Cerebrospinal fluid neurofilament light chains predicts early disease-activity in Multiple Sclerosis.

BACKGROUND: Among biomarkers of axonal damage, neurofilament light chains (NFL) seem to play a major role, representing a promising and interesting tool in Multiple Sclerosis (MS). Our aim was to explore the predictive role of cerebrospinal fluid (CSF) NFL in patients with a recent diagnosis of MS, naïve to any MS therapy. METHODS: We retrospectively collected data of patients diagnosed with MS, referred to the Neurology Clinic of the University-Hospital G. Rodolico of Catania between January 1st 2005 and December 31st 2015. All patients underwent CSF collection at the time of MS diagnosis and were followed-up for at least three years afterwards. NFL levels were measured in CSF samples with Simoa NFLight advantage kit at the CRESM (University Hospital San Luigi Gonzaga, Orbassano, Torino). NFL levels were expressed as LogNFL. Symbol Digit Modalities test (SDMT) was performed at baseline, at 1-year and at 3-year follow-up. Multivariate logistic regression analysis was performed to investigate LogNFL as a potential risk factor of different clinical outcomes. RESULTS: 244 MS patients (230 relapsing-remitting, RRMS; 94.3 %), with a mean age at diagnosis of 37.0 ± 11.1 years, were recruited. LogNFL did not correlate neither with EDSS score at diagnosis and at subsequent follow-up up to 12 years, nor with SDMT performed at diagnosis, at 1 year and at 3 years. LogNFL were an independent factor for the occurrence of at least one relapse during the first two years after MS diagnosis (OR = 2.75; 95 % CI 1.19-6.31; p = 0.02) and for the occurrence of gadolinium-enhanced (Gd+) lesions during the first 2 years from diagnosis at brain and spine MRI scans (OR = 3.45, 95 % CI 1.81-6.57; p < 0.001). CONCLUSION: The detection of CSF NFL at the time of MS diagnosis can be a useful support to predict the two-year risk of clinical and radiological relapses, thus affecting therapeutic choices in the very early phases of the disease.

REal-World effectIveNess of claDribine for patients with multiple sclerosis: a Sicilian multicentric experience (REWIND study).

BACKGROUND: cladribine tablets is a highly effective option for the treatment of relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: to evaluate the effectiveness of cladribine in a real-world setting. METHODS: this prospective real-world study consecutively screened all RRMS patients from seven different MS centers in Sicily (Italy), who completed the 2-year treatment course of cladribine tablets in the period between 11th March 2019 and 31st October 2021. Data about Expanded Disability Status Scale (EDSS), relapses, previous treatments, adverse events (AEs) and magnetic resonance imaging (MRI) were collected. Patients who were previously treated with other DMTs were further stratified in moderately active treatment (MAT) and highly active treatment (HAT) patients. RESULTS: a total of 217 patients, (70% women, with mean age of 38.4 ± 11.3 years), were enrolled. Fifty patients (23.0%) were naïve to treatment and 167 (77%) switched from another disease modifying therapies. After the second year of treatment, about 80% of were EDSS progression free, 88% remained relapse-free at T24, and 48% of patients were MRI activity-free. Kaplan Meier analyses showed significant differences between MT and HAT in terms of time to first clinical relapse (HR: 2.43, IC 1.02 - 5.76; p=0.04), time to the first new T1-gadolinium enhancing lesion (HR: 3.43, IC 1.35 - 8.70; p= 0.009) and time to MRI worsening (HR: 2.42, IC 1.15 - 5.09; p= 0.02). CONCLUSION: this study confirmed that cladribine is an effective treatment for MS, in particular in naïve patients and in those who have switched from MATs.

Pregnancy planning and management for women with multiple sclerosis: what has changed over the last 15 years? An Italian single-center experience.

BACKGROUND: Pregnancy planning is a relevant issue in the management of Multiple Sclerosis (MS), which commonly involves women of childbearing age. Increased knowledge and a wider therapeutic scenario could have changed the approach of neurologists towards this topic over time. Our aim was to describe how pregnancy planning and management for women with MS have changed in the last 15 years. METHODS: We retrospectively collected clinical data of female patients with relapsing-remitting MS (RRMS), referred to the Neurology Clinic of the University-Hospital "Policlinico G. Rodolico" of Catania, who became pregnant between 2005-2020. We compared data about MS and pregnancy between two time periods according to pregnancy onset (2005-2012; 2013-2020). RESULTS: 190 patients with RRMS carried 253 pregnancies in the observation period. Women undergoing a pregnancy in the last period (2013-2020), as compared to women who had pregnancy in the first period (2005-2012), were older (p<0.01), more often treated before and during pregnancy with high-efficacy disease-modifying drugs (DMD) (p<0.001), and exhibited lower annualized relapse rates (ARR) before (p=0.01) and after pregnancy (p<0.001). CONCLUSION: Results from our experience suggest that nowadays DMD are more frequently used in women of childbearing age, even during pregnancy, leading to a reduced ARR before and after delivery in absence of increased obstetric complications.

Simulated visual hallucinations in virtual reality enhance cognitive flexibility.

Historically, psychedelic drugs are known to modulate cognitive flexibility, a central aspect of cognition permitting adaptation to changing environmental demands. Despite proof suggesting phenomenological similarities between artificially-induced and actual psychedelic altered perception, experimental evidence is still lacking about whether the former is also able to modulate cognitive flexibility. To address this, we measure participants' cognitive flexibility through behavioral tasks after the exposure to virtual reality panoramic videos and their hallucinatory-like counterparts generated by the DeepDream algorithm. Results show that the estimated semantic network has a flexible structure when preceded by altered videos. Crucially, following the simulated psychedelic exposure, individuals also show an attenuated contribution of the automatic process and chaotic dynamics underlying the decision process. This suggests that simulated altered perceptual phenomenology enhances cognitive flexibility, presumably due to a reorganization in the cognitive dynamics that facilitates the exploration of uncommon decision strategies and inhibits automated choices.

Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis Patients: Monocentric Case Series and Systematic Review of the Literature.

Multiple sclerosis (MS) is a chronic, inflammatory and immune-mediated disease of the central nervous system (CNS), commonly affecting young adults and potentially associated with life-long disability. About 14 disease-modifying treatments (DMTs) are currently approved for the treatment of MS. However, despite the use of highly effective therapies, some patients exhibit a highly active disease with an aggressive course from onset and a higher risk of long-term disability accrual. In the last few years, several retrospective studies, clinical trials, meta-analyses and systematic reviews have investigated autologous hematopoietic stem cell transplantation (AHSCT) as a possible therapeutic option in order to address this unmet clinical need. These studies demonstrated that AHSCT is a highly efficacious and relatively safe therapeutic option for the treatment of highly active MS. Particularly, over recent years, the amount of evidence has grown, with significant improvements in the development of patient selection criteria, choice of the most suitable transplant technique and clinical experience. In this paper, we present six patients who received AHSCT in our MS center and we systematically reviewed recent evidence about the long-term efficacy and safety of AHSCT and the placement of AHSCT in the rapidly evolving therapeutic armamentarium for MS.

Factors driving delayed time to multiple sclerosis diagnosis: Results from a population-based study.

BACKGROUND: Multiple sclerosis (MS) is a highly complex chronic inflammatory disease, in which a diagnostic delay could reduce the available therapeutic options. Our aim was to identify factors contributing to diagnostic delay in a MS population living in the municipality of Biancavilla. METHODS: This retrospective population-based study consecutively selected patients with MS diagnosed from 1992 to 2018 and resident in the city of Biancavilla. Socio-demographic and clinical data were collected through the iMed database. Date of final MS diagnosis was obtained and diagnostic delay was calculated. RESULTS: A total of 70 patients (66.7% women) were found affected by MS according to the 2011 McDonald criteria in the municipality of Biancavilla in the period between 2005 and 2010. The mean diagnostic delay in the MS cohort of Biancavilla was 33.8 ± 56 months [median 19.5, range 1-315]. The multivariate logistic regression confirmed that age ≥ 40 years, lower educational level (1-5 years) and motor symptoms at onset were associated to longer diagnostic delay. CONCLUSION: In this population-based study a mean delay of about 30 months occurred between initial symptoms and the MS diagnosis. Older age at onset, lower education level and motor symptoms at onset were associated to longer MS diagnostic delay.

Reliability of televisits for patients with mild relapsing-remitting multiple sclerosis in the COVID-19 era.

BACKGROUND: Evidence of the cost-effectiveness of telemedicine (TM) for the management of Multiple Sclerosis (MS) has been provided recently. However, some doubts persist about the accuracy of neurological examinations performed remotely. OBJECTIVES: This study investigated the reliability of neurological evaluations performed through TM in mild MS patients as compared with standard in-person visits. METHODS: In total, 76 patients with relapsing-remitting MS and Expanded Disability Status Scale (EDSS) ≤ 3.5 were consecutively recruited. Of them, 40 patients (52.6%) accepted to undergo both in-person and TM evaluations with independent examiners within 48 h. We alternatively asked patients to assure or not the presence of a caregiver during TM visits. A satisfaction questionnaire was administered to all participants. RESULTS: The inter-rater agreement attributed by two independent neurologists during TM visit was high (κ > 0.80) for EDSS and Functional Systems (FS) scores. Moderate agreement between TM and in-person evaluations emerged for pyramidal (κ = 0.57; p < 0.001), brainstem (κ = 0.57; p < 0.001), bowel and bladder (κ = 0.54; p < 0.001) and sensory (κ = 0.51; p < 0.001) FS scores, higher in patients providing the support of a caregiver. A good reliability was reported for EDSS scores computed during remote and in-person visits (ICC = 0.83; 95% CI 0.70-0.91; p < 0.001). CONCLUSIONS: Despite the complexity of neurological examination, TM could be useful in monitoring MS patients with low disability.

Changes in John Cunningham Virus Index in Multiple Sclerosis Patients Treated with Different Disease-Modifying Therapies.

BACKGROUND: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored. OBJECTIVE: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs. METHODS: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1). RESULTS: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index <0.90 was found to be significantly increased in the ALM group (16.7 % versus 66.7 %, p = 0.05), while the percentage of patients with JCV index >1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index <0.90 was also found (23.5 % versus 1.4 %, p = 0.0006). The mean JCV index was reduced in the RTX/OCR and ALM groups, while a significant increase was observed in the FTY group. CONCLUSION: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

Balancing novelty and appropriateness leads to creative associations in children.

Creative problem solving is a fundamental skill of human cognition and is conceived as a search process whereby a novel and appropriate solution is generated. However, it is unclear whether children are able to balance novelty and appropriateness to generate creative solutions and what are the underlying computational mechanisms. Here, we asked children, ranging from 10 to 11 years old, to perform a word association task according to three instructions, which triggered a more appropriate (ordinary), novel (random), or balanced (creative) response. Results revealed that children exhibited greater cognitive flexibility in the creative condition compared to the control conditions, as revealed by the structure and resiliency of the semantic networks. Moreover, responses' word embeddings extracted from pretrained deep neural networks showed that semantic distance and category switching index increased in the creative condition with respect to the ordinary condition and decreased compared to the random condition. Critically, we showed how children efficiently solved the exploration/exploitation trade-off to generate creative associations by fitting a computational reinforcement learning (RL) model that simulates semantic search strategies. Our findings provide compelling evidence that children balance novelty and appropriateness to generate creative associations by optimally regulating the level of exploration in the semantic search. This corroborates previous findings on the adult population and highlights the crucial contribution of both components to the overall creative process. In conclusion, these results shed light on the connections between theoretical concepts such as bottom-up/top-down modes of thinking in creativity research and the exploration/exploitation trade-off in human RL research.

Natalizumab administration in multiple sclerosis patients during active SARS-CoV-2 infection: a case series.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) caused by the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a pandemic, affecting the therapeutic management for Multiple Sclerosis (MS). Any decision regarding the discontinuation of high-potency agents for moderate and highly active MS should be carefully evaluated, taking into account the potential risk of rebound of the disease. In particular, no data about clinical outcome of patients with MS receiving Natalizumab (NTZ) during active COVID-19 infection have been reported yet. CASES PRESENTATION: We reported on 6 patients treated with NTZ for relapsing MS during active COVID-19 infection, who recovered without reporting any worsening or new symptoms. Most of the patients were asymptomatic, with the exception of one patient who had a slight worst COVID-19 clinical course. No patients received O2-therapy or required intensive care. No neurological complications were observed. CONCLUSIONS: This paper reported the clinical outcome of patients with MS receiving NTZ during active COVID-19 infection. This case series suggests that treatment with NTZ during pandemic is relatively safe and might be continued in selected patients who are infected by COVID-19, thereby reducing the risk of MS disease rebound.

Thematic Reanalysis in the Left Posterior Parietal Sulcus: A TMS Study.

Understanding who does what to whom is at the core of sentence comprehension. The actors that contribute to the verb meaning are labeled thematic roles. We used transcranial magnetic stimulation (TMS) to verify the possible impact of verb semantics on the thematic role encoding process that has been shown to involve the posterior portion of the left posterior parietal sulcus (PPS; Finocchiaro et al., 2015). Sixteen participants underwent TMS and sham stimulation sessions while performing an agent-decision task, in which they had to decide by key press which of the two arguments was the agent of visually presented sentences or pseudo-sentences. The (pseudo)sentences were all reversible and were presented in the active or passive diathesis. Double pulse TMS was delivered to the posterior part of the intraparietal sulcus in an event-related fashion, at two different time windows: 200-400 ms (T1) or 600-800 ms (T2) time-locked to the presentation of the (pseudo)sentence. Results showed that TMS increased accuracy on passive sentences and pseudo-sentences as compared to active sentences and to the baseline, sham condition. Indeed, the presence of a verb with a full semantic representation was not a necessary precondition for the TMS-induced facilitation of passive (pseudo)sentences. Stimulation timing had no effect on accuracy for sentences vs. pseudo-sentences. These observations support the idea that the posterior parietal site is recruited when the correct interpretation of a sentence requires reanalysis of temporarily encoded thematic roles (as in reversible passive sentences) even when the verb is not an entry in the lexicon and hence does not have a semantic representation. Results are consistent with previous evidence and deserve further investigation in larger experimental samples. Increasing the number and variety of stimulus sentences, and administering TMS to additional control sites will be key to further articulate the conclusions allowed by these initial findings.

Revealing the Role of Divergent Thinking and Fluid Intelligence in Children's Semantic Memory Organization.

The current theories suggest the fundamental role of semantic memory in creativity, mediating bottom-up (divergent thinking) and top-down (fluid intelligence) cognitive processes. However, the relationship between creativity, intelligence, and the organization of the semantic memory remains poorly-characterized in children. We investigated the ways in which individual differences in children's semantic memory structures are influenced by their divergent thinking and fluid intelligence abilities. The participants (mean age 10) were grouped by their levels (high/low) of divergent thinking and fluid intelligence. We applied a recently-developed Network Science approach in order to examine group-based semantic memory graphs. Networks were constructed from a semantic fluency task. The results revealed that divergent thinking abilities are related to a more flexible structure of the semantic network, while fluid intelligence corresponds to a more structured semantic network, in line with the previous findings from the adult sample. Our findings confirm the crucial role of semantic memory organization in creative performance, and demonstrate that this phenomenon can be traced back to childhood. Finally, we also corroborate the network science methodology as a valid approach to the study of creative cognition in the developmental population.

The role of the l-IPS in the comprehension of reversible and irreversible sentences: an rTMS study.

Thematic roles can be seen as semantic labels assigned to who/what is taking part in the event denoted by a verb. Encoding thematic relations is crucial for sentence interpretation since it relies on both syntactic and semantic aspects. In previous studies, repetitive transcranial magnetic stimulation (rTMS) over the left inferior intraparietal sulcus (l-IPS) selectively influenced performance accuracy on reversible passive (but not active) sentences. The effect was attributed to the fact that in these sentences the assignment of the agent and theme roles requires re-analysis of the first-pass sentence parsing. To evaluate the role of reversibility and non-canonical word order (passive voice) on the effect, rTMS was applied over l-IPS during a sentence comprehension task that included reversible and irreversible, active and passive sentences. Participants were asked to identify who/what was performing the action or who/what the action was being performed on. Stimulation of the l-IPS increased response time on reversible passive sentences but not on reversible active sentences. Importantly, no effect was found on irreversible sentences, irrespective of sentence diathesis.Results suggest that neither reversibility nor sentence diathesis alone are responsible for the effect and that the effect is likely to be triggered/constrained by a combination of semantic reversibility and non-canonical word order. Combined with the results of previous studies, and irrespective of the specific role of each feature, these findings support the view that the l-IPS is critically involved in the assignment of thematic roles in reversible sentences.

What About the Role of Virtual Reality in Parkinson Disease's Cognitive Rehabilitation? Preliminary Findings From a Randomized Clinical Trial.

BACKGROUND: The purpose of this study is to evaluate the effects of a virtual reality training with BTS Nirvana (BTS-N) system in the cognitive and behavioral recovery in patients with Parkinson disease (PD). The BTS-N is a semi-immersive therapy system used for motor and cognitive rehabilitation of patients with neurological diseases, by creating virtual scenarios with which the patient may interact. METHODS: We enrolled 20 patients with PD undergoing neurorehabilitation. All the patients were randomized into 2 groups: experimental group performing semi-immersive virtual reality training with BTS-N and control group undergoing traditional cognitive training. Each participant was evaluated before and immediately after the end of the training. Each cognitive training consisted of 3 sessions a week, each lasting 60 minutes, for 8 weeks, for a total of 24 sessions in each group. RESULTS: Experimental group showed a greater improvement in cognitive functioning, with regard to executive and visuospatial abilities, as compared with the control group. CONCLUSION: Our findings suggest that rehabilitation through a new virtual reality instrument could be a valuable tool in improving cognitive and behavioral outcomes of patients with PD.

The dissociability of lexical retrieval and morphosyntactic processes for nouns and verbs: A functional and anatomoclinical study.

Nouns and verbs can dissociate following brain damage, at both lexical retrieval and morphosyntactic processing levels. In order to document the range and the neural underpinnings of behavioral dissociations, twelve aphasics with disproportionate difficulty naming objects or actions were asked to apply phonologically identical morphosyntactic transformations to nouns and verbs. Two subjects with poor object naming and 2/10 with poor action naming made no morphosyntactic errors at all. Six of 10 subjects with poor action naming showed disproportionate or no morphosyntactic difficulties for verbs. Morphological errors on nouns and verbs correlated at the group level, but in individual cases a selective impairment of verb morphology was observed. Poor object and action naming with spared morphosyntax were associated with non-overlapping lesions (inferior occipitotemporal and fronto-temporal, respectively). Poor verb morphosyntax was observed with frontal-temporal lesions affecting white matter tracts deep to the insula, possibly disrupting the interaction of nodes in a fronto-temporal network.

Thematic role assignment in the posterior parietal cortex: A TMS study.

Verbs denote relations between entities acting a role in an event. Thematic roles are essential to the correct use of verbs and involve both semantic and syntactic aspects. We used repetitive Transcranial Magnetic Stimulation (rTMS) to study the involvement of three different left parietal sites in the understanding of thematic roles. In a sentence-to-picture matching task, twelve participants were asked to judge whether or not a given picture matched with a written sentence. Pictures represented simple reversible actions, and sentences were in the active or passive diathesis. Whereas both active and passive sentences require the correct encoding of thematic roles, passives also imply thematic reanalysis, as the canonical order of thematic roles is systematically reversed. The experiment was divided in three sessions. In each session a different parietal site (anterior, middle, posterior) was stimulated at 5 Hz in an event-related fashion, time-locked to the presentation of visual stimuli. Results showed increased accuracy for passive sentences following posterior parietal stimulation. The effect appeared to be (a) TMS-related, as no effect was observed in a control, no-TMS experiment with eighteen new participants; (b) independent from semantic processes involved in word-picture association, as no TMS-related effects were observed in a picture-word matching task. We interpret the results as showing that the posterior parietal site is specifically involved in the assignment of thematic roles, in particular when the correct interpretation of a sentence requires reanalysis of temporarily encoded thematic roles, as in passive reversible sentences.

Contribution of motor representations to action verb processing.

Electrophysiological and brain imaging studies show a somatotopic activation of the premotor cortex while subjects process action verbs. This somatotopic motor activation has been taken as an indication that the meaning of action verbs is embedded in motor representations. However, discrepancies in the literature led to the alternative hypothesis that motor representations are activated during the course of a mental imagery process emerging only after the meaning of the action has been accessed. In order to address this issue, we asked participants to decide whether a visually presented verb was concrete or abstract by pressing a button or a pedal (primary task) and then to provide a distinct vocal response to low and high sounds played soon after the verb display (secondary task). Manipulations of the visual display (lower vs. uppercase), verb imageability (concrete vs. abstract), verb meaning (hand vs. foot-related), and response effector (hand vs. foot) allowed us to trace the perceptual, semantic and response stages of verb processing. We capitalized on the psychological refractory period (PRP), which implies that the initiation of the secondary task should be delayed only by those factors that slow down the central decision process in the primary task. In line with this prediction, our results showed that the time cost resulting from the processing of abstract verbs, when compared to concrete verbs, was still observed in the subsequent response to the sounds, whereas the overall advantage of hand over foot responses did not influence sound judgments. Crucially, we also observed a verb-effector compatibility effect (i.e., foot-related verbs are responded faster with the foot and hand-related verbs with the hand) that contaminated the performance of the secondary task, providing clear evidence that motor interference from verb meaning occurred during the central decision stage. These results cannot be explained by a mental imagery process that would deploy only during the execution of the response to verb judgments. They rather indicate that the motor activation induced by action verbs accompanies the lexico-semantic processes leading to response selection.

A kinematic approach to the conceptual representations of this and that.

The Italian demonstrative pronouns questo/a ('this([mas/fem])') and quello/a ('that([mas/fem])') implicitly convey information about objects' distance with respect to the speaker. Our study investigated the referents of questo/a ('this([mas/fem])') and quello/a ('that([mas/fem])') by analysing their influence on reach-to-grasp actions towards objects located near to (12cm) or far from (30cm) the participant. Upon acoustic instruction containing one or the other pronoun, participants had to reach for and grasp a target object. Results showed an effect of pronoun on movement planning. When the object was in the far position, reaction times were faster for the congruent pronoun quello/a, whereas when it was in the near position they were faster for the congruent pronoun questo/a. Interactions between implied and real target distance suggest that the conceptual spaces of questo/a and quello/a do not map onto a strict distinction between peripersonal and extrapersonal space.

Gender agreement and multiple referents.

We report a new pattern of usage in current, spoken Italian that has implications for both psycholinguistic models of language production and linguistic theories of language change. In Italian, gender agreement is mandatory for both singular and plural nouns. However, when two or more nouns of different grammatical gender appear in a conjoined noun phrase (NP), masculine plural agreement is required. In this study, we combined on-line and off-line methodologies in order to assess the mechanisms involved in gender marking in the context of multiple referents. The results of two pronoun production tasks showed that plural feminine agreement was significantly more difficult than plural masculine agreement. In a separate study using offline judgements of acceptability, we found that agreement violations in Italian are tolerated more readily in the case of feminine conjoined noun phrases (e.g., la mela e la banana 'the:fem apple:fem and the: fem banana: fem') than masculine conjoined noun phrases (e.g., il fiore e il libro 'the:mas flower: mas and the:mas book:mas'). Implications of these results are discussed both at the level of functional architecture within the language production system and at the level of changes in language use.