab plus chemotherapy was associated with a lower adjusted cancer mortality rate (Hazard Ratio [HR] 0.54; 95% Confidence Interval [CI] 0.39-0.74; p < .001) than trastuzumab alone among patients who received trastuzumab as part of first-line therapy. Adding chemotherapy to first-line trastuzumab for metastatic breast cancer is associated with improved cancer survival.     

Effectiveness of ultrasonic activation over glycolic acid on microhardness,cohesive strength,flexural strength,and fracture resistance of the root dentin

Clinical Oral Investigations - The aim of this study was to evaluate the effectiveness of ultrasonic activation (US) over glycolic acid on microhardness, cohesive strength, flexural strength, and...