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Cooperation triggers expectations on our partners’ contributions to achieve a common goal. A partner, however, may sometimes violate such expectations, driving us to perform immediate adjustments. What neurophysiological mechanisms support these adaptations? We tested the hypothesis of an interaction-specific brain system that can decode a partner’s error and promote adaptive responses when cooperating toward a shared goal. During functional magnetic resonance imaging, the participants played short melodies with a virtual partner by performing one note each in turn-taking. A colored cue indicated which melody they had to execute at each trial, thus generating expectations on what notes the partner would play. The participants also performed the task in a perceptually matched Non-Interactive context. The results showed that task interactivity modulates the brain responses to a partner’s error in dorsal fronto-temporoparietal and medial cingulo-opercular networks. Multivariate pattern analysis revealed that these neural activations reflect deep decoding of the partner’s mistake. Within these networks, the automatic tendency to correct the partner’s errors, as indexed by specific reaction times adaptations, depended on the activity of a right-lateralized fronto-opercular system that may enable mutual support during real-life cooperation. Future studies may unveil the role of this putative “interaction monitoring” brain system in social dysfunctions and their motor foundations.

The logopenic variant of primary progressive aphasia (lvPPA) is the most recent variant of primary progressive aphasia (PPA) to be identified; thus far, it has been poorly investigated. Despite being typically associated with Alzheimer disease (AD), lvPPA has recently been linked to frontotemporal lobe degeneration (FTLD), with distinctive cognitive and neural features that are worthy of further investigation. Here, we describe the neuropsychological and linguistic profile, as well as cerebral abnormalities, of an individual exhibiting PPA and carrying a pathogenetic variant in the GRN gene, from a 3-year longitudinal perspective. The individual's initial profile resembled lvPPA because it was characterized by word-finding difficulties and phonological errors in spontaneous speech in addition to sentence repetition and phonological short-term memory impairments. The individual's structural and metabolic imaging data demonstrated left temporal and bilateral frontal atrophy and hypometabolism, respectively. On follow-up, as the pathology progressed, dysprosody, stereotypical speech patterns, agrammatism, and orofacial apraxia appeared, suggesting an overlap with the nonfluent variant of PPA (nfvPPA). Severe sentence comprehension impairment also became evident. Our longitudinal and multidisciplinary diagnostic approach allowed us to better characterize the progression of a GRN-positive lvPPA profile, providing neuropsychological and imaging indicators that might be helpful to improve classification between different PPA variants and to address a nosological issue. Finally, we discuss the importance of early diagnosis of PPA given the possible overlap between different PPA variants during the progression of the pathology.

In the current opinion paper, we suggest a new perspective on the neuroimaging studies investigating the neural bases of food-cue regulation. Stemming from the evidence that different factors can modulate the neural response to drug cues (Jasinska et al. 2014, Neurosc. Biobeh. Rev.), we addressed the role of the major internal (e.g., biological, psychological) and external (e.g., environmental, cue-specific) factors that influence the neural reactivity to food-related cues, highlighting the brain circuits affected by the simple and interactive effects across different factors. The proposed model will be useful to frame new research ideas in which different contextual factors are modeled according to a factorial design, allowing to explore higher-order interactions at the neurofunctional level. Elucidating such interactions will not only lead to a better understanding of the neurocognitive bases of the normal and pathological eating behavior, but it will also pave the way to more effective, ecological, and tailor-made (behavioral or brain-centered) interventions, where internal and external contextual factors are incorporated in the treatment.

Living in a social world requires social monitoring, i.e., the ability to keep track of others’ actions and mistakes. Here, we demonstrate the good reliability of the behavioral and neurophysiological indexes ascribed to social monitoring. We also show that no consensus exists on the cognitive bases of this phenomenology and discuss three alternative hypotheses: (i) the direct matching hypothesis, postulating that observed errors are processed through automatic simulation; (ii) the attentional hypothesis, considering errors as unexpected events that take resources away from task processing; and (iii) the goal representation hypothesis, which weighs social error monitoring depending on how relevant the other's task is to the observer's goals. To date, evidence on the role played by factors that could help to disentangle these hypotheses (e.g., the human vs. non-human nature of the actor, the error rate, and the reward context) is insufficient, although the goal representation hypothesis seems to receive more support. Theory-driven experimental designs are needed to enlighten this debate and clarify the role of error monitoring during interactive exchanges.

Creative production (related to art-making) and aesthetic appreciation (related to art-viewing) are inherently linked in visual arts, but their relationship has never been explored explicitly in cognitive neuroscience, nor the nature of such connection. The available literature suggests two cognitive processes as possible foundations of these two experiences: motor simulation or inhibitory control. In a meta-analysis of fMRI studies, we addressed this issue: we investigated whether there are shared neurofunctional underpinnings behind aesthetic and creative experiences in the visual domain; further, we examined whether any shared brain activation may reflect either motor simulation or inhibitory processes. A conjunction analysis revealed a common involvement of the pre-SMA in both classes of studies, a brain region, if anything, more concerned with top-down inhibitory motor and volitional cognitive control rather than bottom-up motor simulation. In the art-viewing domain, this finding was primarily driven by figurative rather than abstract art. The methodological limitations in the available literature are discussed together with possible new ways to expand the existing findings.

English serves as today’s lingua franca, a role not eased by the inconsistency of its orthography. Indeed, monolingual readers of more consistent orthographies such as Italian or German learn to read more quickly than monolingual English readers. Here, we assessed whether long-lasting bilingualism would mitigate orthography-specific differences in reading speed and whether the order in which orthographies with a different regularity are learned matters. We studied high-proficiency Italian-English and English-Italian bilinguals, with at least 20 years of intensive daily exposure to the second language and its orthography and we simulated sequential learning of the two orthographies with the CDP++ connectionist model of reading. We found that group differences in reading speed were comparatively bigger with Italian stimuli than with English stimuli. Furthermore, only Italian bilinguals took advantage of a blocked presentation of Italian stimuli compared to when stimuli from both languages were presented in mixed order, suggesting a greater ability to keep language-specific orthographic representations segregated. These findings demonstrate orthographic constraints on bilingual reading, whereby the level of consistency of the first learned orthography affects later learning and performance on a second orthography. The computer simulations were consistent with these conclusions.

In healthy subjects, the transient perturbation of body part ownership is accompanied by regional skin temperature decrease. This observation leaves an open question about a possible body part-specific thermoregulatory response in pathological conditions, in which the sense of ownership over that body part is altered. For instance, Body Integrity Dysphoria (BID), a poorly understood neuropsychiatric disorder, is characterised by the non-acceptance of one or more of one's extremities. This unsettling feeling pervasively captures the individuals' attention towards the unwanted limb. Previous studies characterised BID in terms of absent ownership feeling with preserved ownership judgment. We explored for the first time whether this altered feeling is also associated with a specific thermoregulatory response. We recorded thermal image sequences of circumscribed regions of the limbs' skin in seven individuals with BID desiring to remove one leg while they were invited to focus their attention toward one particular limb (arm or leg). Their event-related thermoregulatory pattern was compared to a group of healthy matched controls. In individuals with BID but not in control persons, we found a bilateral decrease in leg temperature when focusing their attention on either the unwanted or accepted leg. The event-related thermoregulatory response for both upper limbs was similar between individuals with BID and healthy controls. Our results suggest that the alteration of the sense of body ownership in neuropsychiatric conditions such as BID may critically rest on specific event-related thermoregulatory patterns in response to modulation of attention to body parts.

Visual drug cues are powerful triggers of craving in drug abusers contributing to enduring addiction. According to previous qualitative reviews, the response of the orbitofrontal cortex to such cues is sensitive to whether subjects are seeking treatment. Here we re-evaluate this proposal and assessed whether the nature of the drug matters. To this end, we performed a quantitative meta-analysis of 64 neuroimaging studies on drug-cue reactivity across legal (nicotine, alcohol) or illegal substances (cocaine, heroin). We used the ALE algorithm and a hierarchical clustering analysis followed by a cluster composition statistical analysis to assess the association of brain clusters with the nature of the substance, treatment status, and their interaction. Visual drug cues activate the mesocorticolimbic system and more so in abusers of illegal substances, suggesting that the illegal substances considered induce a deeper sensitization of the reward circuitry. Treatment status had a different modulatory role for legal and illegal substance abusers in anterior cingulate and orbitofrontal areas involved in inter-temporal decision making. The class of the substance and the treatment status are crucial and interacting factors that modulate the neural reactivity to drug cues. The orbitofrontal cortex is not sensitive to the treatment status per se, rather to the interaction of these factors. We discuss that these varying effects might be mediated by internal predispositions such as the intention to quit from drugs and external contingencies such as the daily life environmental availability of the drugs, the ease of getting them and the time frame of potential reward through drug consumption.

Current neurocognitive models of motor control postulate that accurate action monitoring is crucial for a normal experience of agency—the ability to attribute the authorship of our actions and their consequences to ourselves. Recent studies demonstrated that action monitoring is impaired in Gilles de la Tourette syndrome, a movement disorder characterized by motor and vocal tics. It follows that Tourette syndrome patients may suffer from a perturbed sense of agency, the hypothesis tested in this study. To this end, we recruited 25 Tourette syndrome patients and 25 matched healthy controls in a case-control behavioural and functional magnetic resonance imaging study. As an implicit index of the sense of agency, we measured the intentional binding phenomenon, i.e., the perceived temporal compression between voluntary movements and their external consequences. We found evidence of an impaired sense of agency in Tourette syndrome patients who, as a group, did not show a significant intentional binding. The more reduced was the individual intentional binding, the more severe were the motor symptoms. Specific differences between the two groups were also observed in terms of brain activation patterns. In the healthy controls group, the magnitude of the intentional binding was associated with the activity of a premotor–parietal–cerebellar network. This relationship was not present in the Tourette syndrome group, suggesting an altered activation of the agency brain network for self-generated acts. We conclude that the less accurate action monitoring described in Tourette syndrome also involves the assessment of the consequences of actions in the outside world. We discuss that this may lead to difficulties in distinguishing external consequences produced by their own actions from the ones caused by others in Tourette syndrome patients., Zapparoli et al. report behavioural and functional magnetic resonance imaging evidence of an altered sense of agency in Tourette syndrome, correlated with the severity of tics. This altered appreciation of a causal relationship between self-generated actions and their physical effects is discussed in the context of premotor theories of motor awareness., Graphical Abstract

We tested the hypothesis that Gilles de la Tourette syndrome (GTS) is characterized by perturbed connectivity within cortico-subcortical motor networks. To this end, we performed a dynamic causal modelling (DCM) analysis of fMRI data collected during a finger opposition task in 24 normal controls and 24 GTS patients. The DCM analysis allowed us to assess whether any GTS-specific patterns of brain activity were related to intrinsic and/or to task-dependent connectivity. While no abnormalities were found for task-dependent connectivity, intrinsic connectivity was abnormally increased in the premotor network, with stronger connections from the supplementary motor area (SMA), from the dorsolateral premotor cortex and from the putamen to the right superior frontal gyrus, an area where GTS showed over-activation in a previous univariate analysis. We also found a positive correlation between the connectivity strength from the right basal ganglia to the right primary motor cortex (M1) and disease severity measured by the Yale Global Tic Severity Scale (YGTSS). This pattern was mirrored by a negative correlation between the connection strength from the right SMA to the right area M1 and the YGTSS score. These two reverse correlation effects showed a specific relationship with individual disease severity: the greater the imbalance between subcortical and premotor connectivity towards area M1, the higher the YGTSS score. These results reveal the existence of perturbed intrinsic connectivity patterns in the motor networks of GTS patients with two competing forces operating in a tug of war-like mechanism: aberrant subcortical afferents to M1, compensated for by inputs from the premotor cortex.

Action observation triggers imitation, a powerful mechanism permitting interpersonal coordination. Coordination, however, also occurs when the partners’ actions are nonimitative and physically incongruent. One influential theory postulates that this is achieved via top-down modulation of imitation exerted by prefrontal regions. Here, we rather argue that coordination depends on sharing a goal with the interacting partner: this shapes action observation, overriding involuntary imitation, through the predictive activity of the left ventral premotor cortex (lvPMc). During functional magnetic resonance imaging (fMRI), participants played music in turn with a virtual partner in interactive and noninteractive conditions requiring 50% of imitative/nonimitative responses. In a full-factorial design, both perceptual features and low-level motor requirements were kept constant throughout the experiment. Behaviorally, the interactive context minimized visuomotor interference due to the involuntary imitation of physically incongruent movements. This was paralleled by modulation of neural activity in the lvPMc, which was specifically recruited during the interactive task independently of the imitative/nonimitative nature of the social exchange. This lvPMc activity reflected the predictive decoding of the partner’s actions, as revealed by multivariate pattern analysis. This demonstrates that, during interactions, we process our partners’ behavior to prospectively infer their contribution to the shared goal achievement, generating motor predictions for cooperation beyond low-level imitation.

Purpose of review Gilles de la Tourette syndrome (GTS) is a frequent neurological disorder characterized by the production of tics, and frequently associated with obsessive-compulsive disorder or attention-deficit hyperactivity disorder. The aim of this article is to summarize the contribution of imaging activation techniques to the study of the syndrome. Recent findings GTS has been studied with a variety of functional MRI (fMRI)/PET activation paradigms to characterize the origin of tics or their suppression, and how they compare physiologically with voluntary actions or response inhibitions. Current studies indicate overactivations of prefrontal and premotor cortices, including the supplementary motor area, and subcortical structures. Resting state functional connectivity studies complement activation studies in showing perturbed connectivity of cortico-subcortical networks. Several such findings correlate with the severity of the disease. Summary fMRI activation techniques are contributing a system-level neurophysiological description of GTS and bridge the gap between animal models and clinical observations. fMRI clarifies brain networks involved in different aspects of GTS phenomenology with some good clinical face validity. A future generation of fMRI studies should have higher ambitions and contribute, for example, to treatment optimization including the identification of ideal targets for deep brain stimulation in drug-resistant cases; however, such goals will be achieved only through controlled large-scale cooperative studies.

Several studies have shown age-related changes in motor imagery (MI) in older adults and the associated compensatory brain activation patterns; most of these studies have used explicit MI tasks or implicit MI tasks focused on mental rotation of body parts. Here, we address the effect of ageing on MI for the more complex visuomotor transformations entailed by mentally simulated hand-tool interactions triggered by a grip selection task (GST) for tools used in daily life. We studied 22 young and 22 elderly subjects performing the GST, in which they were asked to report whether they would grip a portrayed tool with an overhand or an underhand grip. We found a behavioral decline in the elderly group, accompanied by reduced activations of the left posterior parietal lobule, in a subregion associated specifically with reaching behavior by previous investigations. No differences were observed in the temporal cortices associated with object semantics. These results suggested a specific age-related vulnerability of the neural substrates, particularly for the imaginary reaching component of the task, rather than for the semantically driven grasping component. The combination of behavioral deficits and reduced activation of specific brain regions speaks in favor of a specific age-associated deficit for the complex imaginary movements required by the GST.

There is growing evidence for the role of the insular cortex in various types of cravings, including food craving. Here, we used resting-state functional brain connectivity (FBC) to explore system-level dysfunctions in the brain of obese (OB) individuals and their correlations with the leptin levels. We first used hierarchical clustering to identify the brain regions whose altered functioning was consistently reported by neuroimaging studies on food perception in OB subjects. We found that a cluster centred in left anterior insula and overlying frontal operculum (AI/fO) was specifically associated with hyper-responsivity in OB. This cluster was then used as a seed for a seed-based FBC analysis in 10 OB and 11 normal weight controls matched for sex, age and education. The analysis implied the calculation of the functional correlations of each brain voxel with the seed along the resting state fMRI time series. OB patients, compared to the control group, showed hyper-connectivity between the left AI/fO and key regions of the reward system, such as the left medial orbitofrontal cortex (OFC), in addition to the bilateral parahippocampal gyri and the posterior cingulate gyrus; conversely, they exhibited hypo-connectivity between the seed and the left dorsolateral prefrontal cortex, a key region involved in inhibitory control (all Ps < .corrected for multiple comparisons). Finally, we found a substantial trend for a negative correlation between AI/fO-OFC hyper-connectivity and plasma levels of leptin (ρ = - .612, p = .06). Our results provide evidence for an imbalance between reward and inhibitory control systems in OB patients, which might be worsened by an altered response to food intake regulatory hormones (e.g., anorexigenic leptin), thus driving the overeating behavior. Moreover, our results suggest that the left AI could be a suitable target for drugs or neuro-modulatory treatment to recalibrate the FBC of a network involved in food intake, reward and cognitive control. Disclosure F. Devoto: None. A. Ferrulli: None. L. Zapparoli: None. R. Bonandrini: None. L. Sconfienza: None. G. Banfi: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew. E. Paulesu: None.

Motor imagery (M.I.) training has been widely used to enhance motor behavior. To characterize the neural foundations of its rehabilitative effects in a pathological population we studied twenty-two patients with rhizarthrosis, a chronic degenerative articular disease in which thumb-to-fingers opposition becomes difficult due to increasing pain while the brain is typically intact. Before and after surgery, patients underwent behavioral tests to measure pain and motor performance and fMRI measurements of brain motor activity.After surgery, the affected hand was immobilized, and patients were enrolled in a M.I. training. The sample was split in those who had a high compliance with the program of scheduled exercises (T+, average compliance: 84%) and those with low compliance (T−, average compliance: 20%; cut-off point: 55%). We found that more intense M.I. training counteracts the adverse effects of immobilization reducing pain and expediting motor recovery. fMRI data from the post-surgery session showed that T+ patients had decreased brain activation in the premotor cortex and the supplementary motor area (SMA); meanwhile, for the same movements, the T− patients exhibited a reversed pattern. Furthermore, in the post-surgery fMRI session, pain intensity was correlated with activity in the ipsilateral precentral gyrus and, notably, in the insular cortex, a node of the pain matrix.These findings indicate that the motor simulations of M.I. have a facilitative effect on recovery by cortical plasticity mechanisms and optimization of motor control, thereby establishing the rationale for incorporating the systematic use of M.I. into standard rehabilitation for the management of post-immobilization syndromes characteristic of hand surgery. Keywords: Mental imagery training, Trapeziometacarpal joint osteoarthritis, Rhizarthrosis, Brain plasticity

Right brain damaged patients sometimes deny that their left arm is paralysed or even claim to have just moved it. This condition is known as anosognosia for hemiplegia (AHP). Here, we used fMRI to study patients with and without AHP during the execution of a motor task. We found that the delusional belief of having moved was preceded by brain activation of the cortical regions that are implicated in motor control in the left intact hemisphere and in the spared motor regions of the right hemisphere; patients without anosognosia did not present with the same degree of activation. We conclude that the false belief of movement is associated with a combination of strategically placed brain lesions and the preceding residual neural activity of the fronto-parietal motor network. These findings provide evidence that the activity of motor cortices contributes to our beliefs about the state of our motor system.

According to recent theories, drug addicted patients suffer of an impaired response inhibition and salience attribution (I-RISA) together with a perturbed connectivity between the nuclei accumbens (NAcs) and the orbito-prefrontal (oPFC) and dorsal prefrontal (dPFC) cortices, brain regions associated with motivation and cognitive control. To empirically test these assumptions, we evaluated the (neuro)psychological trait and the functional organization of the resting state brain networks associated with the NAcs in 18 former cocaine abusers (FCAs), while being in drug abstinence since 5 months. The psychological data were grouped into three empirical variables related with emotion regulation, emotion awareness and strategic and controlled behaviour. Comparison of the resting state patterns between the entire sample of FCAs and 19 controls revealed a reduction of functional connectivity between the NAcs and the dPFC and enhanced connectivity between the NAcs and the dorsal-striatum. In the 8 FCAs who relapsed into cocaine use after 3 months, the level of functional connectivity between the NAcs and dPFC was lower than the functional connectivity estimated in the group of patients that did not relapsed. Finally, in the entire sample of FCAs, the higher the connectivity between the NAc and the oPFC the lower was the level of strategic and controlled behaviour. Taken together, these results are compatible with models of the interactions between the NAcs, the dorsal striatum and frontal cortices in the I-RISA syndrome, showing that such interactions are particularly perturbed in patients at greater risk of relapse into cocaine abuse.

Somatoparaphrenia is a delusional belief whereby a patient feels that a paralyzed limb does not belong to his body; the symptom is typically associated with unilateral neglect and most frequently with anosognosia for hemiplegia. This association of symptoms makes anatomical inference based on single case studies not sufficiently specific. On the other hand, the only three anatomical group studies on somatoparaphrenia are contradictory: the right posterior insula, the supramarginal gyrus and the posterior corona radiata, or the right medial or orbito-frontal regions were all proposed as specific lesional correlates.We compared 11 patients with and 11 without somatoparaphrenia matched for the presence and severity of other associated symptoms (neglect, motor deficits and anosognosia). To take into account the frequent association of SP and neglect and hemiplegia, patients with and without somatoparaphrenia were also compared with a group of fifteen right brain damage patients without neglect and hemiplegia. We found a lesion pattern involving a fronto-temporo-parietal network typically associated with spatial neglect, hemiplegia and anosognosia. Somatoparaphrenic patients showed an additional lesion pattern primarily involving white matter and subcortical grey structures (thalamus, basal ganglia and amygdala). Further cortical damage was present in the middle and inferior frontal gyrus, postcentral gyrus and hippocampus.We propose that somatoparaphrenia occurs providing that a distributed cortical lesion pattern is present together with a subcortical lesion load that prevents most sensory input from being processed in neocortical structures; involvement of deep cortical and subcortical grey structures of the temporal lobe may contribute to reduce the sense of familiarity experienced by somatoparaphrenic patients for their paralyzed limb. © 2011 Elsevier Srl.

Two experiments investigated whether dealing with a homogeneous subset of syllogisms with time-constrained responses encouraged participants to develop and use heuristics for abstract (Experiment 1) and thematic (Experiment 2) syllogisms. An atmosphere-based heuristic accounted for most responses with both abstract and thematic syllogisms. With thematic syllogisms, a weaker effect of a belief heuristic was also observed, mainly where the correct response was inconsistent with the atmosphere of the premises. Analytic processes appear to have played little role in the time-constrained condition, whereas their involvement increased in a self-paced, unconstrained condition. From a dual-process perspective, the results further specify how task demands affect the recruitment of heuristic and analytic systems of reasoning. Because the syllogisms and experimental procedure were the same as those used in a previous neuroimaging study by Goel, Buchel, Frith, and Dolan (2000), the result also deepen our understanding of the cognitive processes investigated by that study.

The current study investigated the neural correlates of voluntary motor control in 24 adult Gilles de la Tourette (GTS) patients. We examined whether imagination and the execution of the same voluntary movement - finger oppositions with either hand - were associated with specific patterns of activation. We also explored whether these patterns correlated with the severity of the syndrome, as measured by the Yale Global Tic Severity Scale (YGTSS) for motor tics. The presence of brain morphometric abnormalities was also assessed using voxel-based morphometry. Crucial to our experiment was the manipulation of the presence of an explicit motor outflow in the tasks. We anticipated a reduction in the ticking manifestation during the explicit motor task and brain activation differences between GTS patients and 24 age/gender-matched normal controls. The anticipated differences were all evident in the form of hyperactivations in the GTS patients in the premotor and prefrontal areas for both motor tasks for both hands; however, the motor imagery hyperactivations also involved rostral pre-frontal and temporo-parietal regions of the right hemisphere. The blood oxygen level-dependent responses of the premotor cortices during the motor imagery task were significantly correlated with the YGTSS scores. In contrast, no significant brain morphometric differences were found. This study provides evidence of a different neurofunctional organisation of motor control between adult patients with GTS and healthy controls that is independent from the actual execution of motor acts. The presence of an explicit motor outflow in GTS mitigates the manifestation of tics and the need for compensatory brain activity in the brain regions showing task-dependent hyperactivations. We used fMRI to investigate the neural correlates of voluntary motor control in adult GTS patients, with two different finger opposition tasks, one explicit and one imagined. We found task-dependent cortical hyperactivations in GTS, broader for motor imagery, proportional to the severity of the disease. The presence of an explicit motor outflow in GTS mitigated the manifestation of tics and the need for compensatory brain activity in the brain regions showing task dependent hyperactivations.

We assessed the effects of age of acquisition and language exposure on the cerebral correlates of lexical retrieval in high‐proficient, early‐acquisition bilinguals. Functional MRI was used to study Spanish–Catalan bilinguals who acquired either Spanish or Catalan as a first language in the first years of life. Subjects were exposed to the second language at 3 years of age, and have used both languages in daily life since then. Subjects had a comparable level of proficiency in the comprehension of both languages. Lexical retrieval with the verbal fluency task resulted in the well‐established pattern of left hemispheric activation centered on the inferior frontal region. The effect of age of acquisition was assessed by dividing the subjects into two groups, on the basis of the language acquired first (Catalan‐born or Spanish‐born bilinguals). Functional comparisons indicated that less extensive brain activation was associated with lexical retrieval in the language acquired earlier in life. The two groups were also different in language usage/exposure, as assessed with a specific questionnaire; in particular, the exposure to the second language (Spanish) was less intensive in the case of Catalans. This was reflected in a significant interaction, indicating a more extensive activation in Catalans during production in Spanish. Overall, these results indicate that, during a production task, both age of acquisition and language exposure affect the pattern of brain activation in bilinguals, even if both languages are acquired early and with a comparable level of proficiency. Hum. Brain Mapping 19:170–182, 2003. © 2003 Wiley‐Liss, Inc.

The existence of multiple solutions in clustering, and in hierarchical clustering in particular, is often ignored in practical applications. However, this is a non-trivial problem, as different data orderings can result in different cluster sets that, in turns, may lead to different interpretations of the same data. The method presented here offers a solution to this issue. It is based on the definition of an equivalence relation over dendrograms that allows developing all and only the significantly different dendrograms for the same dataset, thus reducing the computational complexity to polynomial from the exponential obtained when all possible dendrograms are considered. Experimental results in the neuroimaging and bioinformatics domains show the effectiveness of the proposed method.

The aim of this study was to assess, by positron emission tomography (PET), the effect on cerebral functional activity of a new lorazepam-γ-aminobutyric acid (GABA) conjugate [3-(4-acetamido)-butyrril lorazepam (DDS2700)]. Ten healthy volunteers were studied by PET and [ 18 F]fluoro-deoxy-D-glucose ([ 18 F]FDG) under baseline conditions and following the administration of DDS2700. Regional cerebral blood flow (rCBF) was measured by PET and 15 O-water in three additional participants while they performed attentive tasks, before and after drug administration. DDS2700 induced a decrease in the regional cerebral metabolic rate of glucose (rCMRglu) in the thalamus (-17%), cerebellum (-11%) and caudate nucleus (-8%). The observed effects on glucose metabolism were probably related to the subjective sedation and tiredness reported by the participants. During the attentive tasks, rCBF increased in frontal and temporal regions associated with attentional processing of auditory material. These circuits were no longer active after DDS2700 administration, while rCBF increased in cingulate cortex, occipitoparietal regions, pons and cerebellum. These drug-induced activations might be directly related to intervening sleepiness and to the consequent effort in keeping attention focused on the tasks. The effects of DDS2700 on glucose metabolism at rest, and on rCBF during activation conditions, indicate a drug action on cerebral networks involved in alertness, vigilance and attention maintenance. PET assessment by [ 18 F]FDG and water may provide complementary information in pharmacodynamic studies.

We studied with PET the intra- and interhemispheric pathways subserving a simple, speeded-up visuomotor task. Six normal subjects and one patient with a complete section of the corpus callosum (M.E.) underwent regional cerebral blood flow (rCBF) measurements under conditions of lateralized tachistoscopic visual presentations in a simple manual reaction time paradigm. Confirming previous behavioural findings, we found that on average crossed hand and/or hemifield conditions, i.e. those requiring an interhemispheric transfer of information, yielded a longer RT than uncrossed conditions. This difference (0.7 ms) was dramatically larger (45.6 ms) in the callosum-sectioned patient M.E. In normal subjects the cortical areas selectively activated in uncrossed and crossed conditions were different. In the former condition, most activation foci were anterior to the ventral anterior commissure (VAC) plane, whereas in the latter there was a prevalent parietal and occipital activation. This shows that a simple model in which the cortical visuo-motor pathways are similar in the intra- and the interhemispheric condition, with an extra callosal route for the latter, is too simplistic. Furthermore, these results suggest that the bulk of visuomotor interhemispheric transfer takes place through the widespread callosal fibres interconnecting the parietal cortices of the two hemispheres. The pattern of activation in the two crossing conditions was markedly different in M.E., in whom interhemispheric transfer might take place via his intact anterior commissure or subcortical commissures.

The [18F]fluorodeoxyglucose ([18F]FDG) method for measuring brain metabolism has not the wide clinical application that one might expect, partly because of its high cost and the complexity of the quantification procedure, but also because of reporting techniques based on region of interest (ROI) analysis, which are time-consuming and not fully objective. In this paper we report a clinical validation of statistical parametric mapping (SPM) using rCMRglc (quantitative) and radioactivity distribution (nonquantitative) [18F]FDG PET data. We show that a 10-min noninteractive voxel-based SPM analysis on a standard workstation enables objective assessment, including localization in stereotactic space, of regional glucose consumption abnormalities, whose reliability can be assessed on statistical and clinical grounds. Clinical validity was established using a small series of patients with degenerative or developmental disorders, including probable Alzheimer's disease, progressive aphasia, multiple sclerosis, developmental specific language impairment, and epilepsy. Analysis of quantitative and nonquantitative data showed the same pattern of results, suggesting that, for clinical purposes, quantitation and invasive arterial cannulation can be avoided. This should facilitate a wider application of the technique and the extension of SPM clinical analysis to H215O PET or high resolution SPECT perfusion studies.

Neglect patients' performance during cancellation tasks is characterized by left sided omissions and, in many cases, by the production of inappropriate material of various kinds in the ipsilesional space, e.g. additional marks over already cancelled targets, marks drawn away from targets, scribbles, irrelevant drawings. It is unclear whether these behaviours, which have collectively been called perseverative, are functionally and anatomically connected and whether they correlate with the severity of neglect. Here we report a retrospective study on 33 right brain damaged patients with neglect after right hemisphere lesions in whom we measured the intensity of perseveration of the three following kinds: (1) 'additional marks' (AM) perseveration where patients cancelled a target with two or more well separated marks; (2) 'scribble' perseveration, where patients, instead of cancelling the target with a single pen stroke as required by the task, performed multiple pen strokes without breaking the pen-to-paper contact, with the final product being a scribble; (3) 'flying marks' (FM) perseveration where patients produced cancellation marks well away from the targets. We found that AM and FM perseveration correlated with neglect severity, while 'scribble' perseveration did not. The lesion-symptom mapping showed three separate anatomical areas in the right hemisphere: 'scribble' perseveration was associated with lesions of the orbitofrontal cortex and caudate nucleus; AM perseveration was associated with damage to the rolandic operculum, superior temporal gyrus and inferior frontal gyrus; FM perseveration was associated with damage to the dorsal premotor cortex and the temporal pole. Neglect severity followed damage to a region which grossly corresponds to the sum of the regions associated with AM and FM perseveration respectively. This complex behavioural and anatomical pattern is interpreted in terms of a three-factor model, in which AM perseveration is caused by a deficit of disengagement of attention from the right side (also causing omissions), FM perseveration is caused by directional hypokinesia (also causing left-side omissions), and 'scribble' perseveration is the consequence of a failure to inhibit an initiated motor act, which is completely separate (both anatomically and functionally) from the disorder inducing omissions. © 2013 Elsevier Ltd.

In a small proportion of the normal population, stimulation in one modality can lead to perceptual experience in another, a phenomenon known as synaesthesia. In the most common form of synaesthesia, hearing a word can result in the experience of colour. We have used the technique of PET, which detects brain activity as changes of regional cerebral blood flow (rCBF), to study the physiology of colour-word synaesthesia in a group of six synaesthete women. During rCBF measurements synaesthetes and six controls were blindfolded and were presented with spoken words or pure tones. Auditory word, but not tone, stimulation triggered synaesthesia in synaesthetes. In both groups word stimulation compared with tone stimulation activated the classical language areas of the perisylvian regions. In synaesthetes, a number of additional visual associative areas, including the posterior inferior temporal cortex and the parieto-occipital junctions, were activated. The former has been implicated in the integration of colour with shape and in verbal tasks which require attention to visual features of objects to which words refer. Synaesthetes also showed activations in the right prefrontal cortex, insula and superior temporal gyrus. By contrast, no significant activity was detected in relatively lower visual areas, including areas V1, V2 and V4. These results suggest that colour-word synaesthesia may result from the activity of brain areas concerned with language and visual feature integration. In the case of colour-word synaesthesia, conscious visual experience appears to occur without activation of the primary visual cortex.

Deduction is the ability to draw necessary conclusions from previous knowledge. Here we propose a novel approach to understanding the neural basis of deduction, which exploits fine-grained inter-participant variability in such tasks. Participants solved deductive problems and were grouped by the behavioral strategies employed, i.e., whether they were sensitive to the logical form of syllogistic premises, whether the problems were solved correctly, and whether heuristic strategies were employed. Differential profiles of neural activity can predict membership of the first two of these groups. The predictive power of activity profiles is distributed non-uniformly across the brain areas activated by deduction. Activation in left ventro-lateral frontal (BA47) and lateral occipital (BA19) cortices predicts whether logically valid solutions are sought. Activation of left inferior lateral frontal (BA44/45) and superior medial frontal (BA6/8) cortices predicts sensitivity to the logical structure of problems. No specific pattern of activation was associated with the use of a non-logical heuristic strategy. Not only do these findings corroborate the hypothesis that left BA47, BA44/45 and BA6/8 are critical for making syllogistic deductions, but they also imply that they have different functional roles as components of a dedicated network. We propose that BA44/45 and BA6/8 are involved in the extraction and representation of the formal structure of a problem, while BA47 is involved in the selection and application of relevant inferential rules. Finally, our findings suggest that deductive reasoning can be best described as a cascade of cognitive processes requiring the concerted operation of several, functionally distinct, brain areas.

Two cases of aphasia after right hemispheric stroke in right handed patients are described. The first patient had a severe mixed transcortical aphasia, apraxia and neglect after a lesion involving the right lenticular nucleus and periventricular white matter; aphasia was still present after three months. The second patient had a mild, transient fluent aphasia after a small right hemispheric periventricular lesion. Studies with [18F]FDG and positron emission tomography (PET) showed functional depression extending to the structurally unaffected left hemisphere in both patients in the acute stage. After three months, in the patient with persistent aphasia, metabolism was still reduced in the right hemisphere, with some recovery of hypometabolism on the left, while metabolic values had returned to normal in the patient with full language recovery. A close parallelism between glucose metabolism and clinical course in crossed aphasia is shown, as well as the presence of a functional involvement of the structurally unaffected left hemisphere in the acute stage.

A 2-[18F]-Fluoro-2-Deoxy- D -Glucose ([18F]FDG) and positron emission tomography (PET) study was performed in the acute and chronic phase of stroke in one patient with unilateral neglect due to a right hemispheric lesion. In the acute phase, severe neglect, as well as hypometabolism in both the right and in the left unaffected cerebral hemisphere, was demonstrated. At follow-up evaluation the patient showed an almost complete recovery fromunilateral neglect. This was associated with a return of left hemisphere metabolism to normal values and partial metabolic recovery in the right hemisphere, where frontal and parietal areas remained functionally impaired. Another patient with an extensive right cerebral ischaemic lesion on CT and severe unilateral neglect was studied by PET in chronic phase. A severe metabolic depression in the left unaffected hemisphere and in the right cerebral areas spared by the lesion, was found. These data suggest that the remission of unilateral neglect might be associated to a functional metabolic recovery in both the undamaged left hemisphere and the unaffected regions of the right hemisphere.

This book provides a unique and accessible account of current research on reading and dyslexia in different orthographies. While most research has been conducted in English, this text presents cross-language comparisons to provide insights into universal aspects of reading development and developmental dyslexia in alphabetic and non-alphabetic languages. The book brings together contributions from a group of leading literacy researchers from around the world. It begins by examining the development of language skills in monolingual speakers of alphabetic and non-alphabetic languages; it then explores literacy acquisition in bilingual children learning to read in languages with different spelling-sound rules, including English, French, Greek, Welsh and Japanese. The second section is devoted to developmental dyslexia in monolingual and bilingual speakers of different languages and examines the impact of variations in orthography on the symptoms and aetiology of dyslexia. The final section explores the contribution of brain imaging to the study of impaired and unimpaired reading, giving an up-to-the-minute picture of how the brain deals with different languages and writing systems. This is ideal reading for advanced undergraduates and postgraduates who have an interest in language acquisition, reading and spelling, as well as speech and language therapists, teachers and special educational needs professionals.

Many hypotheses have been proposed about the brain underpinnings of developmental dyslexia, but none of them accommodates the variable deficits observed. To address the issue of anatomical deficits in dyslexia; total and partial volumes, lateralization indices (LI), and local gray matter volumes (LGMV) were measured. Analyses were performed in large samples of control and dyslexic subjects, and in correlation with their performance on phonological, reading, and spelling tests. Results indicate an absence of net differences in terms of volumes but significant continuities and discontinuities between groups in their correlations between LI, LGMV, and performances. Structural connectivity also highlighted correlations between areas showing (dis)continuities between control and dyslexic subjects. Overall, our data put forward the idea of a multifocal brain abnormalities in dyslexia with a major implication of the left superior temporal gyrus, occipital‐temporal cortices, and lateral/medial cerebellum, which could account for the diverse deficits predicted by the different theories. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.

A new head holder for the fixation and repositioning of the patient head in PET, CT, and MR scanners has been designed and tested. With this device, a bidimensional correlation between functional and anatomical brain images can also be obtained. Head fixation and repositioning are achieved using the patient's dental morphology as an anatomical reference. With a dentistic material, a mold of the patient's teeth is obtained in a few minutes. The molding substance rests on a plastic support, fixed to the head holder. Each time the patient undergoes a new study, his/her personal mold is used, ensuring accurate head repositioning. External markers fixed on the head holder (made visible in lateral PET and CT projection images, midsaggital MR images, and also on the axial images) make it possible to record and recognize the angular orientation and the position of the brain in the three-dimensional space, to correlate images of the same patient obtained with different neuroimaging modalities, and to accurately reposition patients for follow-up studies. The head holder was tested on several subjects. Fixation and repositioning accuracy of within 2.5 mm were achieved in the three-dimensional space. Orientation accuracy was 1 degree.

The recognition of dyslexia as a neurodevelopmental disorder has been hampered by the belief that it is not a specific diagnostic entity because it has variable and culture-specific manifestations. In line with this belief, we found that Italian dyslexics, using a shallow orthography which facilitates reading, performed better on reading tasks than did English and French dyslexics. However, all dyslexics were equally impaired relative to their controls on reading and phonological tasks. Positron emission tomography scans during explicit and implicit reading showed the same reduced activity in a region of the left hemisphere in dyslexics from all three countries, with the maximum peak in the middle temporal gyrus and additional peaks in the inferior and superior temporal gyri and middle occipital gyrus. We conclude that there is a universal neurocognitive basis for dyslexia and that differences in reading performance among dyslexics of different countries are due to different orthographies.

We present behavioral and anatomical evidence for a multi-component reading system in which different components are differentially weighted depending on culture-specific demands of orthography. Italian orthography is consistent, enabling reliable conversion of graphemes to phonemes to yield correct pronunciation of the word. English orthography is inconsistent, complicating mapping of letters to word sounds. In behavioral studies, Italian students showed faster word and non-word reading than English students. In two PET studies, Italians showed greater activation in left superior temporal regions associated with phoneme processing. In contrast, English readers showed greater activations, particularly for non-words, in left posterior inferior temporal gyrus and anterior inferior frontal gyrus, areas associated with word retrieval during both reading and naming tasks.

Previous studies achieved conflicting results when correlating magnetic resonance imaging (MRI) abnormalities and cognitive impairment in multiple sclerosis (MS) patients. Recently, the estimation of MS lesion load on T1-weighted images and the analysis of magnetization transfer ratio (MTR) histograms, increased the degree of the correlation between physical disability and MRI findings in MS. We assessed the relationship of conventional and non-conventional MRI-derived measures with frontal lobe dementia in MS. Dual echo, T1-weighted and MT MRI scans of the brain were obtained in 11 MS patients with and in 11 without frontal lobe dementia, matched for age, sex, education and disability. Total (TLL) and frontal (FLL) lesion loads were assessed from T2- and T1-weighted scans. MTR histogram analysis was performed for the whole brain, the frontal lobe and the cerebellum. Median TLL and FLL were significantly higher in cognitively impaired patients on both T2- and T1-weighted scans. The MRI measure that better discriminated the two groups of patients was T1-weighted TLL (median values were 19.1 ml for demented and 1.9 ml for non-demented patients, P=0.006). Average MTR, peak height and location of overall brain and frontal lobe histograms were significantly lower for cognitively impaired than for cognitively intact patients (P values ranged from 0.0001 to 0.001). Cerebellar MTR histogram metrics did not significantly differ in patients with and without cognitive decline. The presence of cognitive decline in MS is associated with the extent and pathological severity of brain MRI abnormalities.

Functional imaging of the presynaptic dopaminergic activity using single-photon emission tomography (SPET) and iodine-123 labelled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) is important for the assessment of disease severity and progression in patients with Parkinson's disease (PD). However, its capability to discriminate between different extrapyramidal disorders has not yet been assessed. The aim of this study was to evaluate the possibility of differentiating patients with PD and with progressive supranuclear palsy (PSP) by means of this method. The distribution of [123I]beta-CIT in the basal ganglia was assessed in six normal subjects, 13 petients with PD and five patients with PSP in whom the disease was mild. SPET images were obtained 24+/-2 h after i.v. injection of the tracer using a brain-dedicated system (CERASPECT). MR and SPET images were co-registered in four normal subjects and used to define a standard set of 16 circular regions of interest (ROIs) on the slice showing the highest striatal activity. The basal ganglia ROIs corresponded to (1) the head of caudate, (2) a region of transition between the head of caudate and the anterior putamen, (3) the anterior putamen and (4) the posterior putamen. A ratio of specific to non-displaceable striatal uptake was calculated normalising the activity of the basal ganglia ROIs to that of the occipital cortex (V3"). ANOVA revealed a global reduction of V3" in all ROIs of PD and PSP patients compared with normal controls (P

The ligand PK11195 is selective for the peripheral benzodiazepine binding site and exhibits minimal binding in normal brain. In brain lesions, however, there is a massive increase in binding, which in vitro studies have demonstrated is associated with infiltrating macrophages and activated microglia. Here, the binding of [11C]PK11195 was studied in the brains of multiple sclerosis patients using a CTI/Siemens 953B positron emission tomograph with retractable septa, acquiring data in either two-dimensional (2D) or 3D mode. Images acquired in 2D following injection of ~ 370 MBq were generally featureless. In some cases, poorly circumscribed signals were observed in brain stem or thalamus but with a minimal signal-to-noise ratio. However, regions showing gadolinium enhancement in magnetic resonance (MR) imaging, indicating a blood-brain barrier disturbance and known from histology to contain macrophages, never showed an elevated [11C]PK11195 signal. Three dimensional positron emission tomography (PET), using similar doses of radioligand, gave a fivefold increase in counts and produced a marked improvement in image quality. Gadolinium-enhancing lesions were clearly visualized, together with hot spots of binding in regions with apparently normal MR imaging appearance. The PET signals were often well delineated and, following coregistration with MR images, could be localized to well-defined anatomical structures such as individual thalamic nuclei and white matter tracts. In several cases, these structures identified pathways correlating with the clinical condition of the patient. It was concluded that while 2D PET and [11C]PK11195 can be used to image gross macrophage infiltration in the central nervous system, more subtle pathology requires 3D scanning in order to realize the full potential of the methodology.

Summary A rhyming and a short-term memory task with visually presented letters were used to study brain activity in five compensated adult developmental dyslexics. Their only cognitive difficulty was in phonological processing, manifest in a wide range of tasks including spoonerisms, phonemic fluency and digit naming speed. PET scans showed that for the dyslexics, a subset only of the brain regions normally involved in phonological processing was activated: Broca 's area during the rhyming task, temporo-parietal cortex during the short-term memory task. In contrast to normal controls these areas were not activated in concert. Furthermore the left insula was never activated. We propose that the defective phonological system of these dyslexics is due to weak connectivity between anterior and posterior language areas. This could be due to a dysfunctional left insula which may normally act as an anatomical bridge between Broca's area, superior temporal and inferior parietal cortex. The independent activation of the posterior and anterior speech areas in dyslexics supports the notion that representations of unsegmented and segmented phonology are functionally and anatomically separate.

The cerebral representation of space depends on the integration of many different sensory inputs. The vestibular system provides one such input and its dysfunction can cause profound spatial disorientation. Using positron emission tomography (PET), we measured regional cerebral perfusion with various vestibular stimulations to map central vestibular projections and to investigate the cerebral basis of spatial disorientation. We showed that the temporoparietal cortex, the insula, the putamen, and the anterior cingulate cortex are the cerebral projections of the vestibular system in man and that the spatial disorientation caused by unilateral vestibular stimulation is associated with their asymmetric activation.

Corpus callosum (CC) atrophy by magnetic resonance imaging (MRI) is a common finding in multiple sclerosis (MS). In order to examine the relationship between CC atrophy and cortical brain metabolism, we compared the cerebral metabolic rates for glucose (CMRglc), measured by positron emission tomography (PET), of 8 MS patients with evidence of CC atrophy on midsagittal MRI, 8 MS patients without CC atrophy and 10 healthy controls. Results showed no significant differences in supratentorial CMRglc absolute values between the three groups, although a slight metabolic reduction was observed in both MS groups compared with normal controls. By contrast, only patients with CC atrophy showed greater directional metabolic asymmetry than normals, the left frontal, temporal and parietal association cortices being significantly lower than the right. Predominant left hemispheric metabolic reductions were not accompanied by a corresponding left-sided predominance in the extent of MRI-detected demyelinating lesions. Therefore our data suggest that CC atrophy interfers more with left than with right metabolic function.

Human amnesia is a clinical syndrome exhibiting the failure to recall past events and to learn new information. Its “pure” form, characterized by a selective impairment of long-term memory without any disorder of general intelligence or other cognitive functions, has been associated with lesions localized within Papez's circuit and some connected areas. Thus, amnesia could be due to a functional disconnection between components of this or other neural structures involved in long-term learning and retention. To test this hypothesis, we measured regional cerebral metabolism with 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) and positron emission tomography (PET) in 11 patients with “pure” amnesia. A significant bilateral reduction in metabolism in a number of interconnected cerebral regions (hippocampal formation, thalamus, cingulate gyrus, and frontal basal cortex) was found in the amnesic patients in comparison with normal controls. The metabolic impairment did not correspond to alterations in structural anatomy as assessed by magnetic resonance imaging (MRI). These results are the first in vivo evidence for the role of a functional network as a basis of human memory.