Neural correlates of perceptual switching while listening to bistable auditory streaming stimuli.

Understanding the neural underpinning of conscious perception remains one of the primary challenges of cognitive neuroscience. Theories based mostly on studies of the visual system differ according to whether the neural activity giving rise to conscious perception occurs in modality-specific sensory cortex or in associative areas, such as the frontal and parietal cortices. Here, we search for modality-specific conscious processing in the auditory cortex using a bistable stream segregation paradigm that presents a constant stimulus without the confounding influence of physical changes to sound properties. ABA_ triplets (i.e., alternating low, A, and high, B, tones, and _ gap) with a 700 ms silent response period after every third triplet were presented repeatedly, and human participants reported nearly equivalent proportions of 1- and 2-stream percepts. The pattern of behavioral responses was consistent with previous studies of visual and auditory bistable perception. The intermittent response paradigm has the benefit of evoking spontaneous perceptual switches that can be attributed to a well-defined stimulus event, enabling precise identification of the timing of perception-related neural events with event-related potentials (ERPs). Significantly more negative ERPs were observed for 2-streams compared to 1-stream, and for switches compared to non-switches during the sustained potential (500-1000 ms post-stimulus onset). Further analyses revealed that the negativity associated with switching was independent of switch direction, suggesting that spontaneous changes in perception have a unique neural signature separate from the observation that 2-stream percepts evoke more negative ERPs than 1-stream. Source analysis of the sustained potential showed activity associated with these differences originating in anterior superior temporal gyrus, indicating involvement of the ventral auditory pathway that is important for processing auditory objects.

A role for adult neurogenesis in spatial long-term memory.

Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown. Using low dose irradiation to inhibit adult hippocampal neurogenesis we show that new neurons aged 4-28 days old at the time of training are required for long-term memory in a spatial version of the water maze. This effect of irradiation was specific since long-term memory for a visibly cued platform remained intact. Furthermore, irradiation just before or after water maze training had no effect on learning or long-term memory. Relationships between learning and new neuron survival, as well as proliferation, were investigated but found non-significant. These results suggest a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.

Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus.

Ongoing neurogenesis in the adult hippocampal dentate gyrus (DG) generates a substantial population of young neurons. This phenomenon is present in all species examined thus far, including humans. Although the regulation of adult neurogenesis by various physiologically relevant factors such as learning and stress has been documented, the functional contributions of the newly born neurons to hippocampal functions are not known. We investigated possible contributions of the newly born granule neurons to synaptic plasticity in the hippocampal DG. In the standard hippocampal slice preparation perfused with artificial cerebrospinal fluid (ACSF), a small (10%) long-term potentiation (LTP) of the evoked field potentials is seen after tetanic stimulation of the afferent medial perforant pathway (MPP). The induction of this ACSF-LTP is resistant to a N-methyl-D-aspartate (NMDA) receptor blocker, D,L-2-amino-5-phosphonovaleric acid (APV), but is completely prevented by ifenprodil, a blocker of NR2B subtype of NMDA receptors. In contrast, slices perfused with picrotoxin (PICRO), a GABA-receptor blocker, revealed a larger (40--50%), APV-sensitive but ifenprodil-insensitive LTP. The ACSF-LTP required lower frequency of stimulation and fewer stimuli for its induction than the PICRO-LTP. All these characteristics of ACSF-LTP are in agreement with the properties of the putative individual new granule neurons examined previously with the use of the whole cell recording technique in a similar preparation. A causal relationship between neurogenesis and ACSF-LTP was confirmed in experiments using low dose of gamma radiation applied to the brain 3 wk prior to the electrophysiological experiments. In these experiments, the new cell proliferation was drastically reduced and ACSF-LTP was selectively blocked. We conclude that the young, adult-generated granule neurons play a significant role in synaptic plasticity in the DG. Since DG is the major source of the afferent inputs into the hippocampus, the production and the plasticity of new neurons may have an important role in the hippocampal functions such as learning and memory.

Influence of chemotherapy administration on monocyte activation by liposomal muramyl tripeptide phosphatidylethanolamine in children with osteosarcoma.

The purpose of these studies was to determine whether chemotherapy interfered with the ability of peripheral blood monocytes from patients with osteosarcoma to respond to the liposome-encapsulated activating agent muramyl tripeptide phosphatidylethanolamine (L-MTP-PE). This was done in preparation of designing an adjuvant therapy protocol that includes L-MTP-PE combined with chemotherapy postoperatively for the treatment of primary osteosarcoma. The majority of patients who fail current adjuvant chemotherapy do so while on chemotherapy. Therefore, we believe it is important to combine L-MTP-PE with chemotherapy early in the treatment course rather than waiting until all chemotherapy cycles are completed. The tumoricidal properties of monocytes from patients with osteosarcoma could be activated by L-MTP-PE to levels equal to or greater than those expressed by normal control monocytes. No intrinsic monocyte defect could be demonstrated. Single-agent chemotherapy consisting of cisplatin (CPD), high-dose methotrexate (MTX), Cytoxan (CTX, cyclophosphamide; Bristol-Myers Co, Evansville, IN), or Adriamycin (ADR, doxorubicin; Adria Laboratories, Columbus, OH) did not interfere with this activation process. There was even a suggestion of enhanced activation potential following the administration of ADR. However, when both ADR and CTX were administered together on the same day, profound suppression in monocyte activation was observed. This suppressed function returned to normal by 3 weeks postcombination therapy. We therefore conclude that L-MTP-PE can be combined with ADR, CPD, MTX, or CTX as single agents but recommend that ADR plus L-MTP-PE is the most effective combination. By contrast, we discourage the use of L-MTP-PE when ADR and CTX are given together.

Effect of recombinant human interleukin 4 on human monocyte activity.

Recombinant human interleukin 4 (rhuIL-4), a lymphokine that reportedly stimulates tumoricidal activity in mouse macrophages, is currently undergoing clinical studies to determine its efficacy in the treatment of cancer. IL-4 is known to participate with other cytokines to regulate growth and differentiation of various hematopoietic cells as well as modulate the immune response. Little is known about the effect of rhuIL-4 on human monocyte tumoricidal activity. The purpose of these studies was to examine the effect of rhuIL-4 on human peripheral blood monocytes. Peripheral blood monocytes isolated from normal donors failed to demonstrate tumoricidal activity or interleukin 1 secretion after treatment with rhuIL-4 in vitro. Furthermore, monocyte-mediated cytotoxicity induced by recombinant human gamma-interferon plus muramyl dipeptide was suppressed in a dose-dependent manner by rhuIL-4. This reduction in cytotoxicity corresponded to a reduction in IL-1 production and secretion. Further investigation of rhuIL-4 and its role in the cytokine network is necessary for the development of effective immunotherapy in cancer patients.

Activation of tumoricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide phosphatidylethanolamine.

This study examined the antitumor properties of blood monocytes isolated from patients undergoing a phase I trial with liposomes containing muramyl tripeptide phosphatidylethanolamine (L-MTP-PE). Peripheral blood monocytes were isolated from 28 patients receiving twice weekly i.v. injections of escalating doses of L-MTP-PE. Monocytes were harvested before therapy and at various times during the 9-week treatment period. Activation of monocyte-mediated tumorilytic activity was found in 24 of the 28 patients at some time during treatment. Whereas the maximum tolerated dose of L-MTP-PE was 4-6 mg/m2, the optimal biological dose in terms of macrophage activation was 0.5-2.0 mg/m2. The spontaneous secretion of interleukin 1 from monocytes isolated pre- and postinfusion was monitored in two patients. In both patients interleukin 1 secretion correlated with the cytotoxic activity of the monocytes. We conclude that the systemic administration of L-MTP-PE can render the blood monocytes of cancer patients tumor cytotoxic. Since L-MTP-PE is an immunomodulator devoid of direct antiproliferative effects on tumor cells, the data suggest that future clinical trials be conducted using the optimal biological dose rather than the maximum tolerated dose.

In vitro and in vivo effect of adriamycin therapy on monocyte activation by liposome-encapsulated immunomodulators.

The purpose of these studies was to determine the effect of Adriamycin (ADR) on the ability of liposome-encapsulated immunomodulators to activate human blood monocytes to the tumoricidal state. We undertook these experiments because we envisioned using encapsulated activators in addition to chemotherapy to destroy pulmonary micrometastases in patients with osteosarcoma (OS). Prior to the initiation of such therapy, it was important to determine whether chemotherapy interferes with monocyte function. First, human peripheral blood monocytes were isolated from normal donors and preincubated with ADR (0.5-500 ng/ml) for 1 h and then washed prior to the addition of free or liposome-encapsulated activators. After 18-24 h incubation, the activating agents were washed off and [125I]IdUrd-labeled A375 melanoma cells were added. Lysis of radiolabeled tumor cells was quantified 72 h later. Monocytes were also incubated with ADR for 24 h in the presence of free or liposome-encapsulated activators and their cytotoxicity quantified. ADR had no effect on the ability of either free or liposome-encapsulated agents to activate monocyte tumoricidal function. We also studied the in vivo effect of ADR therapy on monocyte function in nine patients with OS. At the time of diagnosis and 1 month after ADR therapy (75 mg/m2) patient monocytes could be activated to the tumoricidal state by liposome-encapsulated agents at levels equal to or greater than pretherapy levels. Monocytes isolated from four patients with OS 1 day after ADR therapy and then activated by liposome-encapsulated agents also demonstrated tumoricidal activity. These studies indicated that the monocytes isolated from osteosarcoma patients treated with ADR can be activated in vitro to kill tumor cells and that additional therapy with liposome-encapsulated immunomodulators may be combined with ADR in the treatment of metastatic pulmonary OS.

Traumatic coronary artery fistula.

We report certain diagnostic and therapeutic problems presented by patients with traumatic coronary arteriovenous or arteriocameral fistulas, based on our experience with one case and our review of cases which have previously been reported in detail.