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BACKGROUND AND PURPOSE: Kallmann syndrome is a rare inherited disorder due to defective intrauterine migration of olfactory axons and gonadotropin-releasing hormone neurons, leading to rhinencephalon hypoplasia and hypogonadotropic hypogonadism. Concomitant brain developmental abnormalities have been described. Our aim was to investigate Kallmann syndrome–related brain changes with conventional and novel quantitative MR imaging analyses. MATERIALS AND METHODS: Forty-five male patients with Kallmann syndrome (mean age, 30.7 years; range, 9–55 years) and 23 age-matched male controls underwent brain MR imaging. The MR imaging study protocol included 3D-T1, FLAIR, and diffusion tensor imaging (32 noncollinear gradient-encoding directions; b-value = 800 s/mm2). Voxel-based morphometry, sulcation, curvature, and cortical thickness analyses and tract-based spatial statistics were performed by using Statistical Parametric Mapping 8, FreeSurfer, and the fMRI of the Brain Software Library. RESULTS: Corpus callosum partial agenesis, multiple sclerosis–like white matter abnormalities, and acoustic schwannoma were found in 1 patient each. The total amount of gray and white matter volume and tract-based spatial statistics measures (fractional anisotropy and mean, radial, and axial diffusivity) did not differ between patients with Kallmann syndrome and controls. By specific analyses, patients with Kallmann syndrome presented with symmetric clusters of gray matter volume increase and decrease and white matter volume decrease close to the olfactory sulci; reduced sulcal depth of the olfactory sulci and deeper medial orbital-frontal sulci; lesser curvature of the olfactory sulcus and sharper curvature close to the medial orbital-frontal sulcus; and increased cortical thickness within the olfactory sulcus. CONCLUSIONS: This large MR imaging study on male patients with Kallmann syndrome featured significant morphologic and structural brain changes, likely driven by olfactory bulb hypo-/aplasia, selectively involving the basal forebrain cortex.

Introduction The present study investigates the production of inflected forms from word-stems with a regular vs. an irregular inflection. This issue has been mostly focused on the theoretical debate between Dual Mechanism theories (rule-based procedures vs. recovery of whole forms stored in an associative network, Pinker & Ullman, 2002) and Connectionist models (single procedure for both regular and irregular forms, McClelland & Patterson, 2002). The two accounts make different predictions about the neural underpinnings of lexical processing for regular and irregular verbs. The declarative/procedural model is a modular theory positing that irregular forms are recovered from the mental lexicon which depends on declarative memory and is subserved by the temporal lobe, whereas regular forms are assembled by means of a mental grammar which involves procedural memory and is subserved by the frontal cortex and the basal ganglia (Ullman, 2001). Concurrent models do not postulate a categorical difference between regular and irregular forms and suggest that different pattern of brain activations elicited by regular and irregular verbs are predicted by phonological, semantic and other probabilistic features of verbs (Joanisse & Seidenberg, 2005). However, an alternative hypothesis, mainly grounded on linguistic, behavioral and simulation data (Burzio, 1998; Bordag & Pechmann, 2009; Colombo et al., 2004; 2006; Laudanna, 2007; Laudanna et al., 2004; Pirrelli & Herreros, 2005; Verissimo & Clahsen, 2009), suggests that all inflected forms in the mental lexicon, regardless of regularity, are organized in clusters on the basis of their paradigmatic relations among word-forms other than the regular/irregular distinction and that inflectional processes are likely to be governed by membership of words to specific clusters, namely the inflectional classes. This third positions predicts the possibility to detect experimental effects driven by the membership of words to inflectional classes rather than to the coarse distinction between regular and irregular. In this study we try to shed light on the issue by exploiting a suitable test case, the Italian verb inflectional system. Here, verbs fall into one of three conjugations each exhibiting different degrees of regularity, numerosity and consistency. By using both behavioral and neuroimaging techniques, we aim at demonstrating that mechanisms underlying speaker’s ability to perform inflectional operations rely on grammatical properties of verbs depending on their membership to different inflectional classes. Methods A past-participle generation task was admnistered in a behavioral (42 participants) and an eventrelated fMRI setting (23 participants). A set of 168 Italian verbs was selected and arranged into 6 subsets of experimental stimuli on the basis of Regularity (regulars vs. irregulars) and Conjugation membership (1st vs. 2nd vs. 3rd). The six subsets were matched on frequency, length, N-count, locus and manner of articulation of the initial phoneme, syllabic structure of the initial syllable, syllabic structure of both the infinitive and past-participle form. Different sets of statistical analyses were carried out on response latencies, accuracy rates and BOLD responses. Analyses testing putative effects of Conjugation were restricetd to response Poster session 1 34 patterns only elicited by regular verbs. Analyses on response measures only elicited by 2nd and 3 rd conjugation verbs tested the interaction between Regularity and Conjugation. Results Main effects of the variable Conjugation were obtained both in the behavioural and in the fMRI experiments: 2nd conjugation regular verbs were responded significantly slower and poorer than 1 st and 3rd conjugation regular verbs. The left middle frontal gyrus and the pre-supplementary motor area exhibited a significantly higher BOLD activation response for 2nd and 3rd conjugation regular verbs than for 1st conjugation regular verbs. In addition, the analyses performed on both 2nd and 3rd conjugation regular and irregular verbs revealed that 2nd conjugation verbs were slower and less accurate than 3rd conjugation verbs and that the perigenual part of the left anterior cingulate cortex was significantly more activated for 2nd than for 3rd conjugation verbs. A main effect of Regularity was also observed: irregular verbs were slower and less accurate than regular verbs. The left prefrontal cortex and the anterior part of the left inferior frontal gyrus were found significantly more activated for irregular when compared to regular verbs. Interestingly, a significant Conjugation by Regularity interaction was observed: behaviorally, the Regularity effect was stronger for 3rd than for 2nd conjugation verbs. In the left and right postcentral gyri, the 2nd conjugation irregular verbs elicited significant weaker activation than regular ones; the 3rd conjugation verbs elicited the opposite pattern. Discussion The present study demonstrates that inflecting Italian verbs from different conjugations, irrespective of regularity, requires different cognitive operations since it elicits differences in behavioral response latencies, accuracy rates and cortical activations. Rather than a segregation between different brain structures devoted to the processing of regular and irregular verbs, different patterns of activation for both the regular and irregular verbs in the same structures were found. Differences among regular verbs belonging to different inflectional classes were also obtained both on behavioral and neural grounds. This pattern of data cannot be easily accommodated within either a dual or a single mechanism account. Dual mechanism theories postulate that all regular verbs follow symbolic inflectional rules, thereby no differences among regular verbs are expected. The observed difference cannot be ascribed neither to any formal feature as predicted by single mechanism accounts: actually, in our work we matched many formal features across the experimental categories. Our data corroborate the idea that language-specific properties of inflectional classes might modulate cognitive operations and biological underpinnings of inflectional behavior.

Several studies demonstrated the involvement of GABA and reactive oxygen species (ROS) in trigeminal pain transmission [1, 2, 3, 4]; anyway, there are still poorly understood mechanisms modulating pain, resulting, for instance, in hypoalgesia in hypertensive patients [4]. One possibility is that the activity of afferent neurons during mastication modulates ROS production in second-order sensory neurons [5]. An ongoing research project is aimed to reveal such mechanisms in humans with fMRI; here the preliminary results of the methodological approach to show an asymmetrical mastication will be reported, demonstrating that the chewing gum side-preference test correlates with anatomical features.

INTRODUCTION Previous neuroimaging studies have shown that working memory load has marked effects on regional neural activation[1-5]. However, the mechanism through which working memory load modulates brain connectivity is still unclear. During a working memory task, two of the most involved networks are the default mode network (DMN) and the working memory network (WMN)[6-7]: the selective focus on these networks can be useful in better understanding the load effects. Spatial independent component analysis (ICA)[8] has becomes a reliable technique to investigate the networks involved during an fMRI task, as it extracts spatiotemporal patterns of neural activity maximizing spatial independence. A specific study, conducted with ICA, investigating on how the load and phase of a working memory task are related with the activation and response time, is nowadays lacking. The aim of this work is to use the time course of DMN and WMN, selected by means of ICA, for studying: a) how these networks are involved with the complexity of the task and the phase; b) how, in these networks, complexity and phase are correlated with reaction times. METHODS MR Data Acquisition and preprocessing Fifteen young adult healthy and right-handed were involved. The MR protocol consisted of one anatomical sequence 3D T1-weighted MP-RAGE (Voxel size: 1 x 1 x 1 mm) and three functional acquisitions of 15 minutes each performed with a T2*-weighted EPI sequence (TR/TE: 1500/30, In- plane resolution: 3.5x3.5 mm, Thickness: 3.5 mm, Nr of slices: 24, Field of view: 64 x 64 mm). All the images were collected with a Siemens Allegra 3T MR scanner (Siemens, Erlangen, Germany) and a standard head coil. During the fMRI acquisition the subjects performed a delayed spatial working memory paradigm presented with three levels of difficulty. The memory set consisted of one, three or five circles presented randomly in different locations and to the subjects were asked to judge whether or not a given target stimulus had been part of a previous memory stimulus set. Every experiment consisted of 90 working memory trials, 30 per load, divided in three runs. Data were analyzed with Brain Voyager QX. 2.4 (Brain Innovation, Maastricht, The Netherlands). FMRI preprocessing included: 3D head-motion correction, slice-scan time correction, spatial smoothing, temporal high pass filter and linear trend removal. Anatomic 3D data set was inhomogeneities corrected, filtered and transformed into Talairach coordinates and coregistered with the functional information. Independent Component Analysis This analysis was conducted using Brainvoyager QX 2.4. ICA analysis was performed on each subject’s three functional acquisitions. A subsequent total ICA group analysis[9-10] was achieved by an inter- subject ICA group analysis of all the intra-subject ICA group analysis. From the obtained maps were selected two Independent Components (ICs) containing the WMN[1,2]: WMN1 defined by SPL and Precuneus, and WMN2 with DLPFC and IPS (Fig. 1b-c). Also one IC describing the DMN was considered, with PCC, IPL and MPFC (Fig. 1a)[11]. For each run of all the subjects the ICs time course was considered: three time windows of 3TR (4.5s) for each working memory task phase (encode, maintenance and retrieval) were selected taking into account the haemodynamic response by delaying the window of 5 volumes events from the start of every trial. The window time course was corrected for a baseline value. Mean values of the ICs where examined and a subsequent correlation between the mean values and the response time in every trial was estimated. A 3x3 two-way ANOVA on Fisher transformed correlation was conducted to test the variation of loads (load1=less complex, load3=more complex), phases and runs. Figure 1: Networks selected from ICA analysis (transversal view): (a) DMN, (b) WMN1 (c) WMN2. RESULTS Figure 2 exhibits window mean activities and correlations divided for phase and load. DMN mean activity is negative while WMN1-2 mean activities have opposite behaviors regarding the phase, but similar concerning with the complexity (Fig. 2a-c). DMN shows a reduction of the correlation from encode to retrieval, instead of WM1-2 where it grows (Fig. 2d-f). The ANOVA showed significant variation for the phases over all the subjects in WMN1-2, an interaction of the variation of phases and runs in WMN2 and a interaction of phases, runs and loads in DMN. DISCUSSION These findings suggest that working memory networks (WMNs), as isolated by means of IC A, display substantially opposed mean values related to a different areas specialization. WMN1 seems to be more involved in the first part of the mnemonic phase and the amount of this involvement is associated to the trial: the more complicated the task, the higher the activation with respect to baseline. On the other hand, WMN2 increases from the first to the last part of the trial and is probably more involved in the operation of retrieval. In Figure 2e-f it is also shown that in the retrieval there is a stronger correlation between WMN1-2 mean values and the response time probably because this phase is the more complex. DMN exhibits, over all the phases, smaller than zero mean values (due to the task inducted deactivation). In contrast, its correlation has a different trend and increases above zero during the maintenance, probably due to the free thought of this phase. The different behavior of load 3 is probably due to the fact that this type of complexity is totally different from the other two. In conclusion, this study shows that, by means of ICA, it is possible to isolate networks of connected regions and relate their time courses to task phases and behavioral performance. This is a promising approach to advance the understanding of connectivity modulations in several brain networks, including WMNs and DMN.

BACKGROUND: The relationship between olfactory function, rhinencephalon and forebrain changes in Kallmann syndrome (KS) have not been adequately investigated. We evaluated a large cohort of male KS patients using Sniffin' Sticks and MRI in order to study olfactory bulb (OB) volume, olfactory sulcus (OS) depth, cortical thickness close to the OS, and olfactory phenotype. METHODS: Olfaction was assessed administering Sniffin' Sticks®, in 38 KS patients and 17 controls (by means of Screening 12 test®). All subjects underwent magnetic resonance imaging (MRI) to study OB volume, sulcus depth, and cortical thickness. RESULTS: Compared to controls, KS patients showed smaller OB volume (p