The amygdala is thought to process fear-related stimuli rapidly and nonconsciously. We found that an individual with complete bilateral amygdala lesions, who cannot recognize fear from faces, nonetheless showed normal rapid detection and nonconscious processing of those same fearful faces. We conclude that the amygdala is not essential for early stages of fear processing but, instead, modulates recognition and social judgment.Subject SM has complete bilateral lesions of the amygdala and is impaired in her recognition of fear 1 , an impairment that is consistent with previous studies showing activation of the amygdala to overt and masked fear faces 2 . These studies have suggested that the amygdala is involved in pre-attentive, rapid processing, whereby the amygdala receives subcortical visual information via the superior colliculus and pulvinar thalamus 3 . Such a picture is similar to the known subcortical route for the amygdala in auditory fear conditioning, as demonstrated in rats, and is consistent with blood oxygen level-dependent activation of the amygdala by nonconscious fearful faces in humans 4 . However, there are discrepancies with this view of amygdala function. Some neuroimaging studies have found that the amygdala's response to fearful faces is strongly modulated by conscious detectability, at least when backward masking is used 5 . Electrophysiological latencies recorded in the amygdala are, by and large, inconsistent with rapid visual processing 6 and there is no direct anatomical evidence to support the rapid visual subcortical route that has been hypothesized 7 . These discrepancies suggest that the amygdala modulates social judgments of fear, rather than initial pre-attentive detection.To help resolve this debate regarding the amygdala's contribution to fear processing, we tested subject SM on rapid detection of fear-and threat-related stimuli. In our first experiment, subjects saw a target stimulus (fearful face, angry face or scene showing threat) next to neutral stimuli for 40 ms (unmasked) and had to push a button as rapidly as possible to indicate which face showed more fear/anger or which scene was more threatening (Supplementary Fig. 1).Correspondence should be addressed to N.T. (naotsu@gmail.com). 4 Present address: Department of Radiology, University of California San Diego, San Diego, California, USA. 5 These authors contributed equally to this study.Note: Supplementary information is available on the Nature Neuroscience website. SM's performance on this task was completely normal for all three threat-related categories ( Fig. 1a). As reported previously 1 , SM rated the intensity of fear shown in the same face stimuli substantially lower than did the controls (2.8 and 3.7 s.d. below the normal mean on the two testing sessions). Control experiments ruled out several possible interpretations (Supplementary Methods and Supplementary Table 1). First, we used backward masking in the control experiments, as it might be required to prevent afterimages to demonstrate the amygdala's ...
BackgroundThe hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells.Methodology/Principal FindingsCyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. BM transplants, co-culture systems of tumor cells and BM-derived pro-angiogenic cells (BMPCs) were employed to assess the role of tumor-derived Hh in regulating the BM compartment and the contribution of BM-derived cells to angiogenesis in PDAC. Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. Host-derived Ang-1 and IGF-1 mRNA levels were downregulated by cyclopamine in the tumor xenografts. In vitro co-culture and matrigel plug assays demonstrated that PDAC cell-derived Shh induced Ang-1 and IGF-1 production in BMPCs, resulting in their enhanced migration and capillary morphogenesis activity.Conclusions/SignificanceWe identified the BMPCs as alternative stromal targets of Hh-ligand in PDAC suggesting that the tumor vasculature is an attractive therapeutic target of Hh blockade. Our data is consistent with the emerging concept that BM-derived cells make important contributions to epithelial tumorigenesis.
Hedgehog signaling is important in the pathogenesis of pancreatic cancer. Several recent observations suggest the involvement of sonic hedgehog (SHH) in postnatal neovascularization. We identified a novel role for SHH in tumor-associated angiogenesis in pancreatic cancer. Immunohistochemical analysis revealed that patched homolog 1 (PTCH1), both a receptor for and transcriptional target of hedgehog signaling, was expressed in a small fraction of endothelial cells within pancreatic cancer, but not in normal pancreatic tissue. When endothelial progenitor cells (EPC) isolated from human peripheral blood were cultured with supernatant from SHH-transfected 293 cells or pancreatic cancer cells, mRNA levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 and angiopoietin-1 were significantly increased, whereas no such induction was observed in human umbilical vein endothelial cell (HUVEC) and human dermal microvascular endothelial cell (HMVEC). HUVEC tube formation was stimulated when cocultured with EPC, and preconditioning EPC with supernatant from KP-1 N pancreatic cancer cells highly expressing SHH significantly enhanced the effect. The effect was partially attenuated by specific inhibition of SHH with cyclopamine or a neutralizing antibody. These findings suggest that tumor-derived SHH can induce angiogenesis, and this is mediated by its effects on EPC specifically. Targeting SHH would be a novel therapeutic approach that can inhibit not only proliferation of cancer cells but also EPC-mediated angiogenesis. (Cancer Sci 2008; 99: 1131-1138)
The purpose of the study involves measuring the threshold for electric currents (i.e., current perception threshold or CPT) under several stimulating current frequencies. Specifically, current perception threshold (CPT) was measured in 53 healthy volunteers between the ages of 21 and 67. The stimulation currents were applied on the right index finger with stimulus frequencies in the range of 50 Hz À 300 kHz. The method of limits and method of constant stimuli were combined to measure the CPT. In a manner consistent with the findings obtained by previous studies, the results indicated that CPT was higher in men than in women and in older individuals than in young subjects. Bioelectromagnetics. 40:150-159, 2019.
Purpose. To evaluate the clinical utility of dense array electroencephalography (dEEG) for detecting and localizing interictal spikes in temporal lobe epilepsy. Methods. Simultaneous invasive and noninvasive recordings were performed across two different groups. (1) The first group underwent both noninvasive recording with 128 channels of (scalp) dEEG and invasive sphenoidal electrode recording. (2) The second group underwent both noninvasive recording with 256 channels of (scalp) dEEG and invasive intracranial EEG (icEEG) involving coverage with grids and strips over the lateral and mesial temporal lobe. A noninvasive to noninvasive comparison was made comparing the overall spike detection rate of the dEEG to that of conventional 10/20 EEG. A noninvasive to invasive comparison was made comparing the spike detection rate of dEEG to that of conventional 10/20 EEG plus sphenoidal electrodes. And finally, a noninvasive to invasive evaluation measuring the source localization ability of the dEEG using the icEEG as validation. Results. In the 128-channel dEEG study (1), 90.4% of the interictal spikes detected by the dEEG were not detected in the 10/20 montage. 91% of the dEEG-detected spikes were accurately localized to the medial temporal lobe. In the 256-channel dEEG study (2), 218 of 519 interictal spikes (42%) were detected by dEEG. 85% of these spikes were accurately localized to the medial temporal lobe, close to the position confirmed by subdural electrodes. Conclusion. Dense array EEG may provide more precise information than conventional EEG and has a potential for providing an alternative to sphenoidal electrode monitoring in patients with temporal lobe epilepsy.
Rationale: Dense array EEG (dEEG) evenly covers the whole head surface with over 100 channels contributing to more accurate electrical source imaging due to the higher spatial and temporal resolution. Several studies have shown the clinical utility of dEEG in presurgical clinical evaluation of epilepsy. However validation studies measuring the accuracy of dEEG source imaging are still needed. This can be achieved through simultaneously recording both scalp dEEG with intracranial electrodes (icEEG), which is considered as the true measure of cortical activity at the source. The purpose of this study is to evaluate the accuracy of 256-channel dEEG electrical source estimation for interictal spikes.Methods: Four patients with medically refractory neocortical epilepsy, all surgical candidates, underwent subdural electrode implantation to determine ictal onset and define functional areas. One patient showed a lesion on the magnetic resonance imaging in the right parietal lobe. The patient underwent simultaneous recording of interictal spikes by both scalp 256-channelsvdEEG and icEEG. The dEEG was used to non-invasively estimate the source of the interictal spikes detected by the 256-channel dEEG array, which was then compared to the activity measured directly at the source by the icEEG.Results: From the four patients, a total of 287 interictal spikes were measured with the icEEG. One hundred fifty-five of the 287 spikes (54%) were visually detected by the dEEG upon examination of the 256 channel head surface array. The spike amplitudes detected by the 256-channel dEEG correlated with icEEG spike amplitudes (p < 0.01). All spikes detected in dEEG were localized to the same lobe correctly.Conclusion: Our study demonstrates that 256-channel dEEG can reliably detect interictal spikes and localize them with reasonable accuracy. Two hundred fifty-six-channel dEEG may be clinically useful in the presurgical workup for epilepsy and also reduce the need for invasive EEG evaluation.
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