Knockdown of Efp by DNA-modified small interfering RNA inhibits breast cancer cell proliferation and in vivo tumor growth.

The estrogen-responsive gene Efp promotes the growth of breast cancer cells by stimulating the degradation of a negative cell-cycle regulator, 14-3-3sigma, and is hence considered a suitable molecular target for breast cancer therapy. The use of small interfering RNA (siRNA) and its derivatives to silence cancer-related genes is being investigated with the aim of identifying clinical applications for these molecules. Recently, it has been shown that DNA-modified siRNA (chimeric siRNA) has good potential in clinical applications, because it induces fewer off-target effects or immune responses in mammalian cells. In the present study, we identified the most specific and effective siRNA (siEfp-1) for silencing Efp expression in MCF-7 breast cancer cells. For this purpose, we used an algorithm that primarily eliminates off-target effects. siEfp-1 considerably suppressed the in vitro proliferation and cell-cycle progression of MCF-7 cells, as well as the in vivo growth of MCF-7 tumors, in athymic mice. DNA-modified siEfp-1 (chimeric siEfp) significantly inhibited the expression of Efp, proliferation of cultured cells and the in vivo growth of MCF-7-derived tumors in athymic mice. In addition, the silencing of Efp expression by siEfp-1 and chimeric siEfp increased the expression of the 14-3-3sigma protein. These results suggest that siEfp-1 and chimeric siEfp could be useful in breast cancer therapy. Chimeric siEfp, in particular, has a high specificity and induces few side effects and is therefore expected to be used as a novel nucleic acid-based therapeutic agent.

Intraoperative localisation of the lip sensory area by somatosensory evoked potentials.

Accurate localisation of the central sulcus enables maximum tumour resection with minimum morbidity in peri-Rolandic surgery. We investigated intraoperative somatosensory evoked potentials (SSEPs) with combined recording of lower lip and median nerve stimuli during craniotomy in nine patients with peri-Rolandic glioma. Using a custom clip electrode, the lip mucous membrane was stimulated with biphasic pulses with 0.2 ms duration, 10-14 mA intensity and a frequency of 0.7 Hz. Polarity inversion of the SSEP was detected across the central sulcus using median nerve and/or lower lip stimulation in eight of the nine patients in whom the tumour did not infiltrate the lip or hand sensory area. Recording of SSEPs with lower lip stimulation is useful if the resection margin is planned lateral to the hand representation area, if the hand representation area is not exposed by the craniotomy, or if the SSEPs for median nerve stimulation are not clear due to tumour infiltration.

Non-transcallosal ipsilateral area 3b responses to median nerve stimulus.

We report two patients with left hemisphere lesions who had no normal left hemispheric responses to right median nerve stimulus on magnetoencephalography but displayed right area 3b responses. One patient had suffered a severe left hemispheric contusion and the other left hemispheric infarction. Equivalent current dipoles of these ipsilateral responses were detected on the central sulcus adjacent to the location of the N20m response to left median nerve stimulus. The somatosensory afferent pathway from the hand may extend directly to the ipsilateral area 3b without following the transcallosal pathway in at least part of the population.

Combined three-dimensional anisotropy contrast imaging and magnetoencephalography guidance to preserve visual function in a patient with an occipital lobe tumor.

OBJECTIVE: Three-dimensional anisotropy contrast (3-DAC) magnetic resonance imaging and magnetoencephalography (MEG) of visually evoked magnetic fields (VEFs) were used to accurately localize the optic radiation and primary visual cortex before surgery for an occipital tumor. PATIENT AND METHODS: A 26-year-old male presented with an occipital lobe tumor located intrinsically underneath the right calcarine fissure. 3-DAC imaging showed that the right optic radiation was located along the superior and lateral surfaces of the lesion. Mapping of the VEFs demonstrated that the primary visual cortex was located superior and lateral to the lesion. The lesion was totally resected via an infero-medial cortical incision using a frameless stereotactic system. Histopathology indicated a pilocytic astrocytoma. No visual deficit was found before or after surgery. CONCLUSION: Combined 3-DAC imaging and MEG can provide essential information about the optic radiation and primary visual cortex for planning the surgical treatment of occipital lobe tumors.

Neuromagnetic separation of secondarily bilateral synchronized spike foci: report of three cases.

To demonstrate the high spatiotemporal resolution of magnetoencephalography (MEG), we report three cases with focal epilepsy that exhibited bilateral synchronized spikes on simultaneous scalp EEG and MEG recording. Constant time lags (19.4 +/- 3.0 ms and 20.0 +/- 5.5) between the leading and the following contralateral spikes were noted on MEG and the current dipole sources were localized in the bilateral homotopic regions symmetrically in Cases 1 and 3. In Case 2, MEG indicated leading spikes in the left frontal region, with a time lag of 42.3 +/- 8.4 ms to reach the contralateral frontal and bilateral temporal regions as well. Chronic subdural EEG recording in Cases 1 and 2 confirmed that the leading spike focus in MEG was close to the seizure onset zone in cortical EEG. Spatio-temporal analysis of MEG spikes may be useful to identify the primary epileptic region in patients with synchronized bilateral epileptiform discharges.

Somatosensory-evoked fields for gingiva, lip, and tongue.

To localize the oral primary somatosensory cortex, we measured somatosensory-evoked fields for the lip, gingiva, and tongue in six healthy subjects. The latency of the first peak of the posterior-oriented current in the contralateral hemisphere was 50.9 +/- 8.3 ms for the gingiva, significantly shorter than those for the lip and tongue peaks. The equivalent current dipole was localized on the central sulcus. The gingival dipole was localized significantly inferior to the lip dipole but not different from the tongue dipole. The moment of the gingival dipole was significantly smaller than that of the lip dipole but not different from that of the tongue dipole. Differences in the above parameters were negligible between the left and right, anterior and posterior, and upper and lower locations within the same organ, except that the dipole location for the anterior upper tongue was significantly inferior to that for the lower tongue.

Mesial temporal lobe epilepsy with lateral temporal lobe abnormalities in magnetoencephalography and glucose metabolism.

Magnetoencephalography (MEG) and positron emission tomography (PET) revealed abnormal findings in the lateral temporal lobe of a 22 year old female with mesial temporal lobe epilepsy. Electroencephalography identified the epileptogenic focus in the left mesial temporal lobe and standard anterior temporal lobectomy resulted in a good surgical outcome. These discrepancies can be explained by the presence of anatomical and functional pathways between the mesial and lateral temporal structures, or pathophysiological abnormalities in both the mesial and lateral temporal lobes. Careful evaluation is necessary for analysis of MEG and PET findings in patients with temporal lobe epilepsy.

Movement-related magnetic fields to tongue protrusion.

Movement-related magnetic fields (MRFs) associated with tongue protrusion were measured in five normal subjects using a helmet-shaped magnetoencephalography system. Bihemispherical two-dipolar patterns appeared from approximately -2000 or -1000 to 0 ms to the trigger signal indicating when protrusion of the tongue tip reached the frontal part of the palate. Equivalent current dipoles (ECDs) for the MRFs were localized on the central sulcus, 14.4 +/- 6.1 mm inferior (P < 0.0001) and 7.6 +/- 6.9 mm anterior (P < 0.01) to the ECD for the N20m in the somatosensory evoked fields for median nerve stimuli. The ECD orientations of MRFs were anterior and perpendicular to the central sulcus. These results correspond to the movement-related potentials for tongue protrusion previously recorded from subdural electrodes in patients with epilepsy. Magnetoencephalography can be applied to analyze cortical functions related to tongue movement with high resolution in time and space in normal subjects.

Judging semantic and episodic incongruity: a magnetoencephalographic study.

Evoked magnetic fields over the entire head were measured during a semantic judgment task, in which conditions of the pre-test learning session were manipulated. Subjects learnt related and unrelated category-noun pairs, and were then asked to judge the relationship between category and noun. Unrelated pairs evoked activation around 400 ms in the left temporal area. In addition, newly presented related pairs, of which the categories were used to learn unrelated pairs, also evoked similar activities. Our findings suggest that these activities are not only related to the semantic incongruity between a pair of words as in previous studies, but also to the episodic incongruity between the learning and measurement sessions.

Neuromagnetic localization of N15, the initial cortical response to lip stimulus.

The initial cortical response of the trigeminal somatosensory evoked magnetic fields was measured for electrical stimulation of the lower lip in eleven subjects. The stimulus frequency was 0.7 Hz and stimulus intensity was nine times sensory threshold. The initial contralateral response was detected in 20 hemispheres at a latency of 14.6+/-1.3 ms and was named N15m. The equivalent current dipole of N15m was localized at the posterior bank of the central sulcus with anterior-superior orientation, and inferior to the dipole of N20m for median nerve stimulation.

Somatosensory evoked fields in comatose survivors after severe traumatic brain injury.

OBJECTIVE: To evaluate the cortical function quantitatively in patients in the chronic phase of severe traumatic brain injury. METHODS: Thirteen patients with severe traumatic brain injury due to traffic accident followed by persistent consciousness disturbance and disability were studied. Somatosensory evoked magnetic fields (SEFs) for unilateral median nerve stimulation were measured using a whole-head magnetoencephalography system. The latency and electrical current dipole (ECD) moment for the N20m, P30m, N45m and P60m components were calculated and compared with those of 14 age-matched healthy adults. RESULTS: The peak latency of N20m was longer (P<0.05) and those of P30m and N45m were shorter (P<0.01) in the patients than in normal adults. The ECD moment of N20m and P30m was smaller and that of N45m and P60m was larger in the patients than in normal adults (P<0.01). CONCLUSIONS: These results can be explained by the hypothesis that diffuse brain injury induces decreased and delayed input of the somatosensory afferent and compensational amplification of the response in the primary somatosensory cortex. Middle-latency SEFs may be applicable as a cortical functional measure for patients with severe traumatic brain injury.

Middle and long latency peak sources in auditory evoked magnetic fields for tone bursts in humans.

The relative position of the P50m and the N100m sources of the auditory evoked magnetic field remains unclear. Magnetoencephalography was performed in 24 normal subjects. Contralateral P50m to left and right ear stimulus was observed in 21 and 19hemispheres, respectively. Ipsilateral P50m to left and right ear stimulus was observed in 17 and 16hemispheres, respectively. N100m was observed in all subjects for all stimuli. Relative position of the equivalent current dipole of the P50m was 1.0+/-7.6 (mean+/-SD) mm posterior, 2.0+/-5.8mm inferior and 1.8+/-8.0mm medial to the N100m dipole position considering all observations. We suggest that the P50m and N100m sources are colocated in an extended area of the cortex.

Remote discharges in the posterior language area during basal temporal stimulation.

A 23-year-old woman with refractory complex partial seizures underwent implantation of subdural grid electrodes over the left hemisphere to map epileptic foci and language function. Aphasic symptoms occurred during stimulation of the basal temporal area, which were always associated with intrastimulus remote discharges (ISRDs) in the classical posterior language area. No sequential language deficits occurred after anterior temporal lobectomy including the basal temporal area. These results suggest a close functional relationship between the basal temporal area and posterior language area in patients with temporal lobe epilepsy. ISRDs may explain the paradoxical observation that resection of the basal temporal language area results in no language deficits.

Primary thumb sensory cortex located at the lateral shoulder of the inverted omega-shape on the axial images of the central sulcus.

Useful landmarks on magnetic resonance (MR) images were identified for preoperative prediction of the relationship of a tumor to the primary sensory cortex of the thumb. Functional MR (fMR) imaging and magnetoencephalography were used to retrospectively localize the hand-digit sensorimotor area in four patients who underwent tumor resection around the central sulcus with intraoperative neurophysiological mapping. fMR imaging revealed the hand-digit motor cortex in the so-called "precentral knob" inside the characteristic inverted-omega on axial MR images. Equivalent current dipoles of the N20 m response in somatosensory evoked fields (SEFs) of the thumb, median nerve, and ulnar nerve stimuli were localized at the lateral portion of the inverted omega-shape from the lateral to medial directions. The SEF-based thumb sensory cortex was verified by intraoperative functional mapping with a neuronavigation system. The hand-digit somatosensory cortices were localized at the lateral shoulder of the inverted-omega, in the lateral anterior inferior position to the hand-digit motor cortices in the precentral knob. Axial MR imaging can provide useful preoperative planning information for the surgical treatment of tumors within or adjacent to the motor-somatosensory cortex.

Somatosensory, auditory, and visual evoked magnetic fields in patients with brain diseases.

The features of somatosensory (SEFs), auditory (AEFs), and visual evoked fields (VEFs) in healthy subjects and patients with brain diseases provide the basis for clinical investigations using magnetoencephalography (MEG). The SEFs provide clinically useful information to identify the central sulcus and somatotopic organization of the primary somatosensory cortex. Localization accuracy of the SEFs can be tested by cortical stimulation during surgery. Functional reorganization suggested by SEF studies must be verified by other modalities. The AEFs can localize the auditory cortex in the bilateral temporal lobes. Separation of bilateral activities is much clearer in AEFs than in auditory evoked potentials. Modulation of the interhemispheric differences of latency, amplitude, and source localization of AEFs can be used to evaluate auditory function in patients with intracranial lesions. Pattern reversal VEFs provide stable localization of the primary visual function. Separation of bihemispherical activities is the advantage of VEFs over visual evoked potentials. Investigation of VEFs provides objective evaluation of visual field deficits such as homonymous or bitemporal hemianopsia in patients with intracranial lesions. Evoked magnetic fields can provide useful diagnostic information. Such clinical findings, in turn, provides the opportunity to test the source estimation accuracy of MEG.

Accuracy and limitation of functional magnetic resonance imaging for identification of the central sulcus: comparison with magnetoencephalography in patients with brain tumors.

The aim of the present study was to clarify the accuracy and limitation of functional magnetic resonance imaging (fMRI) for the identification of the central sulcus affected by brain tumors. Twelve normal volunteers and 11 patients with intracranial tumors adjacent to the central sulcus underwent fMRI and magnetoencephalography (MEG). Three patients were evaluated again after surgery. fMRI was performed with a 1.5 Tesla scanner during repetitive opening and closing of each hand. Cross-correlation function was used to identify activation areas, and the central sulcus was defined as the nearest sulcus to the highest activation spots that were determined by elevating correlation coefficient threshold. Somatosensory-evoked fields were measured using a whole head MEG system. The central sulcus was defined as the nearest sulcus to the N20m for the median nerve stimulus. fMRI and MEG coincided in defining the central sulcus in all 24 hemispheres of volunteers and all 10 examined nonaffected hemispheres of patients. The fMRI-defined central sulcus coincided with the MEG-defined central sulcus in nine (82%) but did not in two (18%) affected hemispheres of patients. The preoperative mismatch disappeared after surgery in one of the two patients. The present study indicates that fMRI successfully defined the central sulcus in most of the patients with brain tumors. However, in a few cases, fMRI was not reliable probably due to venous flow changes by tumor compression and/or compensational activity by brain tissues surrounding the primary sensorimotor cortex. For precise functional assessment of the brain affected by intracranial tumors, combination of fMRI and MEG will be recommended.

Low-luminance visual stimuli compared with stroboscopic IPS in eliciting PPR in photosensitive patients.

PURPOSE: Photosensitivity is thought to play the most important role in the genesis of electronic screen games induced seizures (ESGIS). To elicit photoparoxysmal response (PPR) effectively, we performed EEG activation by low-luminance visual stimuli: 20 cd/m2 deep-red flicker and flickering 2 c/deg geometric pattern stimuli produced by strobofilters. We investigated efficacy of eliciting PPR by use of Grass PS33-plus stroboscopic 18-Hz intermittent photic stimulation (IPS) and low-luminance 18-Hz visual stimuli. METHODS: We studied 31 photosensitive patients. We gave stroboscopic IPS (eyes closed and eyes open); after deep-red flicker stimulation (eyes open), we gave flickering geometric-pattern stimuli by using dot, vertical grating, and horizontal grating patterns. RESULTS: Stroboscopic IPS elicited PPR in 14 patients, whereas absence of PPR provocation was found in 17 patients. Low-luminance visual stimuli elicited PPR in 30 patients, whereas absence of PPR provocation was found in only one patient. These PPR provocation differences in both stimuli were statistically significant (p < 0.001). CONCLUSIONS: The data suggest that low-luminance visual stimuli as described are useful for EEG diagnosis of ESGIS when seizures are thought to be due to photosensitivity.

Surgical treatment of intractable epilepsy originating from the primary sensory area of the hand--case report.

A 14-year-old right-handed girl presented with intractable epilepsy originating from the primary sensory area of the hand, manifesting as sensory partial seizures in the left hand with secondary generalization. Neurological examination showed no abnormal findings. Magnetic resonance imaging, magnetoencephalography, and cortical stimulation using chronic subdural electrodes demonstrated a lesion located in the primary sensory cortex of the hand, in which the ictal onset zone was identified by 24-hour intracranial electroencephalographic recording. Surgical resection of the lesion and multiple subpial transections of the adjacent cortices were performed. The histological diagnosis was dysembryoplastic neuroepithelial tumor (DNT). She was completely free of seizures without permanent sensory deficits postoperatively. DNT located in the primary sensory hand area may be resectable without causing postoperative sensory deficits, if accurate functional mapping and surgical resection are performed.