Third order spectral analysis robust to mixing artifacts for mapping cross-frequency interactions in EEG/MEG.

We present a novel approach to the third order spectral analysis, commonly called bispectral analysis, of electroencephalographic (EEG) and magnetoencephalographic (MEG) data for studying cross-frequency functional brain connectivity. The main obstacle in estimating functional connectivity from EEG and MEG measurements lies in the signals being a largely unknown mixture of the activities of the underlying brain sources. This often constitutes a severe confounder and heavily affects the detection of brain source interactions. To overcome this problem, we previously developed metrics based on the properties of the imaginary part of coherency. Here, we generalize these properties from the linear to the nonlinear case. Specifically, we propose a metric based on an antisymmetric combination of cross-bispectra, which we demonstrate to be robust to mixing artifacts. Moreover, our metric provides complex-valued quantities that give the opportunity to study phase relationships between brain sources. The effectiveness of the method is first demonstrated on simulated EEG data. The proposed approach shows a reduced sensitivity to mixing artifacts when compared with a traditional bispectral metric. It also exhibits a better performance in extracting phase relationships between sources than the imaginary part of the cross-spectrum for delayed interactions. The method is then applied to real EEG data recorded during resting state. A cross-frequency interaction is observed between brain sources at 10Hz and 20Hz, i.e., for alpha and beta rhythms. This interaction is then projected from signal to source level by using a fit-based procedure. This approach highlights a 10-20Hz dominant interaction localized in an occipito-parieto-central network.

Adding dynamics to the Human Connectome Project with MEG.

The Human Connectome Project (HCP) seeks to map the structural and functional connections between network elements in the human brain. Magnetoencephalography (MEG) provides a temporally rich source of information on brain network dynamics and represents one source of functional connectivity data to be provided by the HCP. High quality MEG data will be collected from 50 twin pairs both in the resting state and during performance of motor, working memory and language tasks. These data will be available to the general community. Additionally, using the cortical parcellation scheme common to all imaging modalities, the HCP will provide processing pipelines for calculating connection matrices as a function of time and frequency. Together with structural and functional data generated using magnetic resonance imaging methods, these data represent a unique opportunity to investigate brain network connectivity in a large cohort of normal adult human subjects. The analysis pipeline software and the dynamic connectivity matrices that it generates will all be made freely available to the research community.

Frequency specific interactions of MEG resting state activity within and across brain networks as revealed by the multivariate interaction measure.

Resting state networks (RSNs) are sets of brain regions exhibiting temporally coherent activity fluctuations in the absence of imposed task structure. RSNs have been extensively studied with fMRI in the infra-slow frequency range (nominally <10(-1)Hz). The topography of fMRI RSNs reflects stationary temporal correlation over minutes. However, neuronal communication occurs on a much faster time scale, at frequencies nominally in the range of 10(0)-10(2)Hz. We examined phase-shifted interactions in the delta (2-3.5 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta (13-30 Hz) frequency bands of resting-state source space MEG signals. These analyses were conducted between nodes of the dorsal attention network (DAN), one of the most robust RSNs, and between the DAN and other networks. Phase shifted interactions were mapped by the multivariate interaction measure (MIM), a measure of true interaction constructed from the maximization of imaginary coherency in the virtual channels comprised of voxel signals in source space. Non-zero-phase interactions occurred between homologous left and right hemisphere regions of the DAN in the delta and alpha frequency bands. Even stronger non-zero-phase interactions were detected between networks. Visual regions bilaterally showed phase-shifted interactions in the alpha band with regions of the DAN. Bilateral somatomotor regions interacted with DAN nodes in the beta band. These results demonstrate the existence of consistent, frequency specific phase-shifted interactions on a millisecond time scale between cortical regions within RSN as well as across RSNs.

Calibration of a multichannel MEG system based on the signal space separation method.

For an efficient use of multichannel MEG systems, an accurate sensor calibration is extremely important. This includes the knowledge of both channel sensitivities and channel arrangement, which can deviate from original system plans, e.g., because of thermal stresses. In this paper, we propose a new solution to the calibration of a multichannel MEG sensor array based on the signal space separation (SSS) method. It has been shown that an inaccurate knowledge of sensor calibration limits the performances of the SSS method, resulting in a mismatch between the measured neuromagnetic field and its SSS reconstruction. Given a set of known magnetic sources, we show that an objective function, which strongly depends on sensor geometry, can be derived from the principal angle between the measured vector signal and the SSS basis. Hence, the MEG sensor array calibration is carried out by minimizing the objective function through a standard large-scale optimization technique. Details on the magnetic sources and calibration process are presented here. Finally, an application to the calibration of the 153-channel whole-head MEG system installed at the University of Chieti is discussed.

Multimodal integration of fMRI and EEG data for high spatial and temporal resolution analysis of brain networks.

Two major non-invasive brain mapping techniques, electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), have complementary advantages with regard to their spatial and temporal resolution. We propose an approach based on the integration of EEG and fMRI, enabling the EEG temporal dynamics of information processing to be characterized within spatially well-defined fMRI large-scale networks. First, the fMRI data are decomposed into networks by means of spatial independent component analysis (sICA), and those associated with intrinsic activity and/or responding to task performance are selected using information from the related time-courses. Next, the EEG data over all sensors are averaged with respect to event timing, thus calculating event-related potentials (ERPs). The ERPs are subjected to temporal ICA (tICA), and the resulting components are localized with the weighted minimum norm (WMNLS) algorithm using the task-related fMRI networks as priors. Finally, the temporal contribution of each ERP component in the areas belonging to the fMRI large-scale networks is estimated. The proposed approach has been evaluated on visual target detection data. Our results confirm that two different components, commonly observed in EEG when presenting novel and salient stimuli, respectively, are related to the neuronal activation in large-scale networks, operating at different latencies and associated with different functional processes.

A cartesian time--frequency approach to reveal brain interaction dynamics.

The study of large-scale interactions from magnetoencephalographic data based on the magnitude of the complex coherence computed at channel level is a widely used method to track the coupling between neural signals. Traditionally, a measure based on the magnitude of the complex coherence estimated by Fourier analysis, has been used under the assumption that the neural signals are stationary. Here, we split the complex coherence in its real and imaginary parts and focus on the latter with the advantage that the imaginary part is insensitive to spurious connectivity resulting from volume conducted "self interaction". Furthermore, interacting sources alone contribute to a non-vanishing imaginary part of the complex coherence whereas the contribute of non-interacting sources is also mapped from the magnitude of the complex coherence. Since it has been extensively shown that non-stationary stochastic processes contribute to the generation of neural signals, it is fundamental to be able to define interaction measures that are able to follow the temporal variations in the coupling between neural signals. To this purpose time-frequency domain techniques to estimate the magnitude of the complex coherence have been developed in the past decades. Similarly, we extend the analysis of the imaginary part of complex coherence to the time-frequency domain, by using the short-time Fourier transform to analyze the complex coherence as a function of time. In this way, it is possible to get an indication about the dynamic of the underlying source interaction pattern by looking at channel level interactions without the bias introduced by artifactual self-interaction by volume conduction or by the contribute of non-interacting sources. Furthermore, the corresponding imaginary part of the cross-spectrogram can be used to estimate interactions on a source level by localizing pools of sources interacting at a given frequency and by characterizing their dynamics. The method has been applied to magnetoencephalographic data from a cross-modal visual auditory stimulation and provided evidence for the involvement of temporal and occipital areas in the integrated information processing for simultaneous audio-visual stimulation. Furthermore, the source interaction pattern shows a variation in time that reflects a dynamical synchronization of the involved brain sources in the frequency bands of interest.

The use of standardized infinity reference in EEG coherency studies.

The study of large scale interactions in the brain from EEG signals is a promising method for the identification of functional networks. However, the validity of a large scale parameter is limited by two factors: the use of a non-neutral reference and the artifactual self-interactions between the measured EEG signals introduced by volume conduction. In this paper, we propose an approach to study large scale EEG coherency in which these factors are eliminated. Artifactual self-interaction by volume conduction is eliminated by using the imaginary part of the complex coherency as a measure of interaction and the Reference Electrode Standardization Technique (REST) is used for the approximate standardization of the reference of scalp EEG recordings to a point at infinity that, being far from all possible neural sources, acts like a neutral virtual reference. The application of our approach to simulated and real EEG data shows that the detection of interaction, as opposed to artifacts due to reference and volume conduction, is a goal that can be achieved from the study of a large scale parameter.

Open magnetic and electric graphic analysis.

The OMEGA software provides an analysis platform for user-independent, fast, and reproducible multimodal data analysis in one single software environment. Synergetic interactions pursued between the two functional imaging techniques fMRI and MEG use the morphological MRI recording as a basis for a common coordinate frame. In this way, direct interchange, comparison, and integration among the results of the different modalities have become feasible. The fMRI data analysis provides information about the localization of functional activity with low temporal resolution, whereas the MEG recording complements the corresponding time evolution with a high temporal resolution. The implementation of OMEGA allows the analyst to receive comprehensive MEG/fMRI results in a matter of minutes after the measurements have been completed. With OMEGA, the clinical researcher gets comprehensive information in a quick and standardized approach about the sites and the time course of neurological activation, which is useful for clinical applications and diagnostics.

Calibration of a vector-MEG helmet system.

The MEG system Argos 500, recently installed at the University of Ulm, is designed for clinical application and routine use, to allow investigation of a large number of patients per day. To reach this goal, the system design meets the requirements of reliability, high field sensitivity, minimal set-up overhead before each measurement and an easy-to-handle user interface. The sensor system consists of a 163 vector-magnetometer array oriented and located in a suitable way to cover the whole head of the patient. Four additional triplets are available as references to build software gradiometers. To use this system at a high performance level, it must be properly calibrated, with these goals: to determine the actual geometry of the sensors array, which can deviate from the design specifications, and to determine the actual sensitivity of each sensor. The calibrating source consists of 31 coils placed at the corners of a head-size dodecahedron. Various details of the calibration system and process are presented here.

Argos 500: operation of a helmet vector-MEG.

We here describe the MEG system recently installed at the University of Ulm; it is specifically designed for clinical application and routine use, to allow investigation of a large number of patients per day. To reach this goal, the system design meets the requirements of reliability, high field sensitivity, minimal set-up time before each measurement and an easy-to-handle user interface. The sensor system consists of a 163 vector-magnetometers array oriented and located in a suitable way to cover the whole head of the patient. Four additional triplets are available as references to arrange software gradiometers. The helmet shaped sensor system is positioned to accommodate the patient in a supine position. Simultaneously to the MEG, there are 64 EEG channels. Other relevant patient information can be recorded up to a total number of 660 acquisition channels. Noise level of a single magnetometer is about 5 fT/square root of Hz. Maximum sampling rate is 4200 Hz.

Does adjuvant chemotherapy improve the prognosis of cervical carcinoma with lymph-node metastasis? A long-term follow-up.

OBJECTIVE: to verify the efficacy of adjuvant therapy in the prevention of neoplastic recurrence in patients at high risk for lymph-node involvement on surgical examination. METHODS: 72 patients, suffering from squamous cell cervical carcinoma Stage IB-IIB (FIGO) who underwent radical hysterectomy with lymph-node involvement confirmed at the final histological examination, were enrolled. All the patients were treated with adjuvant chemotherapy (AC), which included cisplatin, bleomycin and vinblastine, and were followed for a minimum period of six years. The results were compared with those obtained with a historical group of 78 patients, with comparable age, stage and lymph-node involvement, on whom only radical surgery (RS) was performed. RESULTS: the average total survival rate of the two groups (RS + AC vs RS) at five years was 63.9% and 55.1%, respectively (chi2 = 1.191; p = NS). The disease-free interval was 55.6% vs 46.2% (chi2 = 1.324; p = NS). The best results were obtained in cases where the common iliac lymph-nodes were affected, with the highest survival rate of 16.9% in the RS+AC group, out of a total of 25 cases. CONCLUSIONS: adoption of adjuvant chemotherapy in patients at high risk for lymph-node positivity did not produce statistically significant results in terms of overall and disease-free survival; however, a small number of these patients, approximately 9%, could receive benefit from the treatment.

The role of neoadjuvant chemotherapy for squamous cell cervical cancer (Ib-IIIb): a long-term randomized trial.

OBJECTIVE: to verify whether a regimen of preventive chemotherapy in the treatment of cervical carcinoma allows surgical treatment in a larger number of patients and whether cases treated with this combined neoadjuvant polychemotherapy/surgery regimen improves overall and disease-free survival rates. DESIGN: prospective randomized clinical study. SETTING: Department of Gynaecology and Obstetrics, University of Rome "La Sapienza". METHODS: 192 patients suffering from squamous cell carcinoma of the uterine cervix in Stages Ib-IIb were randomized to one of the following treatments: three courses of neoadjuvant chemotherapy with cisplatin, vincristine, bleomycin (NACT arm; n = 106); conventional surgery or radiotherapy alone (CO arm; n = 86). One hundred and fifty-six patients in Stage Ib-IIb (n = 86, NACT arm and n = 70, CO arm) and 16 patients in Stage III (NACT arm) who proved to be sensitive to the neoadjuvant chemotherapy, underwent radical hysterectomy. Four Stage III patients not sensitive to chemotherapy and 16 patients, Stage III, of the CO arm underwent radiotherapy. RESULTS: the 5-year overall survival rates for the NACT and CO arm, respectively, were 78.6% and 73.2% in Stages Ib-IIa (p = NS), 68.7% and 64.3% in Stage IIb (p = NS). A 5-year disease-free survival rate for the NACT arm and CO arm, respectively, of 77.1% and 64.3% in Stages Ib-IIa (p < .05), 56.2% and 57.1% in Stage IIb (p = NS) was found. CONCLUSIONS: the responsiveness of cervical cancer to neoadjuvant chemotherapy allows surgical treatment in a larger number of patients and results in longer overall and disease-free survival.

Docetaxel and epirubicin plus G-CSF as mobilizing treatment to support high-dose chemotherapy in breast cancer.

BACKGROUND: In order to combine an active regimen with a simultaneous efficient mobilization of peripheral blood precursor cells (PBPC), we explored the combination of Docetaxel 75 mg/m2 and Epirubicin 120 mg/m2 with G-CSF 5 mcg/Kg/day s.c. to mobilize PBPC in breast cancer patients to support high-dose chemotherapy (HDC). PATIENTS AND METHODS: Forty patients were enrolled: 27 high risk and 13 metastatic. The entire procedure, including chemotherapy and PBPC collection, was on an outpatient basis. RESULTS: The median day of starting apheresis was day +10 (range 10-12) and the average value of circulating CD34+ cells at peak was 175/microliter (range 33-403). The median yield of CD34+ cells per apheresis was 8.76 x 10(6)/Kg (range 1.83-27.87). None of the patients developed side effects which required hospitalization. All patients enrolled successively received HDC as consolidation treatment. High risk patients received one and metastatic patients two HDC with PBPC reinfusion. All patients obtained a complete engraftment. No significant differences between high-risk and metastatic patients were observed. CONCLUSIONS: Our study suggests that the combination of Docetaxel, Epirubicin, and G-CSF is feasible, safe and efficient outpatient mobilizing treatment for patients with breast cancer receiving HDC.

Detection of breast cancer cells in the bone marrow or peripheral blood: methods and prognostic significance.

Tumor cells can reach every anatomic district, organ and tissue through the peripheral blood circulation. Tumor cell shedding is considered an early event in the multi-phase process of metastasis, and the possibility of detecting tumor cells in the bloodstream and/or bone marrow before clinical evidence of distant metastases needs to be explored. The use of new sophisticated diagnostic and investigative techniques has boosted the study of tumor cell contamination of bone marrow and peripheral blood. Molecular techniques, such as reverse-transcriptase polymerase chain reaction, may be useful tools to reach this target, but, today, immunocytochemistry is still considered the gold standard to assess new techniques to detect isolated tumor cells in hematopoietic tissue. Little is known about the biology of isolated tumor cells in the peripheral blood or bone marrow. Two crucial points need to be evaluated: the identification of specific markers of breast cancer cells with clonogenic potential and their biologic properties, and the prognostic impact of the detection of isolated tumor cells in the bone marrow or peripheral blood stem cell collections.

[Current role of progesterone therapy in the prevention of spontaneous abortion and in the treatment of threatened abortion]. / Ruolo attuale della terapia progestinica nella prevenzione dell'aborto spontaneo e nel trattamento della minaccia d'aborto.

Progesterone therapy is often used to prevent spontaneous abortion. In this paper the most significant studies on the benefits and risks of this treatment over the last 30 years are analyzed. None of these studies about the effects of progesterone as non-specific therapy in abortion risk and recurrent miscarriage, proved a reduced pregnancy wastage in treated patients compared with patients who received no treatment. The results concerning the use of progesterone in recurrent miscarriage for luteal phase inadequacy are more controversial, but they are still inadequate to encourage progesterone supplementation. To obtain a definitive conclusion about progesterone therapy real effectiveness, it is necessary to carry out randomized double-blind prospected trials. As regards the risks of using progesterone therapy during pregnancy, even if a possible teratologic role has certainly been reduced, it cannot be excluded completely yet. Moreover a high incidence of respiratory problems has been noticed in newborns from patients treated with progesterone, compared with control groups.

[Radical trachelectomy with lymphadenectomy]. / La trachelectomia radicale con linfoadenectomia.

Radical trachelectomy was described for the first time by Dargent in 1987 as an alternative to the traditional radical hysterectomy; it led to a changed procedure in therapy for early cervical cancer in young women who want to preserve their fertility. With this technique it is possible to remove the uterine cervix and parametrius and at the same time preserve the upper part of the cervical canal and uterus. Only a low-risk subset of young patients with early cancer of the cervix are considered eligible for this treatment; to select them histological and clinical staging of the lesion are the most important criteria. We describe the cases of three patients treated with radical trachelectomy between June 1997 and March 1998 in our Institute, reporting in detail the surgical procedure and the results.

[A case of intestinal occlusion caused by endometriosis of the cecum]. / Un caso di occlusione intestinale da endometriosi del cieco.

The purpose of this study is to heighten awareness of intestinal endometriosis, a disease that may mimic other abdominal pathologies (bowel carcinoma, intestinal inflammatory disease, diverticulitis), sometimes found in the emergency setting. The Authors report a case of acute bowel obstruction due to coecal endometriosis with appendix mucocele, peritoneal pseudomyxoma and ovarian endometrioma. The patient was operated on in the emergency setting, a right colectomy was performed and she then received pharmacological suppressive treatment with Gn-RH analogues and danatrol. We remark that preoperative diagnosis is very difficult in those cases that do not have a past history of pelvic endometriosis. An accurate anamnesis regarding the chronology of pain onset (typically only during the menstruation at first), but especially intraoperative histopathologic examination are useful for diagnosis. An increased awareness of intestinal endometriosis in reproductive age women with acute bowel obstruction, associated with an accurate anamnesis of menstrual history may allow pre- or intraoperative diagnosis, which is the clue to a less aggressive operation. Postoperative follow up and hormonal therapy are mandatory.

[The creation of a neovagina with laparoscopic technique]. / Creazione di una neovagina con tecnica laparoscopica.

Vaginal agenesis is sometimes found isolated but more frequently as a part of a malformative syndrome, such as the Rokitansky-Küster-Hauser or the Morris syndrome. In our department the technique of choice for surgical creation of a neovagina is that described by Vecchietti. A pelviscopic approach for this technique has recently been described. Two cases of vaginal atresia are described; one with Rokitansky-Küster-Hauser and the other with Morris syndrome, in which the laparoscopic technique was attempted. Due to the aetiopathogenetic and anatomical differences of the two syndromes, the laparoscopic technique resulted easy in the first case but very difficult in the Morris syndrome case, needing laparotomic conversion. We therefore believe that in choosing the surgical approach, a decisive issue is the type of malformation. Indeed in the Morris syndrome, the contiguity between rectum and bladder makes the laparoscopic technique more difficult.

Biologic prognostic factors in ovarian cancer: a review.

The need of foreseeing the prognosis of ovarian cancer beyond the limits of classical methods based on clinical and histopathological staging has recently caused great interest in a large number of biologic prognostic markers. Studies concern proliferation associated proteins, suppressor genes, abnormal expressions of growth factors, cytokins, and many more. Here some of the most recent and promising factors being studied are described together with their significance for future clinical application.

[Breast scintigraphy with 99mTc-MIBI in the study of breast cancer]. / La scintigrafia mammaria con 99mTc-MIBI nello studio del carcinoma della mammella.

BACKGROUND: The literature latest data point out the 99mTc-MIBI scintimammography role as a mammography diagnostic complement for a better nosologic definition of the breast nodular pathology. The object of this study is to evaluate the device sensibility and specificity with reference to the several dimensions of the neoplastic nodule. METHODS: A group of 50 patients, with breast nodule has been studied comparing scintimammography, mammography, echography and istological examination of the removed nodule. RESULTS: 38 nodules out of 50 were carcinomas, 22 were T1 and 16 T2. As far as scintimammography is concerned, the sensibility is 86% in T1 grade and 100% in T2 grade. The specificity is 91.6%. CONCLUSIONS: Since the mammography often need integration with invasive examinations, (aspiration biopsy, and biopsy) scintigraphy-mammography, global specificity 92%, is suggested as a second level examination in the mammary nodule diagnosis, for the simple performance and for the little risk for the patient.