Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells.

Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, ß-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and ß-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.

Cortical Processing of Vocal and Nonvocal Sounds in Cochlear-Implanted Children: An Electrophysiological Study.

OBJECTIVES: For prelingually deaf children, cochlear implants (CIs) can restore auditory input to the auditory cortex and the ability to acquire spoken language. Language development is strongly intertwined with voice perception. The aim of this electrophysiological study was to investigate human voice processing using measures of cortical auditory evoked potentials (AEPs) in pediatric CI users. DESIGN: Cortical AEPs were measured in 8 CI children (4 to 12 years old) with good auditory and language performance and 8 normal-hearing (NH) age-matched controls. The auditory stimuli were nonspeech vocal sounds (laughing, sighing, coughing) and environmental sounds (e.g., telephones, alarms, cars, bells, water, wind). Independent component analysis was used to minimize the CI artifact in cortical AEPs. RESULTS: Fronto-temporal positivity to vocal sounds was found in NH children, with a significant effect in the 140 to 240 msec latency range. In CI children, there was a positive response to vocal sounds in the 170 to 250 msec latency range, with a more diffuse and anterior distribution than in the NH children. CONCLUSIONS: Cortical responses to vocal sounds were recorded in CI children. The topography and latency of response to voice differed from that of NH children. The results suggest that cortical reorganization for processing vocal sounds may occur in congenitally deaf children fitted with a CI.

Asymmetry of temporal auditory T-complex: right ear-left hemisphere advantage in Tb timing in children.

OBJECTIVE: To investigate brain asymmetry of the temporal auditory evoked potentials (T-complex) in response to monaural stimulation in children compared to adults. METHODS: Ten children (7 to 9 years) and ten young adults participated in the study. All were right-handed. The auditory stimuli used were tones (1100 Hz, 70 dB SPL, 50 ms duration) delivered monaurally (right, left ear) at four different levels of stimulus onset asynchrony (700-1100-1500-3000 ms). Latency and amplitude of responses were measured at left and right temporal sites according to the ear stimulated. RESULTS: Peaks of the three successive deflections (Na-Ta-Tb) of the T-complex were greater in amplitude and better defined in children than in adults. Amplitude measurements in children indicated that Na culminates on the left hemisphere whatever the ear stimulated whereas Ta and Tb culminate on the right hemisphere but for left ear stimuli only. Peak latency displayed different patterns of asymmetry. Na and Ta displayed shorter latencies for contralateral stimulation. The original finding was that Tb peak latency was the shortest at the left temporal site for right ear stimulation in children. Amplitude increased and/or peak latency decreased with increasing SOA, however no interaction effect was found with recording site or with ear stimulated. CONCLUSION: Our main original result indicates a right ear-left hemisphere timing advantage for Tb peak in children. The Tb peak would therefore be a good candidate as an electrophysiological marker of ear advantage effects during dichotic stimulation and of functional inter-hemisphere interactions and connectivity in children.

Is my voice just a familiar voice? An electrophysiological study.

It is not clear whether self-stimuli are processed by the brain as highly familiar overlearned stimuli or as self-specific stimuli. This study examined the neural processes underlying discrimination of one's own voice (OV) compared with a familiar voice (FV) using electrophysiological methods. Event-related potentials were recorded while healthy subjects (n = 15) listened passively to oddball sequences composed of recordings of the French vowel /a/ pronounced either by the participant her/himself, or by a familiar person or an unknown person. The results indicated that, although mismatch negativity displayed similar peak latency and amplitude in both conditions, the amplitude of the subsequent P3a was significantly smaller in response to OV compared with a FV. This study therefore indicated that fewer pre-attentional processes are involved in the discrimination of one's OV than in the discrimination of FVs.

Early neurophysiological correlates of vocal versus non-vocal sound processing in adults.

Electrophysiological correlates of voice processing were studied in twenty adults by comparing auditory evoked potentials in response to voice and environmental sounds in passive condition. Both categories of stimuli elicited similar cortical auditory responses (i.e. N1, P2, N2 peaks); however these peaks were overlapped by two components specifically elicited by voice. The first component was evidenced as a positive deflection recorded over the fronto-temporal sites, and lateralized on the right hemiscalp. This fronto-temporal positivity to voice (FTPV) may constitute the electrophysiological counterpart of the activation of the temporal voice areas previously described in neuroimaging studies. The second component was recorded at occipito-temporo-parietal sites. This occipito-temporo-parietal negativity to voice might correspond to visual mental imagery of the vocal sounds or to some form of mental simulation of the action sounds (e.g. coughing). Both components began as early as 70 ms post-stimulus onset indicating a rapid discrimination of voice in our auditory environment, which might be the basis of communication functions in humans.

My voice or yours? An electrophysiological study.

This study examined the neural processes underlying own voice discrimination using electrophysiological methods. Event-related potentials were recorded while healthy subjects (n = 17) heard passively three oddball sequences composed of recordings of the French vowel/a/pronounced either by the participant her/himself or by two unknown persons. The results indicated that, although the mismatch negativity (MMN) displayed similar peak latency and amplitude in both conditions, the subsequent P3a clearly distinguished the two conditions since its amplitude was significantly smaller for own voice discrimination than for that of unknown voices. Moreover, the own voice discriminative response was associated with an early pre-MMN response. This early response involved a left inferior frontal component, the activity of which lasted throughout the time course of the discriminative response, which included both MMN and P3a.

Candidate electrophysiological endophenotypes of hyper-reactivity to change in autism.

Although resistance to change is a main feature of autism, the brain processes underlying this aspect of the disorder remain poorly understood. The aims of this study were to examine neural basis of auditory change-detection in children with autism spectrum disorders (ASD; N = 27) through electrophysiological patterns (MMN, P3a) and to test whether these are quantitatively related to intolerance of change (using the BSE-R scale). ASD displayed significantly shorter MMN latency and larger P3a than controls, indicating a greater tendency to switch attention to deviant events. These electrophysiological abnormalities were significantly more marked in children who displayed greater difficulties in tolerating change. The atypical neurophysiological mechanism of change perception identified might thus be associated with one of the hallmark behavioural manifestations of autism.

An electrophysiological correlate of voice processing in 4- to 5-year-old children.

Cortical auditory evoked potentials were studied in responses to voice and environmental sounds in 4- to 5-year-old children. A specific response to voice was dissociated from the response to environmental sounds. It appeared as a positive deflection recorded at right fronto-temporal sites and beginning within 60ms of stimulus onset. We termed this response Fronto-Temporal Positivity to Voice (FTPV).

Increased perception of loudness in autism.

Clinical reports on autism describe abnormal responses to auditory stimuli such as intolerance to sounds. The present study assessed subjective perception of loudness in subjects with autism compared to healthy controls, using two psychoacoustic tests. First, the auditory dynamic range was evaluated at six different tone frequencies. Secondly, loudness growth as a function of the intensity level of a 1 kHz tone was estimated. Verbal responses from a group of 11 children and adolescents with autism were compared to responses of 11 age- and gender- matched healthy controls. Smaller auditory dynamic ranges were found in the autistic group than in the control group, as well as increased perception of loudness, indicating hyperacusis in subjects with autism.

Hypersensitivity to acoustic change in children with autism: electrophysiological evidence of left frontal cortex dysfunctioning.

Exaggerated reactions to even small changes in the environment and abnormal behaviors in response to auditory stimuli are frequently observed in children with autism (CWA). Brain mechanisms involved in the automatic detection of auditory frequency change were studied using scalp potential and scalp current density (SCD) mapping of mismatch negativity (MMN) in 15 CWA matched with 15 healthy children. Compared with the response in controls, MMN recorded at the Fz site in CWA showed significantly shorter latency and was followed by a P3a wave. Mapping of potentials indicated significant intergroup differences. Moreover, SCD mapping demonstrated the dynamics of the different MMN generators: Although temporal component was evidenced bilaterally in both groups, it occurred earlier on the left hemisphere in CWA, preceded by an abnormal early left frontal component. The electrophysiological pattern reported here emphasized a left frontal cortex dysfunctioning that might also be implicated in cognitive and behavioral impairment characteristic, of this complex neurodevelopmental disorder.