Preclinical Activity of SAR408701: A Novel Anti-CEACAM5-maytansinoid Antibody-drug Conjugate for the Treatment of CEACAM5-positive Epithelial Tumors.

PURPOSE: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody-drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker. EXPERIMENTAL DESIGN: The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro. The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationships were established. SAR408701 toxicity was evaluated in cynomolgus monkey. RESULTS: SAR408701 bound selectively to human and cynomolgus monkey CEACAM5 with similar apparent Kd values (0.017 nmol/L and 0.024 nmol/L, respectively). Both in vitro and in vivo evaluations showed that SAR408701 has cytotoxic activity, leading to in vivo efficacy in single and repeated dosing. Single doses of SAR408701 induced significant increases in the tumor expression of phosphorylated histone H3, confirming the tubulin-targeting mechanism of action. The overall toxicity profile of SAR408701 in cynomolgus monkey was similar to that observed after intravenous administration of DM4 alone. CONCLUSIONS: On the basis of these preclinical data, the ADC SAR408701 is a promising candidate for development as a potential treatment for patients with CEACAM5-positive tumors.

Decoding Imagined and Spoken Phrases From Non-invasive Neural (MEG) Signals.

Speech production is a hierarchical mechanism involving the synchronization of the brain and the oral articulators, where the intention of linguistic concepts is transformed into meaningful sounds. Individuals with locked-in syndrome (fully paralyzed but aware) lose their motor ability completely including articulation and even eyeball movement. The neural pathway may be the only option to resume a certain level of communication for these patients. Current brain-computer interfaces (BCIs) use patients' visual and attentional correlates to build communication, resulting in a slow communication rate (a few words per minute). Direct decoding of imagined speech from the neural signals (and then driving a speech synthesizer) has the potential for a higher communication rate. In this study, we investigated the decoding of five imagined and spoken phrases from single-trial, non-invasive magnetoencephalography (MEG) signals collected from eight adult subjects. Two machine learning algorithms were used. One was an artificial neural network (ANN) with statistical features as the baseline approach. The other was convolutional neural networks (CNNs) applied on the spatial, spectral and temporal features extracted from the MEG signals. Experimental results indicated the possibility to decode imagined and spoken phrases directly from neuromagnetic signals. CNNs were found to be highly effective with an average decoding accuracy of up to 93% for the imagined and 96% for the spoken phrases.

NeuroVAD: Real-Time Voice Activity Detection from Non-Invasive Neuromagnetic Signals.

Neural speech decoding-driven brain-computer interface (BCI) or speech-BCI is a novel paradigm for exploring communication restoration for locked-in (fully paralyzed but aware) patients. Speech-BCIs aim to map a direct transformation from neural signals to text or speech, which has the potential for a higher communication rate than the current BCIs. Although recent progress has demonstrated the potential of speech-BCIs from either invasive or non-invasive neural signals, the majority of the systems developed so far still assume knowing the onset and offset of the speech utterances within the continuous neural recordings. This lack of real-time voice/speech activity detection (VAD) is a current obstacle for future applications of neural speech decoding wherein BCI users can have a continuous conversation with other speakers. To address this issue, in this study, we attempted to automatically detect the voice/speech activity directly from the neural signals recorded using magnetoencephalography (MEG). First, we classified the whole segments of pre-speech, speech, and post-speech in the neural signals using a support vector machine (SVM). Second, for continuous prediction, we used a long short-term memory-recurrent neural network (LSTM-RNN) to efficiently decode the voice activity at each time point via its sequential pattern-learning mechanism. Experimental results demonstrated the possibility of real-time VAD directly from the non-invasive neural signals with about 88% accuracy.

Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation.

Despite the significant therapeutic advances provided by immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation and reduced regulatory T cells in non-human primates at well-tolerated doses. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.

A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients.

Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4+ T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.

A Robust Multiplex Mass Spectrometric Assay for Screening Small-Molecule Inhibitors of CD73 with Diverse Inhibition Modalities.

CD73/Ecto-5'-nucleotidase is a membrane-tethered ecto-enzyme that works in tandem with CD39 to convert extracellular adenosine triphosphate (ATP) into adenosine. CD73 is highly expressed on various types of cancer cells and on infiltrating suppressive immune cells, leading to an elevated concentration of adenosine in the tumor microenvironment, which elicits a strong immunosuppressive effect. In preclinical studies, targeting CD73 with anti-CD73 antibody results in favorable antitumor effects. Despite initial studies using antibodies, inhibition of CD73 catalytic activity using small-molecule inhibitors may be more effective in lowering extracellular adenosine due to better tumor penetration and distribution. To screen small-molecule libraries, we explored multiple approaches, including colorimetric and fluorescent biochemical assays, and due to some limitations with these assays, we developed a mass spectrometry (MS)-based assay. Only the MS-based assay offers the sensitivity and dynamic range required for screening small-molecule libraries at a substrate concentration close to the Km value of substrate and for evaluating the mode of binding of screening hits. To achieve a throughput suitable for high-throughput screening (HTS), we developed a RapidFire-tandem mass spectrometry (RF-MS/MS)-based multiplex assay. This assay allowed a large diverse compound library to be screened at a speed of 1536 reactions per 40-50 min.

Complementary roles of cortical oscillations in automatic and controlled processing during rapid serial tasks.

Cognitive control may involve adjusting behaviour by inhibiting or altering habitual actions, requiring rapid communication between sensory, cognitive, and motor systems of the brain. Cognitive control may be achieved using top-down processing from frontal areas to inhibit prepared responses, likely mediated through frontal theta (4-8 Hz) oscillations. However there is conflicting evidence for mechanisms of response inhibition, where global and selective inhibition are either considered separate processes, or frontal areas maintain and execute goal-directed actions, including inhibition. In the current study we measured neuromagnetic oscillatory brain activity in twelve adults responding to rapidly presented visual cues. We used two tasks in the same subjects that required inhibition of a habitual "go" response. Presentation of infrequent "target" cues required subjects to completely inhibit responding (go/no-go task) or to perform an alternate response (go/switch task). Source analysis of oscillatory brain activity was compared for correct no-go and switch trials as well as error trials ("go" responses to targets). Frontal theta activity was similar in cortical location, amplitude and time course for correct no-go and switch responses reflecting an equivalent role in both global and selective response inhibition. Error-related frontal theta activity was also observed but was different in source location (errors vs correct, both tasks: p<0.005) and power (go/switch>go/no-go error, correct switch power, p=0.01). We additionally observed sensorimotor high gamma (60-90 Hz) activity accompanying motor responses, which was markedly stronger for correct switch and error responses compared with go responses, and was delayed for errors (p<0.01). These results suggest that gamma signals in the motor cortex may function to integrate inhibitory signals with sensorimotor processing, and may represent a mechanism for the overriding of habitual behaviours, as errors were predicted by a delay in gamma onset. This study supports a role for frontal areas in maintaining and executing goal-directed actions, and demonstrates that frontal theta activity and sensorimotor gamma oscillations have distinct yet complementary functional roles in monitoring and modifying habitual motor plans.

SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies.

PURPOSE: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984. EXPERIMENTAL DESIGN: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice. RESULTS: We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38+ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent proapoptotic activity against CD38+ human primary multiple myeloma cells. CONCLUSION: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in phase I clinical trials in patients with CD38+ B-cell malignancies.

Source localization of interictal spike-locked neuromagnetic oscillations in pediatric neocortical epilepsy.

OBJECTIVE: To evaluate the utility of an event-related beamforming (ERB) algorithm in source localization of interictal discharges. METHODS: We analyzed interictal magnetoencephalography data in 35 children with intractable neocortical epilepsy. We used a spatiotemporal beamforming method to estimate the spatial distribution of source power in individual interictal spikes. We compared ERB results to source localization using the equivalent current dipole model and to the seizure onset zones on intracranial EEG. RESULTS: Focal beamformer localization was observed in 66% of patients and multifocal in the remaining 34%. ERB localized within 2 cm of the equivalent current dipole cluster centroid in 77% of the patients. ERB localization was concordant with the seizure onset zone on intracranial EEG at the gyral level in 69% of patients. Focal ERB localization area was included in the resection margin in 22/23 patients. However, focal ERB localization was not statistically associated with better surgical outcome. CONCLUSIONS: ERB can be used for source localization of interictal spikes and can be predictive of the ictal onset zone in a subset of patients with neocortical epilepsy. SIGNIFICANCE: These results support the utility of beamformer source localization as a fast semi-automated method for source localization of interictal spikes and planning the surgical strategy.

Intended actions and unexpected outcomes: automatic and controlled processing in a rapid motor task.

Human action involves a combination of controlled and automatic behavior. These processes may interact in tasks requiring rapid response selection or inhibition, where temporal constraints preclude timely intervention by conscious, controlled processes over automatized prepotent responses. Such contexts tend to produce frequent errors, but also rapidly executed correct responses, both of which may sometimes be perceived as surprising, unintended, or "automatic". In order to identify neural processes underlying these two aspects of cognitive control, we measured neuromagnetic brain activity in 12 right-handed subjects during manual responses to rapidly presented digits, with an infrequent target digit that required switching response hand (bimanual task) or response finger (unimanual task). Automaticity of responding was evidenced by response speeding (shorter response times) prior to both failed and fast correct switches. Consistent with this automaticity interpretation of fast correct switches, we observed bilateral motor preparation, as indexed by suppression of beta band (15-30 Hz) oscillations in motor cortex, prior to processing of the switch cue in the bimanual task. In contrast, right frontal theta activity (4-8 Hz) accompanying correct switch responses began after cue onset, suggesting that it reflected controlled inhibition of the default response. Further, this activity was reduced on fast correct switch trials suggesting a more automatic mode of inhibitory control. We also observed post-movement (event-related negativity) ERN-like responses and theta band increases in medial and anterior frontal regions that were significantly larger on error trials, and may reflect a combination of error and delayed inhibitory signals. We conclude that both automatic and controlled processes are engaged in parallel during rapid motor tasks, and that the relative strength and timing of these processes may underlie both optimal task performance and subjective experiences of automaticity or control.

Tricyclic series of heat shock protein 90 (Hsp90) inhibitors part I: discovery of tricyclic imidazo[4,5-c]pyridines as potent inhibitors of the Hsp90 molecular chaperone.

A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 µM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.

Neuromagnetic cerebellar activation during seizures arising from the motor cortex.

We utilized the high temporal resolution, whole head coverage and novel analysis methodology of magnetoencephalography (MEG) to record the dynamics of cerebellar activation during focal motor seizures. We analyzed ictal MEG data from a four-year old using an event-related beamformer to localize and display ictal changes over the motor cortex and cerebellum. Contralateral activation of the cerebellum was seen 14s after MEG ictal onset over the motor cortex. These findings represent the first indication of ictal activity within the cerebellum in humans, measured non-invasively with MEG.

Neuromagnetic mismatch field (MMF) dependence on the auditory temporal integration window and the existence of categorical boundaries: comparisons between dissyllabic words and their equivalent tones.

Previous duration-related auditory mismatch response studies have tested vowels, words, and tones. Recently, the elicitation of strong neuromagnetic mismatch field (MMF) components in response to large (>32%) vowel-duration decrements was clearly observed within dissyllabic words. To date, however, the issues of whether this MMF duration-decrement effect also extends to duration increments, and to what degree these duration decrements and increments are attributed to their corresponding non-speech acoustic properties remainto be resolved. Accordingly, this magnetoencephalographic (MEG) study investigated whether prominent MMF components would be evoked by both duration decrements and increments for dissyllabic word stimuli as well as frequency-band matched tones in order to corroborate the relation between the MMF elicitation and the directions of duration changes in speech and non-speech. Further, the peak latency effectsdepending on stimulus types (words vs. tones) were examined. MEG responses were recorded with a whole-head 148-channel magnetometer, while subjects passively listened to the stimuli presented within an odd-ball paradigm for both shortened duration (180-->100%) and lengthened duration (100-->180%). Prominent MMF components were observed in the shortened and lengthened paradigms for the word stimuli, but only in the shortened paradigm for tones. The MMF peak latency results showed that the words ledtoearlier peak latencies than the tones. These findings suggest that duration lengthening as well as shortening in words produces a salient acoustic MMF response when the divergent point between the long and short durations fallswithin the temporal window ofauditory integration post sound onset (<200 ms), and that theearlier latency of the dissyllabic word stimuli over tones is due to a prominent syllable structure in words which is used to generate temporal categorical boundaries.

The elicitation of phonological and semantic neuromagnetic field components by non-words in human auditory sentence comprehension.

The current research examined whether neuromagnetic field components relating to pre-lexical and semantic analysis would be evoked by non-word violations in Japanese auditory sentence comprehension. Stimuli contained semantically congruent short vowel-duration words, long vowel-duration non-words, and short-duration non-words with a deviant second syllable. Native speakers listened to sentences, while neuromagnetic fields were recorded with a twin 37-channel gradiometer system. The results in the 200-400 ms time window showed that at a peak latency of approximately 300 ms, vowel-lengthening and deviant-syllable violations produced larger magnetic fields than congruent words. In the 450-600 ms time range, the magnetic fields in response to deviant-syllable violations, but not vowel-lengthening violations, were larger than congruent words, with the peak latency at approximately 500 ms. The elicitations of M300 and M500 components in this study support the biphasic hypothesis where a pre-lexical phonological analysis stage precedes a post-lexical semantic integration stage in lexical recognition of a native language.

Human neuronal encoding of English syntactic violations as revealed by both L1 and L2 speakers.

Our previous study [M. Kubota, P. Ferrari, T.P.L. Roberts, Magnetoencephalography detection of early syntactic processes in humans: comparison between L1 speakers and L2 learners, Neurosci. Lett. 353 (2003) 107-110] showed that an early syntactic response was elicited in first language (L1) speakers for within-phrase, but not across-phrase violations, implying that there may exist a continuum of neuronal error gravity. Such an early component was not elicited by second-language (L2) learners. The current auditory study investigated whether two types of different syntactic violations regarding noun-phrase raising (NP-raising) and case-filter constructions would elicit a prominent early syntactic component in each hemisphere for both L1 and advanced L2 speakers of English. Neuromagnetic fields were recorded, using a dual 37-channel gradiometer system. A prominent component, peaking at approximately 150 ms post-onset, was observed in both hemispheres of two groups in response to NP-raising induced violations, but not case-filter violations. The findings imply that L1 and L2 speakers have similar neuronal mechanisms subserving syntactic processing of such violations.

UMP kinase from Streptococcus pneumoniae: evidence for co-operative ATP binding and allosteric regulation.

UMP kinase catalyses the phosphorylation of UMP by ATP to yield UDP and ADP. In prokaryotes, the reaction is carried out by a hexameric enzyme, activated by GTP and inhibited by UTP. In the present study, Streptococcus pneumoniae UMP kinase was studied as a target for antibacterial research and its interest was confirmed by the demonstration of the essentiality of the gene for cell growth. In the presence of MnCl2 or MgCl2, the saturation kinetics of recombinant purified UMP kinase was hyperbolic for UMP (K(m)=0.1 mM) and sigmoidal for ATP (the substrate concentration at half-saturation S0.5=9.4+/-0.7 mM and n=1.9+/-0.1 in the presence of MgCl2). GTP increased the affinity for ATP and decreased the Hill coefficient (n). UTP decreased the affinity for ATP and only slightly increased the Hill coefficient. The kcat (175+/-13 s(-1) in the presence of MgCl2) was not affected by the addition of GTP or UTP, whose binding site was shown to be different from the active site. The hydrodynamic radius of the protein similarly decreased in the presence of ATP or GTP. There was a shift in the pH dependence of the activity when the ATP concentration was switched from low to high. These results support the hypothesis of an allosteric transition from a conformation with low affinity for ATP to a form with high affinity, which would be induced by the presence of ATP or GTP.

Prominence of M50 auditory evoked response over M100 in childhood and autism.

This study investigated the 50 ms (M50) and 100 ms (M100) components of the auditory evoked field to explore their change during development. Using MEG, neuromagnetic fields elicited by a 1 kHz sinusoidal tone were recorded in adults and two groups of children and adolescents with typical development or autism spectrum disorder. M50 amplitude was larger in children than in adults, suggesting a developmental trajectory with M50 amplitude decreasing and M100 increasing with age. Child M50 and M100 latencies were prolonged relative to adults. Children with autism did not differ from control children with respect to these observations. The M50 in relation to the M100 is a robust index of early auditory system maturation suitable for future developmental investigations.

Preoperative magnetic source imaging for brain tumor surgery: a quantitative comparison with intraoperative sensory and motor mapping.

OBJECT: The aim of this study was to compare quantitatively the methods of preoperative magnetic source (MS) imaging and intraoperative electrophysiological cortical mapping (ECM) in the localization of sensorimotor cortex in patients with intraaxial brain tumors. METHODS: Preoperative magnetoencephalography (MEG) was performed while patients received painless tactile somatosensory stimulation of the lip, hand, and foot. The early somatosensory evoked field was modeled using a single equivalent current dipole approach to estimate the spatial source of the response. Three-dimensional magnetic resonance image volume data sets with fiducials were coregistered with the MEG recordings to form the MS image. These individualized functional brain maps were integrated into a neuronavigation system. Intraoperative mapping of somatosensory and/or motor cortex was performed and sites were compared. In two subgroups of patients we compared intraoperative somatosensory and motor stimulation sites with MS imaging-based somatosensory localizations. Mediolateral projection of the MS imaging source localizations to the cortical surface reduced systematic intermodality discrepancies. The distance between two corresponding points determined using MS imaging and ECM was 12.5 +/- 1.3 mm for somatosensory-somatosensory and 19 +/- 1.3 mm for somatosensory-motor comparisons. The observed 6.5 mm increase in site separation was systematically demonstrated in the anteroposterior direction, as expected from actual anatomy. In fact, intraoperative sites at which stimulation evoked the same patient response exhibited a spatial variation of 10.7 +/- 0.7 mm. CONCLUSIONS: Preoperative MS imaging and intraoperative ECM show a favorable degree of quantitative correlation. Thus, MS imaging can be considered a valuable and accurate planning adjunct in the treatment of patients with intraaxial brain tumors.

Neuromagnetic auditory cortex responses to duration and pitch changes in tones: cross-linguistic comparisons of human subjects in directions of acoustic changes.

Our recent magnetic mismatch field (MMF) study found that shortened-vowel duration changes and level-to-falling pitch changes in Japanese words elicited a prominent MMF in two hemispheres for both native and nonnative speakers (Inouchi, M., Kubota, M., Ferrari, P. and Roberts, T.P.L., Magnetic mismatch fields elicited by Japanese words: vowel duration and pitch by native and nonnative speakers, Poster presented at the 31st Annual Meeting of Society for Neuroscience, November 10-15, San Diego, CA, 2001). The current study investigated whether shortened duration changes and level-to-falling pitch changes in non-speech (tones) would elicit a more prominent MMF component than lengthened duration changes and falling-to-level pitch changes, respectively. Stimuli included three computer-synthesized tones with varying duration or frequency modulation: (1). short duration and level pitch; (2). long duration and level pitch; (3). long duration and falling pitch. Magnetoencephalography responses were recorded with a dual 37-channel gradiometer system. The results showed that the prominent MMF component was generated in long-to-short duration changes and level-to-falling pitch changes in each hemisphere for both Japanese and American subjects. The component peaked at around 100 ms after change onset for duration changes and 170 ms for pitch changes. The MMF component in tones, like in words, was particularly sensitive to duration shortening and pitch falling. In summary, changes in duration shortening and pitch falling are particularly salient cues for pre-attentive auditory change detection in each hemisphere.

Increased somatosensory neuromagnetic fields ipsilateral to lesions in neurosurgical patients.

This study is aimed to determine whether the presence of a tumor in close proximity to the somatosensory cortex of the post-central gyrus affects the response evoked from such an area by painless tactile stimulation, recorded by MEG. The main finding of this study is that somatosensory evoked field strengths from cortex ipsilateral to and abutting an intracranial tumor are significantly elevated compared with either contralateral control fields, or with somatosensory evoked fields elicited from cortex ipsilateral to, but distant from tumors (typically involving language areas, such as inferior frontal lobe). Biophysical and biochemical explanations implicate hyperactivity of cortical neurons close to the tumor, suggesting a possible role of MEG as a measure of tumor infiltration.