Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Open fourth ventricle prior to 20 weeks' gestation: a benign finding?

OBJECTIVE: To evaluate the role of the brainstem-vermis (BV) angle in the diagnosis of fetal posterior fossa abnormalities at 15-18 weeks' gestation. METHODS: We examined retrospectively three-dimensional (3D) ultrasound volumes acquired at 15-18 gestational weeks in fetuses with normal posterior fossa (controls) and in those with cystic posterior fossa. Whether the fourth ventricle appeared open posteriorly in axial views was noted and the BV angle was measured. A detailed follow-up was obtained in all cases. RESULTS: Of the 139 controls, 46 cases were excluded because of inadequate quality of the 3D volumes. Of the 93 remaining normal fetuses, 84 (90.3%) had a closed fourth ventricle and a BV angle < 20°, whereas 9/93 (9.7%) had an open fourth ventricle and a BV angle between 20° and 37°. The study group of 11 fetuses included seven with Dandy-Walker malformation and four with Blake's pouch cyst. In abnormal cases as a whole, the BV angle was significantly increased compared with that in controls (P < 0.0001). However, fetuses with Blake's pouch cyst and normal fetuses with an open fourth ventricle had strikingly similar sonograms: the BV angle was between 20° and 37° and the fourth ventricle appeared open only when viewed using a more steeply angulated scanning plane than that of the standard transcerebellar plane; in fetuses with Dandy-Walker malformation the fourth ventricle was widely open posteriorly, even in the standard transcerebellar view, and the BV angle was > 45°, significantly increased compared both with that in normal fetuses (P < 0.0001) and with that in fetuses with Blake's pouch cyst (P = 0.004). CONCLUSION: An open fourth ventricle is found in about 10% of normal fetuses at 15-18 weeks' gestation. Measurement of the BV angle is useful in such cases, as a value ≥ 45° is associated with a very high risk of severe posterior fossa malformation.

Investigation of decision-making under uncertainty in healthy subjects: a multi-centric fMRI study.

Decision-making is an everyday routine that entails several subprocesses. Decisions under uncertainty occur when either prior information is incomplete or the outcomes of the decision are unclear. The aim of the present study was to disentangle the neural correlates of information gathering as well as reaching a decision and to explore effects of uncertainty acceptance or avoidance in a large sample of healthy subjects. Sixty-four healthy volunteers performed a decision-making under uncertainty task in a multi-center approach while BOLD signal was measured with fMRI. Subjects either had to indicate via button press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or they had to indicate whether 8 red balls had been presented (baseline condition). During the information gathering phase (contrasted against the counting phase) a widespread network was found encompassing (pre-)frontal, inferior temporal and inferior parietal cortices. Reaching a decision was correlated with activations in the medial frontal cortex as well as the posterior cingulate and the precuneus. Effects of uncertainty acceptance were found within a network comprising of the superior frontal cortex as well as the insula and precuneus while uncertainty avoidance was correlated with activations in the right middle frontal cortex. The results depict two distinct networks for information gathering and the indication of having made a decision. While information-gathering networks are modulated by uncertainty avoidance and - acceptance, underlying networks of the decision itself are independent of these factors.

Vaginal delivery rate in post-term pregnancies with one versus more than one dinoprostone gel administrations: an observational study.

AIM: The study aims to calculate the probability of a successful vaginal delivery in post-term low-risk women by using a set of predictors (maternal, fetal, and ultrasonographic) according to the number of dinoprostone gel applications. METHODS: This was an observational study of a cohort of 174 low-risk post-term singleton pregnancies. Parity, cervical status and length, and amniotic fluid volume (AFI) were evaluated immediately before prostaglandin gel induction at the Department of Obstetrics and Gynecology, University of Bologna, Bologna, Italy between January 2010 and October 2011. RESULTS: A consistent difference in vaginal delivery rates was observed for women who had one gel administration (Group 1) versus those who received either two or three gel administrations (Group 2): 77.5% at 24 hours and 97.4% at 48 hours vs. 27% at 24 hours and 54% at 48 hours (P <0.001 for both the comparisons) respectively. The predictors of a vaginal delivery were cervix dilatation and short cervix for Group 1, lower AFI for Group 2, and parity for both groups. CONCLUSION: Women who require more than one gel administration have a lower rate of vaginal delivery at 24 and 48 hours. Maternal, fetal, and ultrasonographic parameters can predict a successful vaginal delivery.

Intrapartum transperineal ultrasound assessment of fetal head progression in active second stage of labor and mode of delivery.

OBJECTIVE: To compare longitudinal changes in angle of progression (AoP) and midline angle (MLA) during the active second stage of labor according to the mode of delivery. METHODS: A three-dimensional transperineal ultrasound volume was acquired in a series of nulliparous women at the beginning of the active second stage (T1) and every 20 min thereafter (T2, T3, T4, T5 and T6). Following delivery, all ultrasound volumes were analyzed and AoP and MLA were measured. RESULTS: Among 71 women included in the study, 58 underwent spontaneous vaginal delivery (group A) and 13 underwent operative delivery (group B) (eight by vacuum extraction and five by Cesarean section). When compared with Group B, Group A had a wider AoP only at T1 (140.0 ± 20.2° vs. 122.9 ± 16.7°; P = 0.010) and T2 (149.7 ± 20.7° vs. 126.9 ± 17.5°; P = 0.006). MLA was narrower in group A only at T3 (21.2 ± 11.7° vs. 40.8 ± 27.9°; P = 0.043), T4 (18.2 ± 15.0° vs. 47.4 ± 29.6°; P = 0.020) and T5 (18.3 ± 6.0° vs. 34.7 ± 4.2°; P = 0.034). On stepwise forward multiple logistic regression analysis, both AoP and MLA were independently associated with operative delivery (OR = 0.955 and OR = 1.018, respectively). CONCLUSION: Ultrasonographic assessment of fetal head descent in the second stage of labor may play a role in the prediction of the mode of delivery.

Fetal head-symphysis distance: a simple and reliable ultrasound index of fetal head station in labor.

OBJECTIVES: To assess the reproducibility of measurement of a new sonographic index of fetal head station in labor, the fetal head-symphysis distance (HSD), using three-dimensional ultrasound, and its correlation with digital assessment of fetal head descent and with the angle of progression (AoP). METHODS: Three-dimensional (3D) ultrasound volumes were acquired from 47 nulliparous women in active labor following assessment of fetal head station with digital examination. The HSD (the distance between the lower edge of the pubic symphysis and the nearest point of the fetal skull) was measured independently by two operators in order to evaluate intra- and interobserver reproducibility. The correlation between HSD, AoP and fetal head station was evaluated using regression analysis. Using 3D tomographic ultrasound imaging (TUI), measurements of the HSD were obtained in different parasagittal planes to evaluate the influence of inaccurate alignment of the probe with the midline of the pelvis. RESULTS: Measurement of HSD showed high intraobserver (intraclass correlation coefficient (ICC) = 0.995; 95% CI, 0.991-0.997) and interobserver (ICC = 0.991; 95% CI, 0.984-0.995) reliability. In addition, a high correlation was demonstrated between mid-sagittal and parasagittal HSD measurements. HSD showed significant negative correlation with both fetal head station and AoP. CONCLUSION: Fetal HSD is a simple and reliable method for the assessment of fetal head descent in labor.

Hippocampal subfields predict positive symptoms in schizophrenia: first evidence from brain morphometry.

Alterations of hippocampal anatomy have been reported consistently in schizophrenia. Within the present study, we used FreeSurfer to determine hippocampal subfield volumes in 21 schizophrenic patients. A negative correlation between PANSS-positive symptom score and bilateral hippocampal subfield CA2/3 as well as CA1 volume was found on high-resolution magnetic resonance images. Our observation opens the gate for advanced investigation of the commonly reported hippocampal abnormalities in schizophrenia in terms of specific subfields.

Brainstem-vermis and brainstem-tentorium angles allow accurate categorization of fetal upward rotation of cerebellar vermis.

OBJECTIVE: To evaluate the role of the brainstem-vermis (BV) and brainstem-tentorium (BT) angles in the differential diagnosis of upward rotation of the fetal cerebellar vermis. METHODS: The BV and BT angles were measured retrospectively on median sonographic views of the brain in 31 fetuses at 19-28 weeks' gestation with upward rotation of the cerebellar vermis due to Blake's pouch cyst (n = 12), Dandy-Walker malformation (n = 12) and cerebellar vermian hypoplasia (n = 7). Eighty normal fetuses at 20-24 weeks were included as controls. RESULTS: In the control group, BV and BT angles were 9.1 ± 3.5° (range, 4-17°) and 29.3 ± 5.8° (range, 21-44°), respectively. The BV angle was significantly increased in each of the three subgroups of anomalies: Blake's pouch cyst (23 ± 2.8°; range, 19-26°), vermian hypoplasia (34.9 ± 5.4°; range, 24-40°) and Dandy-Walker malformation (63.5 ± 17.6°; range, 45-112°), the angle increasing with increasing severity of the condition. The BT angle had a similar pattern but there was overlap among the different groups. CONCLUSION: The BV angle and, to a lesser degree, the BT angle are simple and reproducible measurements that provide valuable additional information for the categorization of upward rotation of the fetal cerebellar vermis. From mid gestation, a BV angle > 45° is strongly suggestive of a Dandy-Walker malformation, while a measurement < 30° favors the diagnosis of a Blake's pouch cyst.

Prenatal and postnatal imaging of multiple intracranial lipomas: report of a case.

OBJECTIVES: To report the antenatal pictures of a fetus with multiple intracranial lipomas. METHODS: A 36-year-old primigravida, 33 weeks of gestation, was referred to our ultrasound laboratory due to sonographic suspicion of an intracranial hemorrhage. RESULTS: At 2D and 3D ultrasound imaging, three separated round-shaped hyperechoic intracranial masses compatible with multiple lipomas were documented. Absence of corpus callosum was associated. Sonographic findings were confirmed by antenatal and postnatal MRI. CONCLUSIONS: Multiple intracranial lipomas in a fetus with absent corpus callosum have been infrequently described. Prognostic implications remain uncertain.

Increased uterine artery pulsatility index at 34 weeks and outcome of pregnancy.

OBJECTIVES: To evaluate pregnancy outcome in patients with increased uterine artery (UtA) pulsatility at 34 weeks' gestation as an isolated finding. METHODS: Normotensive women attending at 34 weeks' gestation for fetal growth assessment were enrolled in the study if fetal growth was appropriate for age and mean UtA pulsatility index (PI) was persistently above the 95(th) centile for gestational age. Patients were excluded with any of the following conditions: multiple pregnancy, sonographic suspicion of fetal anomaly or fetal growth restriction, history of chronic maternal disease, hypertensive disorder or diabetes in the current pregnancy or one or more adverse events in their past obstetric history. The control group consisted of age- and body mass index-matched low-risk women attending at 34 weeks with normal uterine artery Doppler since the midtrimester. RESULTS: Sixty-six normotensive patients with normal fetal growth and increased UtA-PI at 34 weeks were included in the study group. Women with abnormal Doppler findings compared with controls showed significantly lower gestational age at delivery (38.2 ± 1.6 vs. 38.9 ± 1.3 weeks, P = 0.006), birth weight (2942 ± 583 vs. 3404 ± 469 g, P < 0.001), birth-weight Z-score (-0.61 ± 1.07 vs. 0.19 ± 1.05, P < 0.001) and increased risk of a small-for-gestational-age (SGA) newborn (13/66 vs. 1/66, P < 0.001). The occurrence of late pre-eclampsia (3/66 vs. 0/66, P = 0.24), admission to the neonatal intensive care unit (6/66 vs. 4/66, P = 0.74), rate of induction of labor (16/66 vs. 14/66, P = 0.83) and rate of Cesarean section due to fetal distress (6/66 vs. 3/66, P = 0.49) were comparable between the two groups. CONCLUSION: Increased UtA-PI as an isolated finding at 34 weeks' gestation is associated with an increased risk of delivering an SGA neonate.

Spontaneous brain activity and EEG microstates. A novel EEG/fMRI analysis approach to explore resting-state networks.

The brain is active even in the absence of explicit input or output as demonstrated from electrophysiological as well as imaging studies. Using a combined approach we measured spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal along with electroencephalography (EEG) in eleven healthy subjects during relaxed wakefulness (eyes closed). In contrast to other studies which used the EEG frequency information to guide the functional MRI (fMRI) analysis, we opted for transient EEG events, which identify and quantify brain electric microstates as time epochs with quasi-stable field topography. We then used this microstate information as regressors for the BOLD fluctuations. Single trial EEGs were segmented with a specific module of the LORETA (low resolution electromagnetic tomography) software package in which microstates are represented as normalized vectors constituted by scalp electric potentials, i.e., the related 3-dimensional distribution of cortical current density in the brain. Using the occurrence and the duration of each microstate, we modeled the hemodynamic response function (HRF) which revealed BOLD activation in all subjects. The BOLD activation patterns resembled well known resting-state networks (RSNs) such as the default mode network. Furthermore we "cross validated" the data performing a BOLD independent component analysis (ICA) and computing the correlation between each ICs and the EEG microstates across all subjects. This study shows for the first time that the information contained within EEG microstates on a millisecond timescale is able to elicit BOLD activation patterns consistent with well known RSNs, opening new avenues for multimodal imaging data processing.

Brain activation patterns underlying fast habituation to painful laser stimuli.

A painful experience is modified by processes like habituation/antinociception or sensitization. Altered habituation may be one characteristic of chronic pain syndromes. In the present study we sought to investigate the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) correlate of rapid habituation to pain using simultaneous single trial electrodermal activity (EDA)/fMRI measurements. A total of N=32 healthy subjects have been investigated. Subjects received painful laser stimulation of the left hand. The fMRI BOLD response was measured simultaneously with continuous EDA recordings. Single trial EDA responses to laser stimulation habituated over time with substantial subject-to-subject differences in the degree and speed of habituation. fMRI BOLD habituation was assessed by contrasting the first half of the experiment against the second half and was found in primary and secondary somatosensory cortices, the insula and the anterior cingulate cortex (ACC). We hypothesized that single trial EDA habituation would reflect BOLD habituation which was investigated separately in subjects with 'faster' (N=15) and 'slower' (N=14) EDA habituation. Significant habituation of the BOLD signal was only found in subjects with 'faster' EDA habituation that was accompanied by a signal increase in the rostral ACC and the periaqueductal grey. Furthermore, subjects with faster EDA habituation provided lower pain ratings. Therefore the EDA habituation profile to painful stimulation may constitute a pain-related (endo)phenotype and may be an informative additional endpoint measure in fMR-imaging of pain, especially when people suffering from chronic pain states in which pain processing is often altered are studied.

Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task.

Using single-trial parameters as a regressor in the General Linear Model (GLM) is becoming an increasingly popular method for informing fMRI analysis. However, the parameter used to characterise or to differentiate brain regions involved in the response to a particular task varies across studies (e.g. ERP amplitude, ERP latency, reaction time). Furthermore, the way in which the single-trial information is used in the fMRI analysis is also important. For example, the single-trial parameters can be used as regressors in the GLM or to modify the duration of the events modelled in the GLM. The aim of this study was to investigate the BOLD response to a target detection task when including P3 amplitude, P3 latency and reaction time parameters in the GLM. Simultaneous EEG-fMRI was recorded from fifteen subjects in response to a visual choice reaction time task. Including P3 amplitude as a regressor in the GLM yielded activation in left central opercular cortex, left postcentral gyrus, left insula, left middle frontal gyrus, left insula and left parietal operculum. Using P3 latency and reaction time as an additional regressor yielded no additional activation in comparison with the conventional fMRI analysis. However, when P3 latency or reaction time was used to determine the duration of events at a single-trial level, additional activation was observed in the left postcentral gyrus, left precentral gyrus, anterior cingulate cortex and supramarginal gyrus. Our findings suggest that ERP amplitudes and latencies can yield different activation patterns when used to modify relevant aspects of the GLM.

Laser-evoked potential P2 single-trial amplitudes covary with the fMRI BOLD response in the medial pain system and interconnected subcortical structures.

Pain is a complex experience with sensory, emotional and cognitive aspects. The cortical representation of pain - the pain matrix - consists of a network of regions including the primary (S1) and secondary (S2) sensory cortex, insula, and anterior cingulate cortex (ACC). These structures interact with brain regions such as the prefrontal cortex and the amygdalae. Simultaneous EEG/fMRI (electroencephalography/functional magnetic resonance imaging) has recently been introduced as a method to study the spatiotemporal characteristics of cognitive processes with high spatial and high temporal resolution at the same time. The present study was conducted to clarify if single trial EEG-informed BOLD modeling supports the definition of functional compartments within the pain matrix and interconnected regions. Twenty healthy subjects received painful laser stimulation while EEG and the fMRI blood oxygen level dependent (BOLD) signal were recorded simultaneously. While the laser-evoked N2 potential provided no additional information for BOLD modeling, the regressor obtained from the single trial laser-evoked P2 potential explained additional variance in a network of cortical and subcortical structures that largely overlapped with the pain matrix. This modeling strategy yielded pronounced activation in the ACC, right amygdala and thalamus. Our results suggest that laser-evoked potential (LEP) informed fMRI can be used to visualize BOLD activation in the pain matrix with an emphasis on functional compartments (as defined by the temporal dynamics of the LEP) such as the medial pain system. Furthermore, our findings suggest a concerted effort of the ACC and the amygdala in the cognitive-emotional evaluation of pain.

Fluctuations in electrodermal activity reveal variations in single trial brain responses to painful laser stimuli--a fMRI/EEG study.

Pain is a complex experience with sensory, emotional and cognitive aspects. It also includes a sympathetic response that can be captured by measuring the electrodermal activity (EDA). The present study was performed to investigate which brain areas are associated with sympathetic activation in experimental pain; an issue that has not been addressed with fMRI (functional magnetic resonance imaging) thus far. Twelve healthy subjects received painful laser stimulation to the left hand. The event-related fMRI BOLD (blood oxygen level dependent) response was measured together with simultaneous EEG (electroencephalography) and EDA recordings. Laser stimuli induced the expected EDA response, evoked EEG potentials and BOLD responses. Single trial EDA amplitudes were used to guide further analysis of fMRI and EEG data. We found significantly higher BOLD responses in trials with high EDA vs. low EDA trials, predominantly in the insula and somatosensory cortex (S1/S2). Likewise, in the EEG we found the N2 laser evoked potentials to have significantly higher amplitudes in trials with high vs. low EDA. Furthermore EDA-informed BOLD modeling explained additional signal variance in sensory areas and yielded higher group level activation. We conclude that the sympathetic response to pain is associated with activation in pain-processing brain regions, predominantly in sensory areas and that single trial (EDA)-information can add to BOLD modeling by taking some of the response variability across trials and subjects into account. Thus, EDA is a useful additional, objective index when pain is studied with fMRI/EEG which might be of particular relevance in the context of genetic- and pharmacoimaging.

The role of leptin in the etiopathogenesis of anorexia nervosa and bulimia.

Leptin is an adipocyte-derived signal factor (167 amino acid protein) encoded by the ob gene in chromosome 7q31 that regulates eating behaviour via central neuroendocrine mechanisms. It has been shown that serum leptin levels correlate with weight and percentage body fat in normal and obese individuals, but the exact correlation between leptin and body weight in anorexic and bulimic patients has not yet been clarified. We investigated leptin levels in the serum of 58 female subjects aged 15-36 years: 10 with bulimia nervosa (BN); 12 with anorexia nervosa (AN); 12 overweight controls (not BN); 12 weight-reduced controls (not AN); and 12 normal weight controls. The aim of the study was to evaluate the possible correlations between leptin levels and the body mass index (BMI) in all five groups. Our results showed that the serum leptin levels of the bulimic patients were similar to those of the healthy controls, with a positive correlation between leptin and BMI. Although bulimic patients have very bad nutritional behaviour, their leptin levels do not appear altered. Serum leptin was significantly (p<0.001) reduced in the anorexic patients because of the dramatic decrease in adipose mass caused by the nutritional defect, as: is further supported by the significantly (p<0.001) low level of transferrinemia. Our data suggest that, although significantly reduced, serum leptin levels in fasting anorexic patients are non-linearly related to body weight (BMI).

Demonstration of actin in neurosecretory cells by treatment with nitrobenzoxadiazole-phallacidin.

Serial sections containing neurosecretory cells from chicken hypothalamus were cut after fixation in formaldehyde and embedding in paraffin. Sections were exposed to NBD-Ph (nitrobenzoxadiazole-phallacidin) and showed evidence of containing actin. By using a medium with sodium borohydride, non-specific fluorescence could be excluded.

Reliability and usefulness of random fecal alpha 1-antitrypsin concentration: further simplification of the method.

The reliability of random fecal alpha 1-antitrypsin (FA-1-AT) concentration has been evaluated by comparing FA-1-AT values on random specimens and on concomitant 24-72 h fecal collections. In order to simplify the method, FA-1-AT data derived from lyophilized fecal samples were compared with those obtained from 37 degrees C heat-dried fecal samples. Random FA-1-AT concentration was assayed in 80 children with various gastrointestinal illnesses and 36 healthy age-matched controls. There was a close relationship between FA-1-AT values obtained from random samples and 1-day or 3-day collections. There was also a significant relationship between FA-1-AT values derived from the two different ways of drying the stools. Mean FA-1-AT values were statistically different when compared to the controls in the following groups of disorders: untreated and after-gluten-challenge celiac disease, post-enteritis syndrome, and cow's milk intolerance. The possible meanings of the abnormal FA-1-AT concentration in the various disorders are discussed. We conclude that FA-1-AT is a simple and reliable test for enteric protein loss. The simplification of the method proposed by us should reduce the cost of the test and moreover make it feasible in all laboratories.