Mismatch negativity in patients with major depressive disorder: A meta-analysis.

OBJECTIVE: Deficits of mismatch negativity (MMN), a general index of echoic memory function, have been documented in patients with schizophrenia. However, it remains controversial whether patients with major depressive disorder (MDD) demonstrate MMN defects compared with healthy controls (HC). METHODS: After screening 41 potential studies identified in PubMed and Medline, 13 studies consisting of 343 HC and 339 patients with MDD were included in the present meta-analysis. The effect sizes (Hedges's g) with a random-effect and inverse-variance weighted model were estimated for the MMN amplitudes and latencies. The effects of different deviant types (i.e., frequency and duration) and of different illness stages (i.e., acute and chronic) on MMN were also examined. RESULTS: We found that 1) MMN amplitudes (g = 1.273, p < 0.001) and latencies (g = 0.303, p = 0.027) to duration, but not frequency deviants, were significantly impaired in patients with MDD compared to HC; 2), acute patients exhibited lower MMN amplitudes (g = 1.735, p < 0.001) and prolonged MMN latencies (g = 0.461, p = 0.007) for the duration deviants compared to HC. Only the attenuated duration MMN amplitudes were detected in patients with chronic MDD (g = 0.822, p = 0.027); and 3) depressive symptoms did not significantly correlate with MMN responses. CONCLUSIONS: Patients with MDD demonstrated abnormal MMN responses to duration deviants compared to HC. SIGNIFICANCE: Duration MMN may constitute an electrophysiological indicator to differentiate HC from patients with MDD, particularly those in the acute stage.

Dysfunctional frontal activation of mismatch negativity in panic disorder: A magnetoencephalographic study.

BACKGROUND: Mismatch negativity (MMN) or its magnetic counterpart (MMNm) is a neurophysiological signal to reflect the automatic change-detection ability. However, MMN studies in patients with panic disorder (PD) showed contrasting results using electroencephalographic (EEG) recordings. The present study attempted to overcome the limitations of EEG methodology by means of a whole-head magnetoencephalography (MEG) combined with the depth-weighted minimum norm estimate method to conduct an in-depth investigation on the MMNm at the cortical level in patients with PD. METHODS: We recruited 22 healthy controls (HC) and 20 patients with PD to perform auditory oddball paradigm during MEG recordings. The cortical MMNm amplitudes and latencies in the superior temporal gyrus, inferior parietal lobule, and inferior frontal gyrus (IFG) were compared between the HC and PD groups. The correlations between MMNm responses and clinical measurement were also examined. RESULTS: Compared with the HC group, the PD group demonstrated significantly reduced MMNm amplitudes in the IFG. Furthermore, higher trait scores of the State-Trait Anxiety Inventory were associated with lower MMNm amplitudes of the right IFG among patients with PD. LIMITATIONS: Generalization of the current results to other settings or samples should be made cautiously due to the use of different medication regimens and presence of comorbidities in our patients. CONCLUSIONS: Our data suggest dysfunctional pre-attentive change-detection ability in patients with PD, particularly in the IFG.

Mismatch negativity to different deviant changes in autism spectrum disorders: A meta-analysis.

OBJECTIVE: Mismatch negativity (MMN) has been continuously used to evaluate the functional integrity of central auditory processing. However, it still remains inconclusive whether patients with autism spectrum disorder (ASD) demonstrate reduced MMN responses in all deviant types. METHODS: To reconcile the previous controversial findings, we performed a meta-analysis of peer-reviewed MMN articles concerning ASD. The potential moderators regarding different deviant types, diagnosis, and age on the effect sizes (Hedges' g) were also assessed. RESULTS: Compared to the controls, ASD patients showed reduced MMN amplitudes (g = -0.37, p = 0.001) and prolonged latencies (g = -0.33, p = 0.041) in response to speech-sound deviants. Children/adolescents with ASD manifested reduced MMN amplitudes in response to tone-duration deviants (g = -0.46, p = 0.014). Furthermore, the results showed significantly shortened MMN latencies to tone-frequency deviants in patients with autism (g = 0.29, p = 0.038) and, in contrast, prolonged MMN latencies (g = -0.74, p = 0.001) in patients with Asperger syndrome. CONCLUSION: MMN deficits are robust in ASD patients, suggesting an altered central ability in auditory discrimination. SIGNIFICANCE: MMN alterations were displayed in different profiles with respect to frequency, duration and phoneme changes.

Altered auditory repetition suppression and MMNm in relation to cognitive tests in older adults.

Cognitive changes with aging have been connected to deficiency in early-stage cortical repetition suppression (RS) and mismatch negativity (MMN). Here, we intended to investigate age-associated alterations of auditory RS and MMN by using a roving standard paradigm, and examine their relations to cognitive performances. Twenty-two young and 22 elderly adults were recorded with a magnetoencephalography. The Chinese Version Verbal Learning Test (CVVLT) and Trail Making Test (TMT) were administered to the older group. Compared to the younger, the elderly exhibited reduced magnitudes of P50m RS in temporal region, and of N100m RS in fronto-temporo-parietal networks. Weaker MMNm responses were also observed. Moreover, practice time of TMT B-A was significantly negatively correlated to magnitude of RS in frontal areas. These findings suggested an age-related decline of early-stage auditory information processing. Conclusively, in the elderly, frontal lobe plays a role in the modulation of automatic cortical filtering and competence of attentional shifting.

Abnormal frontal generator during auditory sensory gating in panic disorder: An MEG study.

Patients with panic disorder (PD) exhibit abnormalities in early-stage information processing, even for the nonthreatening stimuli. A previous event-related potential study reported that PD patients show a deficit in sensory gating (SG), a protective mechanism of the brain to filter out irrelevant sensory inputs. However, there is no clear understanding about the neural correlates of SG deficits in PD. Moreover, whether SG deficits, if any, are associated with clinical manifestations remain unknown. In this study, 18 patients with PD and 20 age- and gender-matched healthy controls were recruited to perform auditory paired-stimulus paradigm using magnetoencephalographic (MEG) recordings. Results showed that PD patients demonstrated significantly higher M50 SG ratios in the right inferior frontal gyrus (RIFG) and higher M100 SG ratios in both RIFG and right superior temporal gyrus (RSTG) than those of the control group. It was important to note that in the RIFG, the M50 SG ratios correlated significantly with the scores of Body Sensation Questionnaire (BSQ) and Distractibility scale of Sensory Gating Inventory among patients with PD. In conclusion, this study suggests that PD patients exhibited a deficient ability to filter out irrelevant information, and such a defect might lead to cognitive misinterpretation of somatic sensations and distractibility.

Melanogenesis Inhibitors from the Rhizoma of Ligusticum Sinense in B16-F10 Melanoma Cells In Vitro and Zebrafish In Vivo.

The rhizoma of Ligusticum sinense, a Chinese medicinal plant, has long been used as a cosmetic for the whitening and hydrating of the skin in ancient China. In order to investigate the antimelanogenic components of the rhizoma of L. sinense, we performed an antimelanogenesis assay-guided purification using semi-preparative HPLC accompanied with spectroscopic analysis to determine the active components. Based on the bioassay-guided method, 24 compounds were isolated and identified from the ethyl acetate layer of methanolic extracts of L. sinense, and among these, 5-[3-(4-hydroxy-3-methoxyphenyl)allyl]ferulic acid (1) and cis-4-pentylcyclohex-3-ene-1,2-diol (2) were new compounds. All the pure isolates were subjected to antimelanogenesis assay using murine melanoma B16-F10 cells. Compound 1 and (3S,3aR)-neocnidilide (8) exhibited antimelanogenesis activities with IC50 values of 78.9 and 31.1 µM, respectively, without obvious cytotoxicity. Further investigation showed that compound 8 demonstrated significant anti-pigmentation activity on zebrafish embryos (10‒20 µM) compared to arbutin (20 µM), and without any cytotoxicity against normal human epidermal keratinocytes. These findings suggest that (3S,3aR)-neocnidilide (8) is a potent antimelanogenic and non-cytotoxic natural compound and may be developed potentially as a skin-whitening agent for cosmetic uses.

Meta-analysis of sensorimotor gating in patients with autism spectrum disorders.

Prepulse inhibition (PPI) of startle response is a well-established neurophysiological marker of sensorimotor gating ability in psychiatric patients including those with autism spectrum disorders (ASD). PPI has been utilized as an indicator of the central inhibitory function and is potentially linked to the clinical features of this disease. However, it remains inconclusive whether ASD patients exhibit PPI deficits compared with healthy controls. The present meta-analysis aimed to explore the pooled effect sizes of PPI in ASD patients. We searched major electronic databases from 1990 to January 2017. Seven studies, consisting of 21 individual investigations with 135 healthy controls and 99 ASD patients, were obtained. The effect size, calculated as Hedges's g and 95% confidence interval, were estimated. Overall, we found ASD patients exhibited an impaired PPI compared with healthy controls (p = 0.008). Specifically, significant PPI deficits were observed among ASD children/adolescents, compared with their healthy counterparts (p = 0.019). However, differences in PPI responses were not observed among adults. Conclusively, our results reconciled the previous studies and showed that ASD children/adolescents, but not adults, exhibit reduced sensorimotor gating function compared to healthy controls. We also suggest that the parameters of PPI are particularly important and the results should be interpreted with cautions.

Resting GABA concentration predicts inhibitory control during an auditory Go-Nogo task.

Inhibitory control plays an important role in goal-directed behavior. Although substantial inter-individual variability exists in the behavioral performance of response inhibition, the corresponding modulating neurochemical and neurophysiological mechanisms remain unclear. Thus, the present study aimed to explore the relationship between behavioral response inhibition, GABA+ concentrations and automatic sensory gating (SG) in the auditory cortices. We recruited 19 healthy adults to undergo magnetoencephalography, magnetic resonance spectroscopy (MRS), and behavioral experiments. A paired-stimulus paradigm was used to study SG of the auditory cortices, and an auditory-driven Go-Nogo task was used to evaluate the behavioral response inhibition. Resting GABA+ concentrations were measured in the bilateral superior temporal gyri by means of MRS. Neither GABA+ concentrations nor auditory SG showed significant hemispheric asymmetry. However, an enhanced SG (lower ratio) was found to correlate with improved behavioral inhibition. Moreover, a higher GABA+ concentration was strongly related to improved inhibitory control. These findings highlight the important role of automatic neurophysiological processes and inhibitory neurotransmitters in the prediction of the behavioral performance of inhibitory control.

Effects of action observation therapy and mirror therapy after stroke on rehabilitation outcomes and neural mechanisms by MEG: study protocol for a randomized controlled trial.

BACKGROUND: Loss of upper-extremity motor function is one of the most debilitating deficits following stroke. Two promising treatment approaches, action observation therapy (AOT) and mirror therapy (MT), aim to enhance motor learning and promote neural reorganization in patients through different afferent inputs and patterns of visual feedback. Both approaches involve different patterns of motor observation, imitation, and execution but share some similar neural bases of the mirror neuron system. AOT and MT used in stroke rehabilitation may confer differential benefits and neural activities that remain to be determined. This clinical trial aims to investigate and compare treatment effects and neural activity changes of AOT and MT with those of the control intervention in patients with subacute stroke. METHODS/DESIGN: An estimated total of 90 patients with subacute stroke will be recruited for this study. All participants will be randomly assigned to receive AOT, MT, or control intervention for a 3-week training period (15 sessions). Outcome measurements will be taken at baseline, immediately after treatment, and at the 3-month follow-up. For the magnetoencephalography (MEG) study, we anticipate that we will recruit 12 to 15 patients per group. The primary outcome will be the Fugl-Meyer Assessment score. Secondary outcomes will include the modified Rankin Scale, the Box and Block Test, the ABILHAND questionnaire, the Questionnaire Upon Mental Imagery, the Functional Independence Measure, activity monitors, the Stroke Impact Scale version 3.0, and MEG signals. DISCUSSION: This clinical trial will provide scientific evidence of treatment effects on motor, functional outcomes, and neural activity mechanisms after AOT and MT in patients with subacute stroke. Further application and use of AOT and MT may include telerehabilitation or home-based rehabilitation through web-based or video teaching. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02871700 . Registered on 1 August 2016.

Automatic inhibitory function in the human somatosensory and motor cortices: An MEG-MRS study.

While the automatic inhibitory function of the human cerebral cortex has been extensively investigated by means of electrophysiological recordings, the corresponding modulating neurochemical mechanisms remain unclear. We aimed to examine whether the primary somatosensory (SI) and primary motor cortical (MI) inhibitory function is associated with endogenous GABA levels. Eighteen young participants received paired-pulse and single-pulse electrical stimulation to the median nerve during magnetoencephalographic recordings. The SI sensory gating (SG), considered as an automatic inhibitory ability, was measured as the amplitude ratio of Stimulus 2 over Stimulus 1, in the paired-pulse paradigm. In addition, stimulus-induced beta activity, considered to originate from MI and also to be related to inhibitory function, was estimated using the single-pulse paradigm. The GABA+ concentration of the sensorimotor cortex was acquired from each subject by using magnetic resonance spectroscopy (MRS). A lower SG ratio in SI was significantly associated with an increased beta power in MI. More importantly, the beta rebound power, but not SI SG ratio, was positively correlated with GABA+ concentration. Our findings show a tight functional relationship between SI and MI during processing of automatic inhibition. GABA+ levels appear to be more closely related to the automatic inhibitory function of MI than SI.

Dietary flavonoids, luteolin and quercetin, inhibit invasion of cervical cancer by reduction of UBE2S through epithelial-mesenchymal transition signaling.

We previously reported that the dietary flavonoids, luteolin and quercetin, might inhibit the invasiveness of cervical cancer by reversing epithelial-mesenchymal transition (EMT) signaling. However, the regulatory mechanism exerted by luteolin and quercetin is still unclear. This study analyzed the invasiveness activation by ubiquitin E2S ligase (UBE2S) through EMT signaling and inhibition by luteolin and quercetin. We found that UBE2S expression was significantly higher in highly invasive A431 subgroup III (A431-III) than A431-parental (A431-P) cells. UBE2S small interfering (si)RNA knockdown and overexpression experiments showed that UBE2S increased the migratory and invasive abilities of cancer cells through EMT signaling. Luteolin and quercetin significantly inhibited UBE2S expression. UBE2S showed a negative correlation with von Hippel-Lindau (VHL) and a positive correlation with hypoxia-induced factor (Hif)-1α. Our findings suggest that high UBE2S in malignant cancers contributes to cell motility through EMT signaling and is reversed by luteolin and quercetin. UBE2S might contribute to Hif-1α signaling in cervical cancer. These results show the metastatic inhibition of cervical cancer by luteolin and quercetin through reducing UBE2S expression, and provide a functional role for UBE2S in the motility of cervical cancer. UBE2S could be a potential therapeutic target in cervical cancer.

Region-specific reduction of auditory sensory gating in older adults.

Aging has been associated with declines in sensory-perceptual processes. Sensory gating (SG), or repetition suppression, refers to the attenuation of neural activity in response to a second stimulus and is considered to be an automatic process to inhibit redundant sensory inputs. It is controversial whether SG deficits, as tested with an auditory paired-stimulus protocol, accompany normal aging in humans. To reconcile the debates arising from event-related potential studies, we recorded auditory neuromagnetic reactivity in 20 young and 19 elderly adult men and determined the neural activation by using minimum-norm estimate (MNE) source modeling. SG of M100 was calculated by the ratio of the response to the second stimulus over that to the first stimulus. MNE results revealed that fronto-temporo-parietal networks were implicated in the M100 SG. Compared to the younger participants, the elderly showed selectively increased SG ratios in the anterior superior temporal gyrus, anterior middle temporal gyrus, temporal pole and orbitofrontal cortex, suggesting an insufficient age-related gating to repetitive auditory stimulation. These findings also highlight the loss of frontal inhibition of the auditory cortex in normal aging.

Effects of aging on the neuromagnetic mismatch detection to speech sounds.

The ability to discriminate speech sounds is crucial for higher language functions in humans. However, it remains unclear whether physiological aging affects the functional integrity of pre-attentive phonological discrimination. The neuromagnetic cortical responses during automatic change detection of speech sounds (/ba/versus/da/) were recorded in 24 young and 21 aged male adults. We used minimum norm estimate of source reconstruction to characterize the spatiotemporal dynamics of magnetic mismatch responses (MMNm). Distributed activations to phonetic changes were identified in the temporal, frontal and parietal regions. Compared to younger participants, elderly volunteers exhibited a significant reduction of cortical responses to phonetic-MMNm, except for the left orbitofrontal cortex and anterior inferior temporal gyrus. However, among the identified regions of interest, we did not observe significant between-group differences in the hemispheric asymmetry of phonetic-MMNm. Conclusively, our results suggest an altered phonetic processing at the perceptual level during physiological aging.

MicroRNA-302b-inhibited E2F3 transcription factor is related to all trans retinoic acid-induced glioma cell apoptosis.

All-trans retinoic acid (ATRA), a derivative of retinoid, is involved in the onset of differentiation and apoptosis in a wide variety of normal and cancer cells. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression. Several miRNAs were identified to participate in ATRA-mediated cell differentiation. However, no studies have demonstrated whether miRNA can enhance ATRA cytotoxicity, thereby resulting in cell apoptosis. This study investigated the effects of ATRA-mediated miRNA expression in activating apoptotic pathways in glioblastoma. First, we found that high-dose ATRA treatment significantly reduced cell viability, caspase-dependent apoptosis, endoplasmic reticular (ER) stress activation, and intracellular reactive oxygen species accumulation. From microarray data, miR-302b was analyzed as a putative downstream regulator upon ATRA treatment. Furthermore, we found that ATRA up-regulated miR-302b expression in a dose- and time-dependent manner through retinoic acid receptor α-mediated pathway. Overexpression and knockdown of miR-302b significantly influenced ATRA-mediated cytotoxicity. E2F3, an important transcriptional regulator of glioma proliferation, was validated to be a direct target gene of miR-302b. The miR-302b-reduced E2F3 levels were also identified to be associated with ATRA-mediated glioma cell death. These results emphasize that an ATRA-mediated miR-302b network may provide novel therapeutic strategies for glioblastoma therapy. We propose that high-dose all-trans retinoic acid (ATRA) treatment, a derivative of retinoid, significantly induces glioblastoma cell apoptosis via caspase-dependent apoptosis, endoplasmic reticular (ER) stress, and intracellular reactive oxygen species (ROS) accumulation. The miR-302b overexpression enhanced by ATRA-mediated retinoic acid receptor (RAR)α pathway was also identified. The E2F3 repression, a novel target gene of miR-302b, was involved in ATRA-induced glioblastoma cell cytotoxicity.

Reduced automatic frontal response to auditory deviance in Huntington's disease as indexed by magnetic mismatch negativity.

Huntington's disease (HD) is a neurodegenerative disorder accompanied by a degradation of dopaminergic receptors. It is evident that dopaminergic dysfunction leads to attention deterioration. However, little is known about the functional integrity of involuntary attention processing in patients with HD. The present study aimed to investigate whether patients with HD exhibit a deficit in automatic deviance detection that can be indexed by magnetic mismatch responses. Magnetoencephalographic responses during a passive oddball task were recorded to examine automatic neural activation to auditory deviants in patients with symptomatic HD and age and sex-matched healthy volunteers. The mean amplitude and peak latency of magnetic mismatch responses were calculated from the waveforms in each hemisphere. Furthermore, minimum current estimate (MCE) was applied to estimate the source strength of temporal and frontal mismatch responses. Compared with healthy participants, patients with HD exhibited a decreased waveform amplitude and a prolonged peak latency of magnetic mismatch responses in the left temporal lobe. The MCE analysis also revealed significantly lower activation of the bilateral frontal mismatch responses in patients. In conclusion, the frontal underactivation to occasional auditory deviance suggests a deficit of involuntary attention switching in HD.

Temporo-frontal functional connectivity during auditory change detection is altered in Alzheimer's disease.

Cortico-cortical connections might be disturbed in patients with Alzheimer's disease (AD). This study aimed to investigate the alterations of functional connectivity in AD during auditory change detection processing by measuring the local neuronal activation and functional connectivity between cortical regions. Magnetoencephalographic responses to deviant and standard sounds were recorded in 16 AD patients, 18 young controls and 16 elderly controls. Larger source amplitudes and shorter peak latencies were found in the right temporal magnetic mismatch responses of young controls compared with elderly controls and AD patients. During deviant stimuli, the right theta temporal-frontal phase synchrony was significantly smaller in AD than in young controls and elderly controls. Moreover, the left temporal-frontal synchronization at theta and alpha bands was reduced in AD and elderly controls compared with young controls. In conclusion, the loss in temporo-frontal theta synchronization might be an electrophysiological hallmark of AD.

Effects of physiological aging on mismatch negativity: a meta-analysis.

Mismatch negativity (MMN) is a promising window on how the functional integrity of auditory sensory memory and change discrimination is modulated by age and relevant clinical conditions. However, the effects of aging on MMN have remained somewhat elusive, particularly at short interstimulus intervals (ISIs). We performed a meta-analysis of peer-reviewed MMN studies that had targeted both young and elderly adults to estimate the mean effect size. Nine studies, consisting of 29 individual investigations, were included and the final total study population consisted of 182 young and 165 elderly subjects. The effects of different deviant types and duration of ISIs on the effect size were assessed. The overall mean effect size was 0.63 (95% CI at 0.43-0.82). The effect sizes for long ISI (>2s, effect size 0.68, 95% CI at 0.31-1.06) and short ISI (<2s, effect size 0.61, 95% CI at 0.39-0.84) were both considered moderate. A further analysis showed a prominent aging-related decrease in MMN responses to duration and frequency changes at short ISIs. It was also interesting to note that the effect size was about 25% larger for duration deviant condition compared to the frequency deviant condition. In conclusion, a reduced MMN response to duration and frequency deviants is a robust feature among the aged adults, which suggests that there has been a decline in the functional integrity of central auditory processing in this population.

Effects of aging on neuromagnetic mismatch responses to pitch changes.

Although aging-related alterations in the auditory sensory memory and involuntary change discrimination have been widely studied, it remains controversial whether the mismatch negativity (MMN) or its magnetic counterpart (MMNm) is modulated by physiological aging. This study aimed to examine the effects of aging on mismatch activity to pitch deviants by using a whole-head magnetoencephalography (MEG) together with distributed source modeling analysis. The neuromagnetic responses to oddball paradigms consisting of standards (1000 Hz, p=0.85) and deviants (1100 Hz, p=0.15) were recorded in healthy young (n=20) and aged (n=18) male adults. We used minimum norm estimate of source reconstruction to characterize the spatiotemporal neural dynamics of MMNm responses. Distributed activations to MMNm were identified in the bilateral fronto-temporo-parietal areas. Compared to younger participants, the elderly exhibited a significant reduction of cortical activation in bilateral superior temporal guri, superior temporal sulci, inferior fontal gyri, orbitofrontal cortices and right inferior parietal lobules. In conclusion, our results suggest an aging-related decline in auditory sensory memory and automatic change detection as indexed by MMNm.

The effects of aging on lifetime of auditory sensory memory in humans.

The amplitude change of cortical responses to repeated stimulation with respect to different interstimulus intervals (ISIs) is considered as an index of sensory memory. To determine the effect of aging on lifetime of auditory sensory memory, N100m responses were recorded in young, middle-aged, and elderly healthy volunteers (n=15 for each group). Trains of 5 successive tones were presented with an inter-train interval of 10 s. In separate sessions, the within-train ISIs were 0.5, 1, 2, 4, and 8 s. The amplitude ratio between N100m responses to the first and fifth stimuli (S5/S1 N100m ratio) within each ISI condition was obtained to reflect the recovery cycle profile. The recovery function time constant (τ) was smaller in the elderly (1.06±0.26 s, p<0.001) and middle-aged (1.70±0.25 s, p=0.009) groups compared with the young group (2.77±0.25 s). In conclusion, the present study suggests an aging-related decrease in lifetime of auditory sensory memory.

Inadequate inhibition of redundant auditory inputs in Alzheimer's disease: an MEG study.

This study aimed to characterize the cortical deficits in processing auditory inputs in patients with Alzheimer's disease (AD). The magnetic counterparts of P50 (M50) and mismatch negativity (MMNm) during a passive oddball paradigm were analyzed with equivalent current dipole modeling. The results showed larger cortical activation of standard-evoked M50 in AD patients compared to young and elderly controls. In contrast, smaller amplitudes and longer peak latencies were found in the MMNm of the elderly and AD patients compared with young adults. The MMNm latency was longer in AD patients than in elderly controls. A Spearman correlation test showed an inverse correlation between the cortical strengths of M50 and MMNm in the right hemisphere. In conclusion, age-related changes in the M50 and MMNm components, which may reflect deficits in central auditory processing, are discussed, along with the possibility that increased M50 responses are related to decreased inhibition of redundant inputs in mild AD.