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Giuseppe PAGNONI

Professore Associato
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Sc. Biomediche

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2024 - Age-specific prevalence of the different clinical presentations of AD and FTD in young-onset dementia [Articolo su rivista]
Zamboni, G.; Maramotti, R.; Salemme, S.; Tondelli, M.; Adani, G.; Vinceti, G.; Carbone, C.; Filippini, T.; Vinceti, M.; Pagnoni, G.; Chiari, A.

Background Studies have shown that the prevalence of all-variants Alzheimer's disease (AD) and frontotemporal dementia (FTD) both increase with age, even before the age of 65. However, it is not known whether their different clinical presentations all increase in prevalence with age in the same way.Methods We studied the prevalence of the different clinical presentations of young-onset AD and FTD by 5-year age groups in a population-based study identifying all dementia patients with a diagnosis of AD and FTD and symptoms onset before age 65 in the Modena province, Italy. By using regression models of cumulative occurrences, we also estimated age-specific prevalence and compared the growth curves of the clinical presentations.Results The prevalence of all-variants AD increased with age, from 18/1,000,000 in the 40-44 age group to 1411/1,000,000 in the 60-64 age group. The prevalence of all-variants FTD also increased with age, from 18/1,000,000 to 866/1,000,000. An estimation of age-specific prevalence functions of each clinical presentation showed that atypical non-amnestic AD and aphasic FTD grew the most in early ages, followed by the behavioural variant of FTD (bvFTD). Then, around the age of 60, amnestic AD took over and its age-specific prevalence continued to increase disproportionally compared to all the other clinical variants of AD and FTD, which, instead, started to decrease in prevalence.Conclusions Amnestic AD is the clinical presentation that increases the most with advancing age, followed by bvFTD, suggesting that there is a differential vulnerability to the effect of ageing within the same neurodegenerative disease.

De Pinto, M.; Coppi, F.; Spinella, A.; Pagnoni, G.; Morgante, V.; Macripo’, P.; Guerra, A. F.; Secchi, O.; Orlandi, M.; Amati, G.; Lumetti F., F.; Sandri, G.; Rossi, R.; Boriani, G.; Mattioli, A. V.; Ferri, C.; Giuggioli., D.

2023 - An exciting path ahead: Comment on “Path integrals, particular kinds, and strange things” by Friston K., Da Costa L., Sakthivadivel D.A.R., Heins C., Pavliotis G.A., Ramstead M., and Parr T [Articolo su rivista]
Pagnoni, G.

2023 - Neural correlates of emotional valence for faces and words [Articolo su rivista]
Ballotta, Daniela; Maramotti, Riccardo; Borelli, Eleonora; Lui, Fausta; Pagnoni, Giuseppe

: Stimuli with negative emotional valence are especially apt to influence perception and action because of their crucial role in survival, a property that may not be precisely mirrored by positive emotional stimuli of equal intensity. The aim of this study was to identify the neural circuits differentially coding for positive and negative valence in the implicit processing of facial expressions and words, which are among the main ways human beings use to express emotions. Thirty-six healthy subjects took part in an event-related fMRI experiment. We used an implicit emotional processing task with the visual presentation of negative, positive, and neutral faces and words, as primary stimuli. Dynamic Causal Modeling (DCM) of the fMRI data was used to test effective brain connectivity within two different anatomo-functional models, for the processing of words and faces, respectively. In our models, the only areas showing a significant differential response to negative and positive valence across both face and word stimuli were early visual cortices, with faces eliciting stronger activations. For faces, DCM revealed that this effect was mediated by a facilitation of activity in the amygdala by positive faces and in the fusiform face area by negative faces; for words, the effect was mainly imputable to a facilitation of activity in the primary visual cortex by positive words. These findings support a role of early sensory cortices in discriminating the emotional valence of both faces and words, where the effect may be mediated chiefly by the subcortical/limbic visual route for faces, and rely more on the direct thalamic pathway to primary visual cortex for words.

2023 - Sparse Bayesian modeling of hierarchical independent component analysis: Reliable estimation of individual differences in brain networks [Articolo su rivista]
Lukemire, J.; Pagnoni, G.; Guo, Y.

Independent component analysis (ICA) is one of the leading approaches for studying brain functional networks. There is increasing interest in neuroscience studies to investigate individual differences in brain networks and their association with demographic characteristics and clinical outcomes. In this work, we develop a sparse Bayesian group hierarchical ICA model that offers significant improvements over existing ICA techniques for identifying covariate effects on the brain network. Specifically, we model the population-level ICA source signals for brain networks using a Dirichlet process mixture. To reliably capture individual differences on brain networks, we propose sparse estimation of the covariate effects in the hierarchical ICA model via a horseshoe prior. Through extensive simulation studies, we show that our approach performs considerably better in detecting covariate effects in comparison with the leading group ICA methods. We then perform an ICA decomposition of a between-subject meditation study. Our method is able to identify significant effects related to meditative practice in brain regions that are consistent with previous research into the default mode network, whereas other group ICA approaches find few to no effects.

2022 - Emergence of associative learning in a neuromorphic inference network [Articolo su rivista]
Gandolfi, D.; Puglisi, F. M.; Boiani, G. M.; Pagnoni, G.; Friston, K. J.; D'Angelo, E.; Mapelli, J.

Objective. In the theoretical framework of predictive coding and active inference, the brain can be viewed as instantiating a rich generative model of the world that predicts incoming sensory data while continuously updating its parameters via minimization of prediction errors. While this theory has been successfully applied to cognitive processes-by modelling the activity of functional neural networks at a mesoscopic scale-the validity of the approach when modelling neurons as an ensemble of inferring agents, in a biologically plausible architecture, remained to be explored.Approach.We modelled a simplified cerebellar circuit with individual neurons acting as Bayesian agents to simulate the classical delayed eyeblink conditioning protocol. Neurons and synapses adjusted their activity to minimize their prediction error, which was used as the network cost function. This cerebellar network was then implemented in hardware by replicating digital neuronal elements via a low-power microcontroller.Main results. Persistent changes of synaptic strength-that mirrored neurophysiological observations-emerged via local (neurocentric) prediction error minimization, leading to the expression of associative learning. The same paradigm was effectively emulated in low-power hardware showing remarkably efficient performance compared to conventional neuromorphic architectures.Significance. These findings show that: (a) an ensemble of free energy minimizing neurons-organized in a biological plausible architecture-can recapitulate functional self-organization observed in nature, such as associative plasticity, and (b) a neuromorphic network of inference units can learn unsupervised tasks without embedding predefined learning rules in the circuit, thus providing a potential avenue to a novel form of brain-inspired artificial intelligence.

2022 - From Generative Models to Generative Passages: A Computational Approach to (Neuro) Phenomenology [Articolo su rivista]
Ramstead, M. J. D.; Seth, A. K.; Hesp, C.; Sandved-Smith, L.; Mago, J.; Lifshitz, M.; Pagnoni, G.; Smith, R.; Dumas, G.; Lutz, A.; Friston, K.; Constant, A.

This paper presents a version of neurophenomenology based on generative modelling techniques developed in computational neuroscience and biology. Our approach can be described as computational phenomenology because it applies methods originally developed in computational modelling to provide a formal model of the descriptions of lived experience in the phenomenological tradition of philosophy (e.g., the work of Edmund Husserl, Maurice Merleau-Ponty, etc.). The first section presents a brief review of the overall project to naturalize phenomenology. The second section presents and evaluates philosophical objections to that project and situates our version of computational phenomenology with respect to these projects. The third section reviews the generative modelling framework. The final section presents our approach in detail. We conclude by discussing how our approach differs from previous attempts to use generative modelling to help understand consciousness. In summary, we describe a version of computational phenomenology which uses generative modelling to construct a computational model of the inferential or interpretive processes that best explain this or that kind of lived experience.

2021 - Bayesian Joint Modeling of Multiple Brain Functional Networks [Articolo su rivista]
Lukemire, J.; Kundu, S.; Pagnoni, G.; Guo, Y.

Investigating the similarity and changes in brain networks under different mental conditions has become increasingly important in neuroscience research. A standard separate estimation strategy fails to pool information across networks and hence has reduced estimation accuracy and power to detect between-network differences. Motivated by an fMRI Stroop task experiment that involves multiple related tasks, we develop an integrative Bayesian approach for jointly modeling multiple brain networks that provides a systematic inferential framework for network comparisons. The proposed approach explicitly models shared and differential patterns via flexible Dirichlet process-based priors on edge probabilities. Conditional on edges, the connection strengths are modeled via Bayesian spike-and-slab prior on the precision matrix off-diagonals. Numerical simulations illustrate that the proposed approach has increased power to detect true differential edges while providing adequate control on false positives and achieves greater network estimation accuracy compared to existing methods. The Stroop task data analysis reveals greater connectivity differences between task and fixation that are concentrated in brain regions previously identified as differentially activated in Stroop task, and more nuanced connectivity differences between exertion and relaxed task. In contrast, penalized modeling approaches involving computationally burdensome permutation tests reveal negligible network differences between conditions that seem biologically implausible. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

2021 - Modeling Early Phases of COVID-19 Pandemic in Northern Italy and Its Implication for Outbreak Diffusion [Articolo su rivista]
Gandolfi, Daniela; Pagnoni, Giuseppe; Filippini, Tommaso; Goffi, Alessia; Vinceti, Marco; D'Angelo, Egidio; Mapelli, Jonathan

The COVID-19 pandemic has sparked an intense debate about the hidden factors underlying the dynamics of the outbreak. Several computational models have been proposed to inform effective social and healthcare strategies. Crucially, the predictive validity of these models often depends upon incorporating behavioral and social responses to infection. Among these tools, the analytic framework known as “dynamic causal modeling” (DCM) has been applied to the COVID-19 pandemic, shedding new light on the factors underlying the dynamics of the outbreak. We have applied DCM to data from northern Italian regions, the first areas in Europe to contend with the outbreak, and analyzed the predictive validity of the model and also its suitability in highlighting the hidden factors governing the pandemic diffusion. By taking into account data from the beginning of the pandemic, the model could faithfully predict the dynamics of outbreak diffusion varying from region to region. The DCM appears to be a reliable tool to investigate the mechanisms governing the spread of the SARS-CoV-2 to identify the containment and control strategies that could efficiently be used to counteract further waves of infection.

2021 - The Impact of Mindfulness Meditation on the Wandering Mind: a Systematic Review [Articolo su rivista]
Feruglio, S.; Matiz, A.; Pagnoni, G.; Fabbro, F.; Crescentini, C.

Through the practice of Mindfulness Meditation (MM), meditators become familiar with the observation of ongoing spontaneous thoughts, while maintaining an attitude of openness and equanimity. The aim of this systematic review is to present a synthesis of available findings of the short and long-term effects of MM on mind wandering (MW). We included studies that considered both first-person and behavioral/physiological measures of MW. The search resulted in 2035 papers, 24 of which were eligible. Reviewed studies revealed a high heterogeneity in designs, outcome measures and interventions. Most of the pre-post intervention studies showed that a protracted practice of MM (at least 2 weeks) reduced MW, limiting its negative effects on different cognitive tasks. Cross-sectional studies highlighted differences between expert meditators and naïve individuals: meditators self-reported less MW and showed decreased Default Mode Network activity, during meditation and resting-state. Further studies are needed to replicate available findings and to more deeply explore how MW is influenced by meditation, also considering its qualitative characteristics that remain largely unexplored.

2020 - Reward-related brain activity and behavior are associated with peripheral ghrelin levels in obesity [Articolo su rivista]
Bogdanov, V. B.; Bogdanova, O. V.; Dexpert, S.; Delgado, I.; Beyer, H.; Aubert, A.; Dilharreguy, B.; Beau, C.; Forestier, D.; Ledaguenel, P.; Magne, E.; Aouizerate, B.; Laye, S.; Ferreira, G.; Felger, J.; Pagnoni, G.; Capuron, L.

Background/objectives: While excessive food consumption represents a key factor in the development of obesity, the underlying mechanisms are still unclear. Ghrelin, a gut-brain hormone involved in the regulation of appetite, is impaired in obesity. In addition to its role in eating behavior, this hormone was shown to affect brain regions controlling reward, including the striatum and prefrontal cortex, and there is strong evidence of impaired reward processing in obesity. The present study investigated the possibility that disrupted reward-related brain activity in obesity relates to ghrelin deficiency. Subjects/methods: Fifteen severely obese subjects (BMI > 35 kg/m2) and fifteen healthy non-obese control subjects (BMI < 30 kg/m2) were recruited. A guessing-task paradigm, previously shown to activate the ventral striatum, was used to assess reward-related brain neural activity by functional magnetic resonance imaging (fMRI). Fasting blood samples were collected for the measurement of circulating ghrelin. Results: Significant activations in the ventral striatum, ventromedial prefrontal cortex and extrastriate visual cortex were elicited by the fMRI task in both obese and control subjects. In addition, greater reward-related activations were present in the dorsolateral prefrontal cortex, and precuneus/posterior cingulate of obese subjects compared to controls. Obese subjects exhibited longer choice times after repeated reward and lower circulating ghrelin levels than lean controls. Reduced ghrelin levels significantly predicted slower post-reward choices and reward-related hyperactivity in dorsolateral prefrontal cortices in obese subjects. Conclusion: This study provides evidence of association between circulating ghrelin and reward-related brain activity in obesity and encourages further exploration of the role of ghrelin system in altered eating behavior in obesity.

2019 - Short-term mindfulness practice attenuates reward prediction errors signals in the brain [Articolo su rivista]
Kirk, U.; Pagnoni, G.; Hetu, S.; Montague, R.

Activity changes in dopaminergic neurons encode the ongoing discrepancy between expected and actual value of a stimulus, providing a teaching signal for a reward prediction process. Previous work comparing a cohort of long-term Zen meditators to controls demonstrated an attenuation of reward prediction signals to appetitive reward in the striatum. Using a cross-commodity design encompassing primary- and secondary-reward conditioning experiments, the present study asks the question of whether reward prediction signals are causally altered by mindfulness training in naive subjects. Volunteers were randomly assigned to 8 weeks of mindfulness training (MT), active control training (CT), or a one-time mindfulness induction group (MI). We observed a decreased response to positive prediction errors in the putamen in the MT group compared to CT using both a primary and a secondary-reward experiment. Furthermore, the posterior insula showed greater activation to primary rewards, independently of their predictability, in the MT group, relative to CT and MI group. These results support the notion that increased attention to the present moment and its interoceptive features - a core component of mindfulness practice - may reduce predictability effects in reward processing, without dampening (in fact, enhancing) the response to the actual delivery of the stimulus.

2019 - The contemplative exercise through the lenses of predictive processing: A promising approach [Capitolo/Saggio]
Pagnoni, Giuseppe

The theory of predictive processing in the comprehensive articulation proposed by Karl Friston is a framework that boasts an impressively wide explanatory power in neurobiology, where processes apparently as diverse as perception, action, attention, and learning unfold, and are coherently orchestrated, according to the single general mandate of free-energy minimization. In the present opinion piece, I argue that the adoption of this theoretical perspective can provide a much needed unitary framework for contemplative research as well, whose explosive growth in terms of the number of published studies and amount of collected data has not been matched yet by a similarly extensive effort to theoretically organize the findings, so that a deeper understanding of meditation-related processes can be attained. After an introduction to the basic notions of predictive processing, a tentative application of the latter to the meditative exercise is discussed, taking as a paradigmatic example the Japanese Zen meditation practice of shikantaza. Finally, I provide a short list of experimental paradigms that seem particularly useful to test the hypotheses born out of the predictive processing approach to contemplative research.

2019 - The epistemic and pragmatic value of non-action: a predictive coding perspective on meditation [Articolo su rivista]
Lutz, Antoine; Mattout, Jérémie; Pagnoni, Giuseppe

The surge of interest about mindfulness meditation is associated with a growing empirical evidence about its impact on the mind and body. Yet, despite promising phenomenological or psychological models of mindfulness, a general mechanistic understanding of meditation steeped in neuroscience is still lacking. In parallel, predictive processing approaches to the mind are rapidly developing in the cognitive sciences with an impressive explanatory power: processes apparently as diverse as perception, action, attention, and learning, can be seen as unfolding and being coherently orchestrated according to the single general mandate of free-energy minimization. Here, we briefly explore the possibility to supplement previous phenomenological models of focused attention meditation by formulating them in terms of active inference. We first argue that this perspective can account for how paying voluntary attention to the body in meditation helps settling the mind by downweighting habitual and automatic trajectories of (pre)motor and autonomic reactions, as well as the pull of distracting spontaneous thought at the same time. Secondly, we discuss a possible relationship between phenomenological notions such as opacity and de-reification, and the deployment of precision-weighting via the voluntary allocation of attention. We propose the adoption of this theoretical framework as a promising strategy for contemplative research. Explicit computational simulations and comparisons with experimental and phenomenological data will be critical to fully develop this approach.

2018 - Pain mirrors: Neural correlates of observing self or others' facial expressions of pain [Articolo su rivista]
Benuzzi, Francesca; Lui, Fausta; Ardizzi, Martina; Ambrosecchia, Marianna; Ballotta, Daniela; Righi, Sara; Pagnoni, Giuseppe; Gallese, Vittorio; Porro, Carlo Adolfo

Facial expressions of pain are able to elicit empathy and adaptive behavioral responses in the observer. An influential theory posits that empathy relies on an affective mirror mechanism, according to which emotion recognition relies upon the internal simulation of motor and interoceptive states triggered by emotional stimuli. We tested this hypothesis comparing representations of self or others' expressions of pain in nineteen young healthy female volunteers by means of functional magnetic resonance imaging (fMRI). We hypothesized that one's own facial expressions are more likely to elicit the internal simulation of emotions, being more strictly related to self. Video-clips of the facial expressions of each volunteer receiving either painful or non-painful mechanical stimulations to their right hand dorsum were recorded and used as stimuli in a 2 × 2 (Self/Other; Pain/No-Pain) within-subject design. During each trial, a 2 s video clip was presented, displaying either the subject's own neutral or painful facial expressions (Self No-Pain, SNP; Self Pain, SP), or the expressions of other unfamiliar volunteers (Others' No-Pain, ONP; Others' Pain, OP), displaying a comparable emotional intensity. Participants were asked to indicate whether each video displayed a pain expression. fMRI signals were higher while viewing Pain than No-Pain stimuli in a large bilateral array of cortical areas including middle and superior temporal, supramarginal, superior mesial and inferior frontal (IFG) gyri, anterior insula (AI), anterior cingulate (ACC), and anterior mid-cingulate (aMCC) cortex, as well as right fusiform gyrus. Bilateral activations were also detected in thalamus and basal ganglia. The Self vs. Other contrast showed signal changes in ACC and aMCC, IFG, AI, and parietal cortex. A significant interaction between Self and Pain [(SP vs. SNP) > (OP vs. ONP)] was found in a pre-defined region of aMCC known to be also active during noxious stimulation. These findings demonstrate that the observation of one's own and others' facial expressions share a largely common neural network, but self-related stimuli induce generally higher activations. In line with our hypothesis, selectively greater activity for self pain-related stimuli was found in aMCC, a medial-wall region critical for pain perception and recognition.

2017 - Remembrance of things to come: a conversation between Zen and neuroscience on the predictive nature of the mind [Articolo su rivista]
Pagnoni, Giuseppe; Guareschi, Fausto Taiten

The notion of the brain as a predictive organ following Bayesian principles has been steadily gaining favor in neuroscience. This perspective, which has broad theoretical and applicative consequences, suggests also a novel way to look at the mind-body processes mobilized by meditative practices. In this article, the topic is introduced and subsequently explored as a conversation between a neuroscientist (GP) and the abbot of a Zen Sōtō monastery (FTG). We believe that such ‘mutual perturbations’ between the third-person descriptions provided by scientific research and the phenomenological depth of Buddhist lore have a great potential for advancing our understanding of both brain function and meditation.

2017 - Voluntary modulation of mental effort investment: An fMRI study [Articolo su rivista]
Khachouf, Omar T.; Chen, Gang; Duzzi, Davide; Porro, Carlo A.; Pagnoni, Giuseppe

Mental effort is a common phenomenological construct deeply linked to volition and self-control. While it is often assumed that the amount of exertion invested in a task can be voluntarily regulated, the neural bases of such faculty and its behavioural effects are yet insufficiently understood. In this study, we investigated how the instructions to execute a demanding cognitive task either "with maximum exertion" or "as relaxed as possible" affected performance and brain activity. The maximum exertion condition, compared to relaxed execution, was associated with speeded motor responses without an accuracy trade-off, and an amplification of both task-related activations in dorsal frontoparietal and cerebellar regions, and task-related deactivations in default mode network (DMN) areas. Furthermore, the visual cue to engage maximum effort triggered an anticipatory widespread increase of activity in attentional, sensory and executive regions, with its peak in the brain stem reticular activating system. Across individuals, this surge of activity in the brain stem, but also in medial wall cortical regions projecting to the adrenal medulla, positively correlated with increases in heart rate, suggesting that the intention to willfully modulate invested effort involves mechanisms related to catecholaminergic transmission and a suppression of DMN activity in favor of externally-directed attentional processes.

2016 - Effects of oxytocin and vasopressin on the neural response to unreciprocated cooperation within brain regions involved in stress and anxiety in men and women [Articolo su rivista]
Chen, Xu; Hackett, Patrick D.; Demarco, Ashley C.; Feng, Chunliang; Stair, Sabrina; Haroon, Ebrahim; Ditzen, Beate; Pagnoni, Giuseppe; Rilling, James K.

Anxiety disorders are characterized by hyperactivity in both the amygdala and the anterior insula. Interventions that normalize activity in these areas may therefore be effective in treating anxiety disorders. Recently, there has been significant interest in the potential use of oxytocin (OT), as well as vasopressin (AVP) antagonists, as treatments for anxiety disorders. In this double-blind, placebo-controlled, pharmaco- fMRI study, 153 men and 151 women were randomized to treatment with either 24 IU intranasal OT, 20 IU intranasal AVP, or placebo and imaged with fMRI as they played the iterated Prisoner’s Dilemma game with same-sex human and computer partners. In men, OT attenuated the fMRI response to unreciprocated cooperation (CD), a negative social interaction, within the amygdala and anterior insula. This effect was specific to interactions with human partners. In contrast, among women, OT unexpectedly attenuated the amygdala and anterior insula response to unreciprocated cooperation from computer but not human partners. Among women, AVP did not significantly modulate the response to unreciprocated cooperation in either the amygdala or the anterior insula. However, among men, AVP attenuated the BOLD response to CD outcomes with human partners across a relatively large cluster including the amygdala and the anterior insula, which was contrary to expectations. Our results suggest that OT may decrease the stress of negative social interactions among men, whereas these effects were not found in women interacting with human partners. These findings support continued investigation into the possible efficacy of OT as a treatment for anxiety disorders.

2015 - Network-based characterization of brain functional connectivity in Zen practitioners [Articolo su rivista]
Kemmer, Phebe B; Guo, Ying; Wang, Yikai; Pagnoni, Giuseppe

In the last decade, a number of neuroimaging studies have investigated the neurophysiological effects associated with contemplative practices. Meditation-related changes in resting state functional connectivity (rsFC) have been previously reported, particularly in the default mode network, frontoparietal attentional circuits, saliency-related regions, and primary sensory cortices. We collected functional magnetic resonance imaging data from a sample of 12 experienced Zen meditators and 12 meditation-naïve matched controls during a basic attention-to-breathing protocol, together with behavioral performance outside the scanner on a set of computerized neuropsychological tests. We adopted a network system of 209 nodes, classified into nine functional modules, and a multi-stage approach to identify rsFC differences in meditators and controls. Between-group comparisons of modulewise FC, summarized by the first principal component of the relevant set of edges, revealed important connections of frontoparietal circuits with early visual and executive control areas. We also identified several group differences in positive and negative edgewise FC, often involving the visual, or frontoparietal regions. Multivariate pattern analysis of modulewise FC, using support vector machine (SVM), classified meditators, and controls with 79% accuracy and selected 10 modulewise connections that were jointly prominent in distinguishing meditators and controls; a similar SVM procedure based on the subjects' scores on the neuropsychological battery yielded a slightly weaker accuracy (75%). Finally, we observed a good correlation between the across-subject variation in strength of modulewise connections among frontoparietal, executive, and visual circuits, on the one hand, and in the performance on a rapid visual information processing test of sustained attention, on the other. Taken together, these findings highlight the usefulness of employing network analysis techniques in investigating the neural correlates of contemplative practices.

2015 - Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans [Articolo su rivista]
Feng, Chunliang; Hackett, Patrick D; Demarco, Ashley C; Chen, Xu; Stair, Sabrina; Haroon, Ebrahim; Ditzen, Beate; Pagnoni, Giuseppe; Rilling, James K.

Recent research has examined the effects of oxytocin (OT) and vasopressin (AVP) on human social behavior and brain function. However, most participants have been male, while previous research in our lab demonstrated sexually differentiated effects of OT and AVP on the neural response to reciprocated cooperation. Here we extend our previous work by significantly increasing the number of participants to enable the use of more stringent statistical thresholds that permit more precise localization of OT and AVP effects in the brain. In a double-blind, placebo-controlled study, 153 men and 151 women were randomized to receive 24 IU intranasal OT, 20 IU intranasal AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner's Dilemma Game with same-sex partners. Sex differences were observed for effects of OT on the neural response to reciprocated cooperation, such that OT increased the caduate/putamen response among males, whereas it decreased this response among females. Thus, 24 IU OT may increase the reward or salience of positive social interactions among men, while decreasing their reward or salience among women. Similar sex differences were also observed for AVP effects within bilateral insula and right supramarginal gyrus when a more liberal statistical threshold was employed. While our findings support previous suggestions that exogenous nonapeptides may be effective treatments for disorders such as depression and autism spectrum disorder, they caution against uniformly extending such treatments to men and women alike.

2014 - Cognitive modulation of pain and predictive coding. Comment on "Facing the experience of pain: a neuropsychological perspective" by Fabbro and Crescentini [Articolo su rivista]
Pagnoni, Giuseppe; Porro, Carlo Adolfo

A commentary on the article “Facing the experience of pain: A neuropsychological perspective” by Fabbro and Crescentini, where the potential usefulness of adopting a predictive coding approach to understand pain perception is outlined.

2014 - Decreased basal ganglia activation in subjects with chronic fatigue syndrome: association with symptoms of fatigue [Articolo su rivista]
Miller, Andrew H; Jones, James F; Drake, Daniel F; Tian, Hao; Unger, Elizabeth R; Pagnoni, Giuseppe

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation. In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses. Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

2014 - Ranking brain areas encoding the perceived level of pain from fMRI data [Articolo su rivista]
S., Favilla; A., Huber; Pagnoni, Giuseppe; Lui, Fausta; P., Facchina; Cocchi, Marina; Baraldi, Patrizia; Porro, Carlo Adolfo

Pain perception is thought to emerge from the integrated activity of a distributed brain system, but the relative contribution of the different network nodes is still incompletely understood. In the present functional magnetic resonance imaging (fMRI) study,we aimed to identify themore relevant brain regions to explain the time profile of the perceived pain intensity in healthy volunteers, during noxious chemical stimulation (ascorbic acid injection) of the left hand. To this end, we performed multi-way partial least squares regression of fMRI data from twenty-two a-priori defined brain regions of interest (ROI) in each hemisphere, to build a model that could efficiently reproduce the psychophysical pain profiles in the same individuals; moreover, we applied a novel three-way extension of the variable importance in projection (VIP) method to summarize each ROI contribution to the model. Brain regions showing the highest VIP scores included the bilateral mid-cingulate, anterior and posterior insular, and parietal operculum cortices, the contralateral paracentral lobule, bilateral putamen and ipsilateral medial thalamus.Most of these regions, with the exception of medial thalamus,were also identified by a statistical analysis on mean ROI beta values estimated using the time course of the psychophysical rating as a regressor at the voxel level. Our results provide the first rank-ordering of brain regions involved in coding the perceived level of pain. These findings in amodel of acute prolonged pain confirm and extend previous data, suggesting that a bilateral array of cortical areas and subcortical structures is involved in pain perception

2014 - Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction [Articolo su rivista]
James K., Rilling; Ashley C., Demarco; Patrick D., Hackett; Xu, Chen; Pritam, Gautam; Sabrina, Stair; Ebrahim, Haroon; Richmond, Thompson; Beate, Ditzen; Rajan, Patel; Pagnoni, Giuseppe

Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses of males more similar to responses of females in the placebo group and vice versa, raising the prospect of an inverted u-shaped dose response to central OT levels. These findings emphasize the need to fully characterize the effects of intranasal OT and AVP in both males and females and at multiple doses before widespread clinical application will be warranted.

2014 - Spatial extent of pain influences gray matter volume in fibromyalgia patients. [Poster]
Huber, Alexa; Lui, Fausta; Duzzi, Davide; Pagnoni, Giuseppe; Santarcangelo, E. L.; Carli, G.; Porro, Carlo Adolfo

Aim of Investigation: Fibromyalgia (FS) is a syndrome characterised by chronic widespread pain, whose pathophysiology is still controversial. Previous studies assessing alterations in local gray matter volume (GMV) in FS have obtained somewhat inconsistent results, possibly due to differences in clinical features. Our aim was to assess GMV changes in FS compared to a control group, and their correlations with the severity of clinical aspects, including illness duration, pain intensity and quality, body pain area, number of positive tender points and depression. Methods: Thirty-four women with FS diagnosed by a rheumatologist and 38 healthy women (controls, C) without chronic pain matched for age (FS: range 18-55 ys, mean 44; C: 25-60 ys, mean 45.6), menopausal status, educational level, handedness and caffeine consumption, participated in the study. The control subjects had experienced no pain (N=9) or episodic/recurrent pain without (N=20) or with use of pain killers (N=9) over the past year. Depressive symptoms were assessed using the Center for Epidemiology Studies-Depression Scale (CES-D); the sensory (S), affective (A) and evaluative (E) quality of spontaneous pain were tested using the Italian adaptation of the McGill Pain Questionnaire (Questionario Italiano del Dolore - QUID). Spatial extent of pain was assessed using Margolis body pain area drawings. Pressure pain thresholds were measured by means of an algometer applied to the 18 defining tender points and to 10 additional points to obtain a detailed picture of spatial distribution of allodynia. A high-resolution structural T1-weighted brain scan (360 sagittal slices without gap; isotropic voxel size 0.5mm; FOV 240 x 240 x 180mm; TR 35ms; flip angle 50; TE 5.7ms) was acquired for each subject, using a 3T Philips Achieva MR scanner. GMV was assessed applying voxel-based morphometry Oasis, The Online Abstract Submission System 1 of 3 03/07/2014 01:46 PM International Association for the Study of Pain 1510 H Street NW, Suite 600 Washington, DC 20005-1020 USA Phone: +1-202-524-5300 (VBM) to modulated data in SPM8 using the VBM8 toolbox (voxel-wise critical p < 0.005; cluster size corrected for multiple comparisons using AlphaSim with 10,000 Monte Carlo simulations). Results: Patients showed no significant differences in GMV compared to the total control group. In the patient sample, GMV was negatively correlated with QUID-E score in BA 6 and with the spatial extent of spontaneous pain in the bilateral parahippocampal gyrus (pHG), and it was positively correlated with illness duration in the cerebellum. GMV was independent of pain intensity, tender point count, CES-D, QUID-S and QUID-A score. Reported pain extent ranged from 9-90% of body surface (mean/median: 48%). Patients with below-median pain extent had greater GMV than patients with above-median values in the bilateral pHG and cerebellum, left paracentral lobule (BA 6) and cingulate gyrus (BA 31). GMV values of the controls in these brain areas were intermediate between the two patient groups. Spatial extent of pain was positively correlated with tender point count and with QUID-S and was independent of all other clinical and nuisance variables included in the study. Conclusions: Some, but not all, previous VBM studies have reported reduced GMV in the pHG and in the cingulate cortex in FS (Wood, 2010). Our results point to a possible explanation for these inconsistent findings: depending on how widespread their pain, FS patients may show either reduced or increased GMV in the pHG and cingulate cortex, i.e. they are more different from each other than from the control group. Further research is needed to explore the possible causes of these inter-individual differences within the FS population. Reference: Wood PB. Variations in brain gray matter associated with chronic pain. Curr Rheumatol Rep 2010;12:462-469.

2014 - Structural and functional cerebral correlates of hypnotic suggestibility [Articolo su rivista]
Huber, Alexa; Lui, Fausta; Duzzi, Davide; Pagnoni, Giuseppe; Porro, Carlo Adolfo

Little is known about the neural bases of hypnotic suggestibility, a cognitive trait referring to the tendency to respond to hypnotic suggestions. In the present magnetic resonance imaging study, we performed regression analyses to assess hypnotic suggestibility-related differences in local gray matter volume, using voxel-based morphometry, and in waking resting state functional connectivity of 10 resting state networks, in 37 healthy women. Hypnotic suggestibility was positively correlated with gray matter volume in portions of the left superior and medial frontal gyri, roughly overlapping with the supplementary and pre-supplementary motor area, and negatively correlated with gray matter volume in the left superior temporal gyrus and insula. In the functional connectivity analysis, hypnotic suggestibility was positively correlated with functional connectivity between medial posterior areas, including bilateral posterior cingulate cortex and precuneus, and both the lateral visual network and the left fronto-parietal network; a positive correlation was also found with functional connectivity between the executive-control network and a right postcentral/parietal area. In contrast, hypnotic suggestibility was negatively correlated with functional connectivity between the right fronto-parietal network and the right lateral thalamus. These findings demonstrate for the first time a correlation between hypnotic suggestibility, the structural features of specific cortical regions, and the functional connectivity during the normal resting state of brain structures involved in imagery and self-monitoring activity.

2013 - Human Parietofrontal Networks Related to Action Observation Detected at Rest [Articolo su rivista]
E., Molinari; Baraldi, Patrizia; M., Campanella; Duzzi, Davide; L., Nocetti; Pagnoni, Giuseppe; Porro, Carlo Adolfo

Recent data show a broad correspondence between human resting state and task-related brain networks. We performed a functional magnetic resonance imaging (fMRI) study to compare, in the same subjects, the spatial independent component analysis (ICA) maps obtained at rest and during the observation of either reaching/grasping hand actions or matching static pictures. Two parietofrontal networks were identified by ICA from action observation task data. One network, specific to reaching/grasping observation, included portions of the anterior intraparietal cortex and of the dorsal and ventral lateral premotor cortices. A second network included more posterior portions of the parietal lobe, the dorsomedial frontal cortex, and more anterior and ventral parts,respectively, of the dorsal and ventral premotor cortices, extending toward Broca’s area; this network was more generally related to the observation of hand action and static pictures. A good spatial correspondence was found between the 2 observation-related ICA maps and 2 ICA maps identified from resting-state data. The anatomical connectivity among the identified clusters was tested in the same volunteers, using persistent angular structure--MRI and deterministic tractography. These findings extend available knowledge of human parietofrontal circuits and further support the hypothesis of a persistent coherence within functionally relevant networks during rest.

2013 - Hypnotic susceptibility explains differences in resting state functional connectivity [Poster]
Huber, Alexa; Lui, Fausta; Pagnoni, Giuseppe; Duzzi, Davide; Summers, Paul Eugene; Porro, Carlo Adolfo

Introduction: Hypnotic susceptibility (HS) is a measurable cognitive trait defined as the generalized tendency to respond to hypnotic suggestions [1]. Very little is known about the neural bases of HS [2]. Our aim was to assess HS-related differences in resting state func tional c onnec tivity. Methods: N=35 healthy women (3 ambidextrous, 4 left-handed; age range 19-56 yrs, mean 36.9 yrs) partic ipated in the study. HS was assessed with the Stanford Hypnotic Susc eptibility Sc ale – Form A (SHSS:A), mental absorption with the T ellegen Absorption Sc ale (T AS) and trait anxiety with the State-T rait Anxiety Inventory Form Y (ST AI-Y2). Subjec ts were not in any way pre-selec ted for SHSS sc ore. T o measure spontaneous BOLD signal fluc tuations at rest, two runs of EPI sc ans were ac quired while subjec ts lay in the sc anner relaxed with eyes c losed (for eac h run: 200 volumes; T R 2 s; isometric voxel size 3.6 mm; 35 axial slic es without gap; matrix 80 x 63 voxels; FOV 286 x 229 mm; ac quisition time 7 min), using a 3T Philips Ac hieva MR sc anner. A T 1-weighted brain image (isotropic voxel size 0.5 mm) was ac quired for inter-subjec t alignment. EPI data were analysed using AFNI. Preproc essing inc luded the removal of physiologic al, white matter and hardware related noise using RET ROICOR and ANAT ICOR proc edures, lowpass filtering to remove frequenc ies >0.1 Hz, and 6-mm FWHM spatial smoothing. Seed-based func tional c onnec tivity (FC) was quantified as the z-transformed Pearson c orrelation with the seed signal (average BOLD signal within a sphere of 6mm radius). Seeds were plac ed (a) within key regions of the Default Mode Network (DMN) taken from the literature; (b) in the two areas (anterior c ingulate c ortex – ACC; dorsolateral prefrontal c ortex – DLPFC) desc ribed in Hoeft et al. [2]; and (c ) in 15 seeds ad-hoc plac ed along the c ingulate c ortex in eac h hemisphere. HS-related differenc es in FC were assessed by using SHSS sc ore as a between-subjec ts linear regressor to explain FC z-sc ores. Furthermore, some of the c lusters whic h resulted signific antly c onnec ted with the above mentioned seeds, e.g. orbitofrontal c ortex (OFC), were, in turn, used as seeds (d). Results: SHSS sc ores ranged from 0-10 (mean 3.6). Eighteen subjec ts had low (SHSS<4), 14 medium (SHSS=4-7) and 3 high SHSS sc ores (SHSS>7). SHSS was independent of age, educ ational level, handedness, trait anxiety and mental absorption. SHSS was positively c orrelated with FC (a) of DMN seeds, i.e., the right medial PFC, left posterior c ingulate c ortex (PCC) and left posterior insula with c erebellar foc i, and (b) of Hoeft et al.'s [2] ACC seed with c erebellar regions, and of right DLPFC with left OFC. When foc using on the c ingulate c ortex (c ), SHSS was positively c orrelated with FC of ACC with mid-c ingulate c ortex (MCC), of various seeds in the ACC and MCC with c erebellar foc i, and of MCC with bilateral OFC. SHSS was also positively c orrelated with FC of the OFC foc i (d) with a wide network of regions, inc luding MCC, bilateral DLPFC (see Fig. 1), pre- and postcentral gyri, superior temporal gyri and insula as well as cerebellum and contralateral precuneus (Fig. 2). Conclusions:Among healthy women, individuals with higher HS show higher resting state FC between OFC, DLPFC, cingulate cortex and cerebellum. Further researc h is needed to c onfirm these relationships in men, and to assess their cognitive correlates.

2013 - The Neurobiology of Imagination: Possible Role of Interaction-Dominant Dynamics and Default Mode Network [Articolo su rivista]
Agnati, Luigi Francesco; Diego, Guidolin; L., Battistin; Pagnoni, Giuseppe; K., Fuxe

This work aims at presenting some hypotheses about the potential neurobiological substrate of imagery and imagination. For the present purposes, we will define imagery as the production of mental images associated with previous percepts, and imagination as the faculty of forming mental images of a novel character relating to something that has never been actually experienced by the subject but at a great extent emerges from his inner world. The two processes appear intimately related and imagery can arguably be considered as one of the main components of imagination. In this proposal, we argue that exaptation and redeployment, two basic concepts capturing important aspects of the evolution of biological structures and functions (Anderson, 2007), could also be useful in explaining imagery and imagination. As far as imagery is concerned it is proposed that neural structures originally implicated in performing certain functions, e.g., motor actions, can be reused for the imagery of the virtual execution of that function. As far as imagination is concerned we speculate that it can be the result of a "tinkering" that combines and modifies stored perceptual information and concepts leading to the creation of novel "mental objects" that are shaped by the subject peculiar inner world. Hence it is related to his self-awareness. The neurobiological substrate of the tinkering process could be found in a hierarchical model of the brain characterized by a multiplicity of functional modules (FMs) that can be assembled according to different spatial and temporal scales. Thus, it is surmised that a possible mechanism for the emergence of imagination could be represented by modulatory mechanisms controlling the perviousness of "modifiers" along the communication channels within and between FMs leading to their dynamically reassembling into novel configurations.

2013 - The embodied transcendental: a Kantian perspective on neurophenomenology [Articolo su rivista]
Omar T., Khachouf; Stefano, Poletti; Pagnoni, Giuseppe

Neurophenomenology is a research programme aimed at bridging the explanatory gap between first-person subjective experience and neurophysiological third-person data, through an embodied and enactive approach to the biology of consciousness. The present proposal attempts to further characterize the bodily basis of the mind by adopting a naturalistic view of the phenomenological concept of intentionality as the a priori invariant character of any lived experience. Building on the Kantian definition of transcendentality as "what concerns the a priori formal structures of the subject's mind" and as a precondition for the very possibility of human knowledge, we will suggest that this transcendental core may in fact be rooted in biology and can be examined within an extension of the theory of autopoiesis. The argument will be first clarified by examining its application to previously proposed elementary autopoietic models, to the bacterium, and to the immune system; it will be then further substantiated and illustrated by examining the mirror-neuron system and the default mode network as biological instances exemplifying the enactive nature of knowledge, and by discussing the phenomenological aspects of selected neurological conditions (neglect, schizophrenia). In this context, the free-energy principle proposed recently by Karl Friston will be briefly introduced as a rigorous, neurally-plausible framework that seems to accomodate optimally these ideas. While our approach is biologically-inspired, we will maintain that lived first-person experience is still critical for a better understanding of brain function, based on our argument that the former and the latter share the same transcendental structure. Finally, the role that disciplined contemplative practices can play to this aim, and an interpretation of the cognitive processes taking place during meditation under this perspective, will be also discussed.

2012 - Altered resting-state effective connectivity of fronto-parietal motor control systems on the primary motor network following stroke [Articolo su rivista]
C. S., Inman; G. A., James; S., Hamann; J. K., Rajendra; Pagnoni, Giuseppe; A. J., Butler

Previous brain imaging work suggests that stroke alters the effective connectivity (the influence neural regions exert upon each other) of motor execution networks. The present study examines the intrinsic effective connectivity of top-down motor control in stroke survivors (n = 13) relative to healthy participants (n = 12). Stroke survivors exhibited significant deficits in motor function, as assessed by the Fugl-Meyer Motor Assessment. We used structural equation modeling (SEM) of resting-state fMRI data to investigate the relationship between motor deficits and the intrinsic effective connectivity between brain regions involved in motor control and motor execution. An exploratory adaptation of SEM determined the optimal model of motor execution effective connectivity in healthy participants, and confirmatory SEM assessed stroke survivors' fit to that model. We observed alterations in spontaneous resting-state effective connectivity from fronto-parietal guidance systems to the motor network in stroke survivors. More specifically, diminished connectivity was found in connections from the superior parietal cortex to primary motor cortex and supplementary motor cortex. Furthermore, the paths demonstrated large individual variance in stroke survivors but less variance in healthy participants. These findings suggest that characterizing the deficits in resting-state connectivity of top-down processes in stroke survivors may help optimize cognitive and physical rehabilitation therapies by individually targeting specific neural pathway.

2012 - Brain Activation in Primary Motor and Somatosensory Cortices during Motor Imagery Correlates with Motor Imagery Ability in Stroke Patients [Articolo su rivista]
Linda, Confalonieri; Pagnoni, Giuseppe; Lawrence W., Barsalou; Justin, Rajendra; Simon B., Eickhoff; Andrew J., Butler

Aims. While studies on healthy subjects have shown a partial overlap between the motor execution and motor imagery neural circuits, few have investigated brain activity during motor imagery in stroke patients with hemiparesis. This work is aimed at examining similarities between motor imagery and execution in a group of stroke patients. Materials and Methods. Eleven patients were asked to perform a visuomotor tracking task by either physically or mentally tracking a sine wave force target using their thumb and index finger during fMRI scanning. MIQ-RS questionnaire has been administered. Results and Conclusion. Whole-brain analyses confirmed shared neural substrates between motor imagery and motor execution in bilateral premotor cortex, SMA, and in the contralesional inferior parietal lobule. Additional region of interest-based analyses revealed a negative correlation between kinaesthetic imagery ability and percentage BOLD change in areas 4p and 3a; higher imagery ability was associated with negative and lower percentage BOLD change in primary sensorimotor areas during motor imagery.

2012 - Changes in heart rate variability of depressed patients after electroconvulsive therapy [Articolo su rivista]
E. B., Royster; L. M., Trimble; G., Cotsonis; B., Schmotzer; A., Manatunga; N. N., Rushing; Pagnoni, Giuseppe; S. F., Auyeung; A. R., Brown; J., Schoenbeck; S., Murthy; W. M., Mcdonald; D. L., Musselman

Objective. As few, small studies have examined the impact of electroconvulsive therapy (ECT) upon the heart rate variability of patients with major depressive disorder (MDD), we sought to confirm whether ECT-associated improvement in depressive symptoms would be associated with increases in HRV linear and nonlinear parameters. Methods. After providing consent, depressed study participants (n = 21) completed the Beck Depression Index (BDI), and 15-minute Holter monitor recordings, prior to their 1st and 6th ECT treatments. Holter recordings were analyzed for certain HRV indices: root mean square of successive differences (RMSSD), low-frequency component (LF)/high-frequency component (HF) and short-(SD1) versus long-term (SD2) HRV ratios. Results. There were no significant differences in the HRV indices of RMSDD, LF/HF, and SD1/SD2 between the patients who responded, and those who did not, to ECT. Conclusion. In the short term, there appear to be no significant improvement in HRV in ECT-treated patients whose depressive symptoms respond versus those who do not. Future studies will reveal whether diminished depressive symptoms with ECT are reliably associated with improved sympathetic/parasympathetic balance over the long-term, and whether acute changes in sympathetic/parasympathetic balance predict improved mental- and cardiac-related outcomes.

2012 - Dopaminergic Mechanisms of Reduced Basal Ganglia Responses to Hedonic Reward during Interferon-alpha Administration [Articolo su rivista]
L., Capuron; Pagnoni, Giuseppe; D. F., Drake; B. J., Woolwine; J. R., Spivey; R. J., Crowe; J. R., Votaw; M. M., Goodman; A. H., Miller

Context: Previous studies have shown that inflammatory cytokines or cytokine inducers can alter basal ganglia activity including reduced responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function.Objective: To determine whether chronic administration of the inflammatory cytokine interferon (IFN)-alpha reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior.Design: One cross-sectional and one longitudinal study.Setting: Outpatient research unit and neuroimaging facilities at Emory University.Participants: Medically stable, adult male and female patients with chronic hepatitis C virus (HCV) infection, eligible for IFN-alpha treatment.Main Outcome Measures: Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging (fMRI). Uptake and turnover of radiolabeled [18F]DOPA in caudate and putamen using positron emission tomography. IFN-alpha-induced depression, anhedonia, fatigue and neurotoxicity.Results: HCV patients receiving IFN-alpha for 4-6 weeks (n=14) exhibited significantly reduced bilateral activation of the ventral striatum in the win versus lose condition of a gambling task compared to HCV patients awaiting IFN-alpha treatment (n=14). Reduced activation of ventral striatum was in turn significantly correlated with anhedonia, depression and fatigue. In a separate longitudinal study, HCV patients treated with IFN-alpha for 4-6 weeks (n=12) exhibited significantly increased [18F]DOPA uptake and decreased [18F]DOPA turnover in caudate and putamen as well as in the same ventral striatal regions identified in the fMRI study. Baseline and percent change in [18F]DOPA uptake and turnover were correlated with behavioral alterations during IFN-alpha administration including depression, fatigue and neurotoxicity.Conclusions. These data replicate and extend findings that inflammatory stimuli including inflammatory cytokines such as IFN-alpha alter basal ganglia activity and reduce hedonic reward in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis and/or release.

2012 - Dynamical properties of BOLD activity from the ventral posteromedial cortex associated with meditation and attentional skills [Articolo su rivista]
Pagnoni, Giuseppe

Neuroimaging data suggest a link between the spontaneous production of thoughts during wakeful rest and slow fluctuations of activity in the default mode network (DMN), a set of brain regions with high basal metabolism and a major neural hub in the ventral posteromedial cortex (vPMC). Meta-awareness and regulation of mind-wandering are core cognitive components of most contemplative practices and to study their impact on DMN activity we collected functional MRI (fMRI) data from a cohort of experienced Zen meditators and meditation-naive controls engaging in a basic attention-to-breathing protocol. We observed a significant group difference in the skewness of the fMRI blood-oxygen level dependent (BOLD) signal from the vPMC, suggesting that the relative incidence of states of elevated vPMC activity was lower in meditators; furthermore, the same parameter was significantly correlated with performance on a rapid visual information processing (RVIP) test for sustained attentionconducted outside the scanner. Finally, a functional connectivity (fc) analysis with the vPMC seed revealed a significant association of RVIP performance and the degree of temporal correlation between vPMC and the right temporo-parietal junction (TPJ),a region strongly implicated in stimulus-triggered reorienting of attention. Taken together, these findings suggest that the vPMC BOLD signal skewness and the temporal relationship of vPMC and TPJ activities reflect the dynamic tension between mind-wandering, meta-awareness, and directed attention, and may represent a use-ful endophenotype for studying individual differences in attentional abilities and the impairment of the latter in specific clinical conditions.

2012 - Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men [Articolo su rivista]
J. K., Rilling; A. C., Demarco; P. D., Hackett; R., Thompson; B., Ditzen; R., Patel; Pagnoni, Giuseppe

The neural mechanisms supporting social bonds between adult men remain uncertain. In this double-blind, placebo-controlled study, we investigate the impact of intranasally administered oxytocin (OT) and vasopressin (AVP) on behavior and brain activity among men in the context of an iterated Prisoner's Dilemma game, which models a real-life social situation. fMRI results show that, relative to both AVP and placebo, OT increases the caudate nucleus response to reciprocated cooperation, which may augment the reward of reciprocated cooperation and/or facilitate learning that another person can be trusted. OT also enhances left amygdala activation in response to reciprocated cooperation. Behaviorally, OT was associated with increased rates of cooperation following unreciprocated cooperation in the previous round compared with AVP. AVP strongly increased cooperation in response to a cooperative gesture by the partner compared with both placebo and OT. In response to reciprocated cooperation, AVP increased activation in a region spanning known vasopressin circuitry implicated in affiliative behaviors in other species. Finally, both OT and AVP increase amygdala functional connectivity with the anterior insula relative to placebo, which may increase the amygdala's ability to elicit visceral somatic markers that guide decision making. These findings extend our knowledge of the neural and behavioral effects of OT and AVP to the context of genuine social interactions.

2011 - The posterior cingulate BOLD duty cycle during meditation predicts attentional skills [Poster]
Pagnoni, Giuseppe

Introduction: Recent findings about the human brain's wakeful resting state suggest a link between the spontaneous generation of task-unrelated thoughts (mind-wandering), and the slow fluctuations of activity in the 'default mode network' (DMN), a consistent set of brain regions with a major hub in the posterior cingulate cortex (PCC). Meta-awareness and regulation of mind-wandering are core cognitive components of many meditation practices, and to study their relationship to the DMN activity we collected fMRI data from a cohort of experienced Zen meditators and meditation-naive controls engaging in a simple meditative protocol, along with their performance on a computerized sustained attention task. By introducing a simple duty cycle measure for the fMRI BOLD signal from the PCC, we hypothesized that this could be taken as an endophenotype5 of the individual capacity to regulate mind-wandering and would thus correlate with performance in the sustained attention task. Methods: Subjects: 12 Zen meditators with > 3 years of daily practice and 12 control subjects, matched for age and education level. Meditative task: subjects were asked to maintain their attention on their breathing throughout the scan and gently redirect attention to breathing every time they found themselves distracted or mind-wandering. MRI acquisition: a single series of gradient-echo EPI volumes (200 scans, TR=2.35s, 35 3x3x3mm axial slices) and a T1-weighted hi-res volume (MPRAGE, 176 1x1x1 mm sagittal slices) were acquired on a 3.0 Tesla Siemens Magnetom Trio scanner. Imaging analysis: The EPI series were corrected for slice-timing and head motion, and warped to MNI space using the T1-weighted image to estimate the warping parameters. The time series were then band-pass filtered (0.01-0.1 Hz), along with least-square removal of the global signal and estimated motion parameters. The average processed BOLD time courses from a PCC region of interest (center-of-mass MNI coordinates: -6, -56, 22; size=82 voxels), identified by a previous study on the same subject sample using a conceptual processing task 6, were extracted and a duty cycle measure was computed as the ratio of the cumulative time that the signal lay above its temporal mean and the total scanning time. Sustained attention task: each subject completed the Rapid Visual Information Processing (RVIP) task from the CANTAB neuropsychological computerized battery 7. Performance was assessed in terms of reaction times (RT) and A-prime, a nonparametric sensitivity index ranging from 0 to 1 based on the number of hits and false alarms (1=perfect performance). Correlation analysis: Pearson's correlation tests were computed between individual scores in the RVIP task (RT and A-prime) and the PCC duty cycle values. Image processing and statistics were performed with the software packages AFNI, SPM5, and R. Results: We observed a significant correlation between the values of the PCC BOLD duty cycle during the meditative procedure and the individual scores in the RVIP task (A-prime: r=-0.64, p= 0.0007; RT: r=+0.58, p=0.003): subjects with a lower PCC duty cycle tended to respond faster and more accurately on the sustained attention task (see Figure). Conclusions: Although these findings need to be confirmed by a larger study, they support the notion that individual capacity for top-down attentional control and resistance to mind-wandering is inversely related to the relative abundance of high levels of activity of the central DMN node, the PCC, when such activity is mobilized by the processes of meta-awareness and regulation of spontaneous mentation that characterize the meditative exercise. The simple time-domain measure of the PCC BOLD activity proposed here, i.e. its duty cycle while subjects attempt to keep their attention on their breathing, appears as a promising candidate for an endophenotype of individual attentional skills.

2009 - Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression [Articolo su rivista]
Raison, Cl; Borisov, As; Majer, M; Drake, Df; Pagnoni, Giuseppe; Woolwine, Bj; Vogt, Gj; Massung, B; Miller, Ah

BACKGROUND: Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. METHODS: Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. RESULTS: Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r(2) = -.25, p < .05). CONCLUSIONS: These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.

2009 - Brain Imaging in Psychopharmacology [Capitolo/Saggio]
Haroon, E; Pagnoni, Giuseppe; Heim, C; Berns, Gs; Mayberg, H.

Its last edition hailed as “an essential volume for psychiatry residents as well as clinicians” (Journal of Psychiatric Practice), The American Psychiatric Publishing Textbook of Psychopharmacology is now updated to keep you abreast of the latest research and trends in the field. Covering both basic science and clinical practice, this new edition draws on the talents of 53 new contributors—with the total increased from 139 to 158—to guarantee fresh, authoritative perspectives on advances in psychiatric drug therapy.

2008 - "Thinking about non-thinking": neural correlates of conceptual processing during Zen meditation [Articolo su rivista]
Pagnoni, Giuseppe; Cekic, M; Guo, Y.

Recent neuroimaging studies have identified a set of brain regions that are metabolically active during wakeful rest and consistently deactivate in a variety of demanding tasks. This "default network" has been functionally linked to the stream of thoughts occurring automatically in the absence of goal-directed activity and which constitutes an aspect of mental behavior specifically addressed by many meditative practices. Zen meditation, in particular, is traditionally associated with a mental state of full awareness but reduced conceptual content, to be attained via a disciplined regulation of attention and bodily posture. Using fMRI and a simplified meditative condition interspersed with a lexical decision task, we investigated the neural correlates of conceptual processing during meditation in regular Zen practitioners and matched control subjects. While behavioral performance did not differ between groups, Zen practitioners displayed a reduced duration of the neural response linked to conceptual processing in regions of the default network, suggesting that meditative training may foster the ability to control the automatic cascade of semantic associations triggered by a stimulus and, by extension, to voluntarily regulate the flow of spontaneous mentation.

2008 - A unified framework for group independent component analysis for multi-subject fMRI data [Articolo su rivista]
Guo, Y; Pagnoni, Giuseppe

Independent component analysis (ICA) is becoming increasingly popular for analyzing functional magnetic resonance imaging (fMRI) data. While ICA has been successfully applied to single-subject analysis, the extension of ICA to group inferences is not straightforward and remains an active topic of research. Current group ICA models, such as the GIFT [Calhoun, V.D., Adali, T., Pearlson, G.D., Pekar, J.J., 2001. A method for making group inferences from functional MRI data using independent component analysis. Hum. Brain Mapp. 14, 140-151.] and tensor PICA [Beckmann, C.F., Smith, S.M., 2005. Tensorial extensions of independent component analysis for multisubject FMRI analysis. Neuroimage 25, 294-311.], make different assumptions about the underlying structure of the group spatio-temporal processes and are thus estimated using algorithms tailored for the assumed structure, potentially leading to diverging results. To our knowledge, there are currently no methods for assessing the validity of different model structures in real fMRI data and selecting the most appropriate one among various choices. In this paper, we propose a unified framework for estimating and comparing group ICA models with varying spatio-temporal structures. We consider a class of group ICA models that can accommodate different group structures and include existing models, such as the GIFT and tensor PICA, as special cases. We propose a maximum likelihood (ML) approach with a modified Expectation-Maximization (EM) algorithm for the estimation of the proposed class of models. Likelihood ratio tests (LRT) are presented to compare between different group ICA models. The LRT can be used to perform model comparison and selection, to assess the goodness-of-fit of a model in a particular data set, and to test group differences in the fMRI signal time courses between subject subgroups. Simulation studies are conducted to evaluate the performance of the proposed method under varying structures of group spatio-temporal processes. We illustrate our group ICA method using data from an fMRI study that investigates changes in neural processing associated with the regular practice of Zen meditation.

2008 - Effect of the menstrual cycle on resting brain glucose metabolism in female rhesus monkeys [Articolo su rivista]
Rilling, Jk; Lacreus, A; Barks, Sk; Elfenbein, Ha; Pagnoni, Giuseppe; Votaw, Jr; Herndon, Jg

Little is known about the effects of the menstrual cycle on brain activity in primates. Here, we use 18F-fluorodeoxyglucose positron emission tomography to monitor changes in resting brain glucose metabolism across the menstrual cycle in female rhesus monkeys. Results showed greater activity in right lateral orbitofrontal cortex, a region involved in processing negatively valenced emotional stimuli, in the follicular compared with luteal phase. Estradiol levels were negatively correlated with activity in cortical and brainstem regions involved in emotional processing, and positively correlated with activity in areas involved in cognitive control and emotion regulation. In summary, the data suggest that in primates, fluctuations of ovarian hormones across the menstrual cycle influence activity in brain areas involved in emotion and its regulation.

2008 - IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C [Articolo su rivista]
Majer, M; Welberg, La; Capuron, L; Pagnoni, Giuseppe; Raison, Cl; Miller, Ah

Interferon (IFN)-alpha has been used to investigate pathways by which innate immune cytokines influence the brain and behaviour. Previous studies suggest that altered basal ganglia function may contribute to IFN-alpha-induced neuropsychological and behavioural changes. To further examine IFN-alpha effects on neuropsychological functions related to basal ganglia (as well as other brain regions), and explore the relationship between altered neuropsychological function and IFN-alpha-induced depression and fatigue, a selected subset of the Cambridge Neuropsychological Test Automated Battery was administered to 32 hepatitis C patients at baseline (Visit 1) and following approximately 12 weeks (Visit 2) of either no treatment (n=12) or treatment with IFN-alpha plus ribavirin (n=20). Symptoms of depression and fatigue were assessed using the Montgomery-Asberg Depression Rating Scale and the Multidimensional Fatigue Inventory. Compared to control subjects, patients treated with IFN-alpha/ribavirin exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task and slower response times in the rapid visual information processing task, a task of sustained attention. Decreased motor speed on the five-choice movement segments of the reaction time task was in turn correlated with increased symptoms of depression and fatigue (R=0.47, p<0.05 and R=0.48, p<0.05, respectively). IFN-alpha/ribavirin treatment had no effects on executive function, decision time in the reaction time task, or target detection accuracy in the sustained attention task. Motor slowing and its correlation with psychiatric symptoms suggest that altered basal ganglia function may contribute to the pathogenesis of IFN-alpha-induced behavioural changes.

2008 - Neuropsychological performance in persons with chronic fatigue syndrome: results from a population-based study [Articolo su rivista]
Majer, M; Welberg, La; Capuron, L; Miller, Ah; Pagnoni, Giuseppe; Reeves, Wc

OBJECTIVE: To examine the neuropsychological function characterized in subjects with chronic fatigue syndrome (CFS) at the same time controlling for relevant confounding factors. CFS is associated with symptoms of neuropsychological dysfunction. Objective measures of neuropsychological performance have yielded inconsistent results possibly due to sample selection bias, diagnostic heterogeneity, comorbid psychiatric disorders, and medication usage. METHOD: CFS subjects (n = 58) and well controls (n = 104) from a population-based sample were evaluated, using standardized symptom severity criteria. Subjects who had major psychiatric disorders or took medications known to influence cognition were excluded. Neuropsychological function was measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Compared with controls, CFS subjects exhibited significant decreases in motor speed as measured in the simple and five-choice movement segments of the CANTAB reaction time task. CFS subjects also exhibited alterations in working memory as manifested by a less efficient search strategy on the spatial working memory task, fewer % correct responses on the spatial recognition task, and prolonged latency to a correct response on the pattern recognition task. A significantly higher percentage of CFS subjects versus controls exhibited evidence of neuropsychological impairment (defined by performance 1 standard deviation below the CANTAB normative mean) in tasks of motor speed and spatial working memory. Impairment in CFS subjects versus control subjects ranged from 20% versus 4.8% in five-choice movement time (p = .002) to 27.8% versus 10.6% in search strategy on the spatial working memory task (p = .006). CONCLUSIONS: These results confirm and quantify alterations in motor speed and working memory in CFS subjects independent of comorbid psychiatric disease and medication usage.

2008 - Social cognitive neural networks during in-group and out-group interactions [Articolo su rivista]
Rilling, Jk; Dagenais, Je; Goldsmith, Dr; Glenn, Al; Pagnoni, Giuseppe

Several functionally connected networks of activity have now been identified in the resting human brain that may be amplified or attenuated by specific goal-directed tasks. However, it is not known whether there exists a particular network that becomes more active when a person is engaged in a social interaction. fMRI was used to measure brain activity in subjects as they completed a social interactive task and a non-social control task sharing many of the same features. Comparison across the two tasks revealed a network of functionally connected areas that was consistently more active in the social task. This network included default mode network areas, raising the possibility that activity previously observed in default mode regions at rest is related to social cognition. Within this network, information appears to flow from regions involved in salience detection (e.g. anterior insula) to regions involved in mentalizing (dorsomedial prefrontal cortex) to regions involved in executive control (dorsolateral prefrontal cortex). In a second experiment, subjects played the same social interactive task with alleged members of both an experimentally induced in-group and out-group. The default mode network was again active during the task, and several noteworthy differences distinguished interactions with in-group and out-group partners, providing a potential neural substrate for the human tendency to more readily identify with in-group members and more readily distrust, fear and discriminate against out-group members.

2008 - The neural correlates of the affective response to unreciprocated cooperation [Articolo su rivista]
Rilling, Jk; Goldsmith, Dr; Glenn, Al; Jairam, Mr; Elfenbein, Ha; Dagenais, Je; Murdock, Cd; Pagnoni, Giuseppe

Humans excel at reciprocal altruism in which two individuals exchange altruistic acts to their mutual advantage. The evolutionary stability of this system depends on recognition of and discrimination against non-reciprocators, and the human mind is apparently specialized for detecting non-reciprocators. Here we investigate the neural response to non-reciprocation of cooperation by imaging human subjects with fMRI as they play an iterated Prisoner's dilemma game with two assumed human partners. Unreciprocated cooperation was associated with greater activity in bilateral anterior insula, left hippocampus and left lingual gyrus, compared with reciprocated cooperation. These areas were also more responsive to unreciprocated cooperation than to unsuccessful risk taking in a non-social context. Finally, functional connectivity between anterior insula and lateral orbitofrontal cortex (OFC) in response to unreciprocated cooperation predicted subsequent defection. The anterior insula is involved in awareness of visceral, autonomic feedback from the body and, in concert with the lateral orbitofrontal cortex, may be responsible for negative feeling states that bias subsequent social decision making against cooperation with a non-reciprocating partner.

2007 - A Comparison of Resting State Brain Activity in Humans and Chimpanzees [Articolo su rivista]
Rilling, Jk; Barks, Sk; Parr, La; Preuss, Tm; Faber, Tl; Pagnoni, Giuseppe; Bremner, Jd; Votaw, Jr

In humans, the wakeful resting condition is characterized by a default mode of brain function involving high levels of activity within a functionally connected network of brain regions. This network has recently been implicated in mental self-projection into the past, the future, or another individual's perspective. Here we use [(18)F]-fluorodeoxyglucose positron emission tomography imaging to assess resting-state brain activity in our closest living relative, the chimpanzee, as a potential window onto their mental world and compare these results with those of a human sample. We find that, like humans, chimpanzees show high levels of activity within default mode areas, including medial prefrontal and medial parietal cortex. Chimpanzees differ from our human sample in showing higher levels of activity in ventromedial prefrontal cortex and lower levels of activity in left-sided cortical areas involved in language and conceptual processing in humans. Our results raise the possibility that the resting state of chimpanzees involves emotionally laden episodic memory retrieval and some level of mental self-projection, albeit in the absence of language and conceptual processing.

2007 - Age effects on gray matter volume and attentional performance in Zen meditation [Articolo su rivista]
Pagnoni, Giuseppe; Cekic, M.

Zen meditation, a Buddhist practice centered on attentional and postural self-regulation, has been speculated to bring about beneficial long-term effects for the individual, ranging from stress reduction to improvement of cognitive function. In this study, we examined how the regular practice of meditation may affect the normal age-related decline of cerebral gray matter volume and attentional performance observed in healthy individuals. Voxel-based morphometry for MRI anatomical brain images and a computerized sustained attention task were employed in 13 regular practitioners of Zen meditation and 13 matched controls. While control subjects displayed the expected negative correlation of both gray matter volume and attentional performance with age, meditators did not show a significant correlation of either measure with age. The effect of meditation on gray matter volume was most prominent in the putamen, a structure strongly implicated in attentional processing. These findings suggest that the regular practice of meditation may have neuroprotective effects and reduce the cognitive decline associated with normal aging.

2007 - Basal Ganglia Hypermetabolism and Symptoms of Fatigue during Interferon-alpha Therapy [Articolo su rivista]
Capuron, L; Pagnoni, Giuseppe; Demetrashvili, M; Lawson, Dh; Fornwalt, F; Woolwine, Bj; Berns, Gs; Nemeroff, Cb; Miller, Ah

Interferon (IFN)-alpha is a cytokine of the innate immune response that is well known for inducing behavioral alterations and has been used to study effects of cytokines on the nervous system. Limited data, however, are available on the sites of action of IFN-alpha within the brain and their relationship with specific IFN-alpha-induced symptoms. Using a longitudinal design, whole-brain metabolic activity as assessed by fluorine-18-labeled fluorodeoxyglucose uptake and positron emission tomography was examined before and 4 weeks after IFN-alpha administration in patients with malignant melanoma. Changes in metabolic activity in relevant brain regions were then correlated with IFN-alpha-induced behavioral changes. IFN-alpha administration was associated with widespread bilateral increases in glucose metabolism in subcortical regions including the basal ganglia and cerebellum. Decreases in dorsal prefrontal cortex glucose metabolism were also observed. Prominent IFN-alpha-induced behavioral changes included lassitude, inability to feel, and fatigue. Correlational analyses revealed that self-reported fatigue (specifically as assessed by the 'energy' subscale of the Visual Analog Scale of Fatigue) was associated with increased glucose metabolism in the left nucleus accumbens and putamen. These data indicate that IFN-alpha as well as other cytokines of the innate immune response may target basal ganglia nuclei, thereby contributing to fatigue-related symptoms in medically ill patients.

2007 - Neural correlates of social cooperation and non-cooperation as a function of psychopathy [Articolo su rivista]
Rilling, Jk; Glenn, Al; Jairam, Mr; Pagnoni, Giuseppe; Goldsmith, Dr; Elfenbein, Ha; Lilienfeld, So

BACKGROUND: Psychopathy is a disorder involving a failure to experience many emotions that are necessary for appropriate social behavior. In this study, we probed the behavioral, emotional, and neural correlates of psychopathic traits within the context of a dyadic social interaction. METHODS: Thirty subjects were imaged with functional magnetic resonance imaging while playing an iterated Prisoner's Dilemma game with human confederates who were outside the scanner. Subjects also completed two self-report psychopathy questionnaires. RESULTS: Subjects scoring higher on psychopathy, particularly males, defected more often and were less likely to continue cooperating after establishing mutual cooperation with a partner. Further, they experienced more outcomes in which their cooperation was not reciprocated (cooperate-defect outcome). After such outcomes, subjects scoring high in psychopathy showed less amygdala activation, suggesting weaker aversive conditioning to those outcomes. Compared with low-psychopathy subjects, subjects higher in psychopathy also showed weaker activation within orbitofrontal cortex when choosing to cooperate and showed weaker activation within dorsolateral prefrontal and rostral anterior cingulate cortex when choosing to defect. CONCLUSIONS: These findings suggest that whereas subjects scoring low on psychopathy have emotional biases toward cooperation that can only be overcome with effortful cognitive control, subjects scoring high on psychopathy have an opposing bias toward defection that likewise can only be overcome with cognitive effort.

2006 - Human striatal activation reflects degree of stimulus saliency [Articolo su rivista]
Zink, Cf; Pagnoni, Giuseppe; Chappelow, Jc; MARTIN SKURSKI, Me; Berns, Gs

Salient stimuli are characterized by their capability to perturb and seize available cognitive resources. Although the striatum and its dopaminergic inputs respond to a variety of stimuli categorically defined as salient, including rewards, the relationship between striatal activity and saliency is not well understood. Specifically, it is unclear if the striatum responds in an all-or-none fashion to salient events or instead responds in a graded fashion to the degree of saliency associated with an event. Using functional magnetic resonance imaging, we measured activity in the brains of 20 participants performing a visual classification task in which they identified single digits as odd or even numbers. An auditory tone preceded each number, which was occasionally, and unexpectedly, substituted by a novel sound. The novel sounds varied in their ability to interrupt and reallocate cognitive resources (i.e., their saliency) as measured by a delay in reaction time to immediately subsequent numerical task-stimuli. The present findings demonstrate that striatal activity increases proportionally to the degree to which an unexpected novel sound interferes with the current cognitive focus, even in the absence of reward. These results suggest that activity in the human striatum reflects the level of saliency associated with a stimulus, perhaps providing a signal to reallocate limited resources to important events.

2006 - Neurobiologic Substrates of Dread [Articolo su rivista]
Berns, Gs; Chappelow, J; Cekic, M; Zink, Cf; Pagnoni, Giuseppe; MARTIN SKURSKI, Me

Given the choice of waiting for an adverse outcome or getting it over with quickly, many people choose the latter. Theoretical models of decision-making have assumed that this occurs because there is a cost to waiting-i.e., dread. Using functional magnetic resonance imaging, we measured the neural responses to waiting for a cutaneous electric shock. Some individuals dreaded the outcome so much that, when given a choice, they preferred to receive more voltage rather than wait. Even when no decision was required, these extreme dreaders were distinguishable from those who dreaded mildly by the rate of increase of neural activity in the posterior elements of the cortical pain matrix. This suggests that dread derives, in part, from the attention devoted to the expected physical response and not simply from fear or anxiety. Although these differences were observed during a passive waiting procedure, they correlated with individual behavior in a subsequent choice paradigm, providing evidence for a neurobiological link between the experienced disutility of dread and subsequent decisions about unpleasant outcomes.

2005 - Anterior cingulate activation and error processing during interferon-alpha treatment [Articolo su rivista]
Capuron, L; Pagnoni, Giuseppe; Demetrashvili, M; Woolwine, Bj; Nemeroff, Cb; Berns, Gs; Miller, Ah

BACKGROUND: There has been increasing interest in the role of immunologic processes, notably cytokines, in the development of behavioral alterations, especially in medically ill patients. Interferon (IFN)-alpha is notorious for causing behavioral symptoms, including depression, fatigue, and cognitive dysfunction, and has been used to investigate the effects of cytokines on the brain. METHODS: In the present study we assessed the effects of low-dose IFN-alpha on brain activity, using functional magnetic resonance imaging during a task of visuospatial attention in patients infected with hepatitis C virus (HCV). RESULTS: Despite endorsing symptoms of impaired concentration and fatigue, IFN-alpha-treated patients (n = 10) exhibited task performance and activation of parietal and occipital brain regions similar to that seen in HCV-infected control subjects (n = 11). Interestingly, however, in contrast to control subjects, IFN-alpha-treated patients exhibited significant activation in the dorsal part of the anterior cingulate cortex (ACC), which highly correlated with the number of task-related errors. No such correlation was found in control subjects. CONCLUSIONS: Consistent with the role of the ACC in conflict monitoring, ACC activation during IFN-alpha administration suggests that cytokines might increase processing conflict or reduce the threshold for conflict detection, thereby signaling the need to exert greater mental effort to maintain performance. Such alterations in ACC activity might in turn contribute to cytokine-induced behavioral changes.

2005 - Neurobiological correlates of social conformity and independence during mental rotation [Articolo su rivista]
Berns, Gs; Chappelow, Jc; Zink, Cf; Pagnoni, Giuseppe; MARTIN SKURSKI, Me; Richards, J.

BACKGROUND: When individual judgment conflicts with a group, the individual will often conform his judgment to that of the group. Conformity might arise at an executive level of decision making, or it might arise because the social setting alters the individual's perception of the world. METHODS: We used functional magnetic resonance imaging and a task of mental rotation in the context of peer pressure to investigate the neural basis of individualistic and conforming behavior in the face of wrong information. RESULTS: Conformity was associated with functional changes in an occipital-parietal network, especially when the wrong information originated from other people. Independence was associated with increased amygdala and caudate activity, findings consistent with the assumptions of social norm theory about the behavioral saliency of standing alone. CONCLUSIONS: These findings provide the first biological evidence for the involvement of perceptual and emotional processes during social conformity.

2004 - Brain imaging in Psychopharmacology [Capitolo/Saggio]
Pagnoni, Giuseppe; Berns, Gs

Covering both basic science and clinical practice, this new edition of the definitive psychopharmacology text has been thoroughly updated and expanded to keep you current with the explosive growth in this burgeoning field. The book contains 62 chapters overall with 24 new chapters and 30 new authors.

2004 - Human striatal responses to monetary reward depend on saliency [Articolo su rivista]
Zink, Cf; Pagnoni, Giuseppe; MARTIN SKURSKI, Me; Chappelow, Jc; Berns, Gs

While the striatum has been implicated in reward processing, an alternative view contends that the striatum processes salient events in general. Using fMRI, we investigated human striatal responses to monetary reward while modulating the saliency surrounding its receipt. Money was maximally salient when its receipt depended on a correct response (active) and minimally salient when its receipt was completely independent of the task (passive). The saliency manipulation was confirmed by skin conductance responses and subjective ratings of the stimuli. Significant caudate and nucleus accumbens activations occurred following the active compared to passive money. Such activations were attributed to saliency rather than the motor requirement associated with the active money because striatal activations were not observed when the money was replaced by inconsequential, nonrewarding stimuli. The present study provides evidence that the striatum's role in reward processing is dependent on the saliency associated with reward, rather than value or hedonic feelings.

2004 - Long-term effects of vaccination on attentional performance [Articolo su rivista]
Nicoletti, Roberto; Porro, Carlo Adolfo; G., Brighetti; Monti, Daniela; Pagnoni, Giuseppe; Guido, Marcello; Rubichi, Sandro; Franceschi, Claudio

To investigate the possible influence of stimulation of the immune system on cognitive tasks, C healthy volunteers were vaccinated against hepatitis B and tested over a 6 month-period in a simple reaction times and the Stroop task. In general, the Stroop effect demonstrates that both the name and meaning of a word are automatically processed even when voluntary attention is trying hard not to process them. Unlike placebo group, vaccinated subjects showed a persistent lack of the classical Stroop effect. These findings may be explained by a constraint satisfaction model of the Stroop task, assuming a selective weakening of the connection matrix, and suggest that immune-cognitive effects may occur, besides the well known immune-cognitive influences like those elicited by emotional stress.

2003 - Human striatal response to salient nonrewarding stimuli [Articolo su rivista]
Zink, Cf; Pagnoni, Giuseppe; Martin, Me; Dhamala, M; Berns, Gs

Although one proposed function of both the striatum and its major dopamine inputs is related to coding rewards and reward-related stimuli, an alternative view suggests a more general role of the striatum in processing salient events, regardless of their reward value. Here we define saliency as an event that both is unexpected and elicits an attentional-behavioral switch (i.e., arousing). In the present study, human striatal responses to nonrewarding salient stimuli were investigated. Using functional magnetic resonance imaging (fMRI), the blood oxygenation level-dependent signal was measured in response to flickering visual distractors presented in the background of an ongoing task. Distractor salience was manipulated by altering the frequency of distractor occurrence. Infrequently presented distractors were considered more salient than frequently presented distractors. We also investigated whether behavioral relevance of the distractors was a necessary component of saliency for eliciting striatal responses. In the first experiment (19 subjects), the distractors were made behaviorally relevant by defining a subset of them as targets requiring a button press. In the second experiment (17 subjects), the distractors were not behaviorally relevant (i.e., they did not require any response). The fMRI results revealed increased activation in the nucleus accumbens after infrequent (high salience) relative to frequent (low salience) presentation of distractors in both experiments. Caudate activity increased only when the distractors were behaviorally relevant. These results demonstrate a role of the striatum in coding nonrewarding salient events. In addition, a functional subdivision of the striatum according to the behavioral relevance of the stimuli is suggested.

2003 - Neural correlates of the complexity of rhythmic finger tapping [Articolo su rivista]
Dhamala, M; Pagnoni, Giuseppe; Wiesenfeld, K; Zink, Cf; Martin, M; Berns, Gs

Using functional magnetic resonance imaging (fMRI), we studied the neural correlates of the complexity of rhythmic finger tapping. Our experiments measured the brain activity of 13 subjects performing rhythmic tapping on a response box with multistable rhythms of 1 to 5 different interresponse intervals. From the button press response times, we constructed phase portraits where we identified the number of clusters of periodic points in a rhythm that corresponded to the number of different beats of the rhythm performed. We then constructed a statistical model for correlation analysis involving the following behavioral parameters: rate of tapping and number of beats in a rhythm. The tapping rate correlated with the brain activity in the ipsilateral pre/postcentral gyrus, and the number of beats (complexity) was correlated with activations in the primary motor cortex, supplementary motor area, basal ganglia, thalamus, and cerebellum. A region of interest (ROI) average analysis showed that the complexity of a rhythm had a differential correlation with the activity in these regions. The cerebellum and the thalamus showed increasing activity, and the basal ganglia showed decreasing activity with complexity of a rhythm. These results identify the areas involved in a rhythm generation and the modulation of brain activity with the complexity.

2002 - A neural basis for social cooperation [Articolo su rivista]
Rilling, Jk; Gutman, D; Zeh, T; Pagnoni, Giuseppe; Berns, Gs; Kilts, C.

Cooperation based on reciprocal altruism has evolved in only a small number of species, yet it constitutes the core behavioral principle of human social life. The iterated Prisoner's Dilemma Game has been used to model this form of cooperation. We used fMRI to scan 36 women as they played an iterated Prisoner's Dilemma Game with another woman to investigate the neurobiological basis of cooperative social behavior. Mutual cooperation was associated with consistent activation in brain areas that have been linked with reward processing: nucleus accumbens, the caudate nucleus, ventromedial frontal/orbitofrontal cortex, and rostral anterior cingulate cortex. We propose that activation of this neural network positively reinforces reciprocal altruism, thereby motivating subjects to resist the temptation to selfishly accept but not reciprocate favors.

2002 - Activity in human ventral striatum locked to errors of reward prediction [Articolo su rivista]
Pagnoni, Giuseppe; Zink, Cf; Montague, Pr; Berns, Gs

The mesolimbic dopaminergic system has long been known to be involved in the processing of rewarding stimuli, although recent evidence from animal research has suggested a more specific role of signaling errors in the prediction of rewards. We tested this hypothesis in humans, using functional magnetic resonance imaging (fMRI) and an operant conditioning paradigm for the discrete delivery of small quantities of fruit juice, along with a control experiment in which juice was substituted with a neutral visual stimulus. A local estimation of the activity in the ventral striatum showed a significant differentiation when the juice was withheld at the expected time of delivery; this finding was not replicated in the case of visual stimulation, providing evidence for time-locked processing of reward prediction errors in human ventral striatum.

2002 - Does anticipation of pain affect cortical nociceptive systems? [Articolo su rivista]
Porro, Carlo Adolfo; Baraldi, Patrizia; Pagnoni, Giuseppe; Serafini, M.; Facchin, P.; Maieron, Marta; Nichelli, Paolo Frigio

Anticipation of pain is a complex state that may influence the perception of subsequent noxious stimuli. We used functional magnetic resonance imaging (fMRI) to study changes of activity of cortical nociceptive networks in healthy volunteers while they expected the somatosensory stimulation of one foot, which might be painful (subcutaneous injection of ascorbic acid) or not. Subjects had no previous experience of the noxious stimulus. Mean fMRI signal intensity increased over baseline values during anticipation and during actual stimulation in the putative foot representation area of the contralateral primary somatosensory cortex (SI). Mean fMRI signals decreased during anticipation in other portions of the contralateral and ipsilateral SI, as well as in the anteroventral cingulate cortex. The activity of cortical clusters whose signal time courses showed positive or negative correlations with the individual psychophysical pain intensity curve was also significantly afected during the waiting period. Positively correlated clusters were found in the contralateral SI and bilaterally in the anterior cingulate, anterior insula, and medial prefrontal cortex. Negatively correlated clusters were found in the anteroventral cingulate bilaterally. In all of these areas, changes during anticipation were of the same sign as those observed during pain but less intense (similar to30-40% as large as peak changes during actual noxious stimulation). These results provide evidence for top-down mechanisms, triggered by anticipation, modulating cortical systems involved in sensory and affective components of pain even in the absence of actual noxious input and suggest that the activity of cortical nociceptive networks may be directly influenced by cognitive factors.

2002 - Human brain language by functional magnetic lexical decision task processing areas identified resonance imaging using a lexical decision task [Articolo su rivista]
CALANDRA BUONAURA, Giovanna; Basso, Gianpaolo; Gorno Tempini, Ml; Serafini, M.; Pagnoni, Giuseppe; Baraldi, Patrizia; Porro, Carlo Adolfo; Nichelli, Paolo Frigio

The purpose of this study was to validate a functional magnetic resonance imaging (fMRI) paradigm to activate both anterior and posterior language areas while collecting accuracy and reaction time data on subjects' performance. The paradigm was based on alternating graphemic and lexical decision tasks. In line with the classical model of language organisation, based on lesion data, and with the results of previous neuroimaging studies, cortical activation associated with lexical decision-making was strongly lateralised to the left hemisphere and involved a network of regions in the frontal, temporal and parietal lobes. Single subject analysis demonstrated that the activation paradigm we propose is suitable for detecting language processing areas in humans for clinical studies.

2002 - Hyperscanning: simultaneous fMRI during linked social interactions [Articolo su rivista]
Montague, Pr; BERNS GS COHEN, Jd; Mcclure, Sm; Pagnoni, Giuseppe; Dhamala, M; Wiest, Mc; Karpov, I; King, Rd; Apple, N; Fisher, Re

"Plain question and plain answer make the shortest road out of most perplexities." Mark Twain-Life on the Mississippi. A new methodology for the measurement of the neural substrates of human social interaction is described. This technology, termed "Hyperscan," embodies both the hardware and the software necessary to link magnetic resonance scanners through the internet. Hyperscanning allows for the performance of human behavioral experiments in which participants can interact with each other while functional MRI is acquired in synchrony with the behavioral interactions. Data are presented from a simple game of deception between pairs of subjects. Because people may interact both asymmetrically and asynchronously, both the design and the analysis must accommodate this added complexity. Several potential approaches are described.

2002 - Measurements of brain activity complexity for varying mental loads. [Articolo su rivista]
Dhamala, M; Pagnoni, Giuseppe; Wiesenfeld, K; Berns, Gs

Using functional magnetic resonance imaging, we investigate the variation in dynamical complexity of human brain activity for different mental loads. Our experiments measured the activity of ten subjects under three experimental conditions: a rest condition, a periodic task of finger opposition, and a task of finger opposition alternated with mathematical serial calculation. We used the correlation dimension to gauge the spatiotemporal complexity of brain activity. The experiments show a direct relationship between this complexity and the difficulty of the task. A natural interpretation is that higher levels of mental load recruit a larger number of independent neural processes that contribute to complex brain dynamics. These results suggest the possibility that the relative change in correlation dimension can be a useful global measure of brain dynamics, e.g., in determining the levels of mental activity, even if little is known about the underlying neurological processes.

2002 - Metafore e neurofisiologia [Capitolo/Saggio]
Pagnoni, Giuseppe

Paralleli tra la teoria delle metafore sviluppata da Lakoff e Johnson nel campo della "embodied cognition" e recenti scoperte delle neuroscienze, in particolare sui "neuroni specchio".

2001 - Explicit and incidental facial expression processing: an fMRI study [Articolo su rivista]
Gorno Tempini, Ml; Pradelli, S.; Serafini, M.; Pagnoni, Giuseppe; Baraldi, Patrizia; Porro, Carlo Adolfo; Nicoletti, Roberto; Umita, C.; Nichelli, Paolo Frigio

Considerable evidence indicates that processing facial expression involves both subcortical (amygdala and basal ganglia) and cortical (occipito-temporal, orbitofrontal, and prefrontal cortex) structures. However, the specificity of these regions for single types of emotions and for the cognitive demands of expression processing, is still unclear. This functional magnetic resonance imaging (fMRI) study investigated the neural correlates of incidental and explicit processing of the emotional content of faces expressing either disgust or happiness. Subjects were examined while they were viewing neutral, disgusted, or happy faces., The incidental task required subjects to decide about face gender, the explicit task to decide about face expression. In the control task subjects were requested to detect a white square in a greyscale mosaic stimulus. Results showed that the left inferior frontal cortex and the bilateral occipito-temporal junction responded equally to all face conditions. Several cortical and subcortical regions were modulated by task type, and by facial expression. Right neostriatum. and left amygdala were activated when subjects made explicit judgements of disgust, bilateral orbitofrontal cortex when they made judgement of happiness, and right frontal and insular cortex when they made judgements about any emotion.

2001 - Predictability modulates human brain response to reward [Articolo su rivista]
Berns, Gs; Mcclure, Sm; Pagnoni, Giuseppe; Montague, Pr

Certain classes of stimuli, such as food and drugs, are highly effective in activating reward regions. We show in humans that activity in these regions can be modulated by the predictability of the sequenced delivery of two mildly pleasurable stimuli, orally delivered fruit juice and water. Using functional magnetic resonance imaging, the activity for rewarding stimuli in both the nucleus accumbens and medial orbitofrontal cortex was greatest when the stimuli were unpredictable. Moreover, the subjects' stated preference for either juice or water was not directly correlated with activity in reward regions but instead was correlated with activity in sensorimotor cortex. For pleasurable stimuli, these findings suggest that predictability modulates the response of human reward regions, and subjective preference can be dissociated from this response.

2000 - Aree corticali di rappresentazione bilaterale dei movimenti della mano [Articolo su rivista]
Baraldi, Patrizia; Serafini, M.; Pagnoni, G.; Crisi, G.; Basso, G. P.; Cettolo, V.; Nichelli, Paolo Frigio; Porro, Carlo Adolfo

PET and fMRI studies have disclosed areas of activation in the ipsilateral primary sensorimotor cortex, which appears to be spatially much more extensive in the dominant hemisphere during sequential finger movements. This study directly investigated the presence and spatial distribution of controlateral, bilateral and ipsilateral cortical motor representations in both hemispheres using echo planar fMRI. FMRI disclosed different populations of neurons with specific functional characteristics in an anatomically defined area. There was no purely ipsilateral representation of movement; the ipsilateral component of cortical activation seems to reflect a population of neurons activated during movement of both right and left hands with greater extension in the dominant hemisphere. This bilateral population is presumably involved in movement planning. A second neuron population, activated only during the controlateral movement, was found in both hemispheres in the posterior portion of the precentral gyrus, probably corresponding to the primary motor area.

2000 - Brain pattern of activity during anticipation of pain [Articolo su rivista]
Porro, C. A.; Baraldi, P.; Pagnoni, G.; Serafini, M.; Murari, C.; Nichelli, P.

2000 - Localizzazione cerebrale funzionale delle aree del linguaggio per mezzo di un compito di decisione lessicale [Articolo su rivista]
Basso, G.; Gorno-tempini, M. L.; Calandra Buonaura, G.; Serafini, M.; Pagnoni, G.; Mavilla, L.; Baraldi, Patrizia; Nichelli, Paolo Frigio; Porro, Carlo Adolfo

The aim of this study was to develop a language rest to be used with functional magnetic resonance imaging (fMR1). The study is part of a larger project aimed at standardizing the rise of fMR1 in the clinical environment on brain lesioned patients selected for neurosurgery or language rehabilitation treatment. We present preliminary results based on the analysis of data obtained from ten, right-handed normal volunteers and one brain damaged patient.

1999 - Bilateral representation of sequential finger movements in human cortical areas [Articolo su rivista]
Baraldi, Patrizia; Porro, Carlo Adolfo; M., Serafini; Pagnoni, Giuseppe; Nichelli, Paolo Frigio; Corazza, Ruggero; C., Murari

The spatial distribution of cortical neural clusters activated during movement of either hand ('bilateral' population), or only of one hand, was investigated in healthy right-handed volunteers performing a sequential finger opposition task, using echo-planar functional magnetic resonance imaging. 'Bilateral' clusters were found in the mesial premotor, perirolandic and adjacent lateral premotor cortex of the two hemispheres, and in the left superior parietal lobule. In the precentral gyrus, their spatial extent was larger on the left hemisphere. Clusters activated exclusively during contralateral finger movements were equally distributed in the left and right perirolandic cortex. No cluster activated exclusively during ipsilateral finger movements was detected. These findings support a role of the motor/lateral premotor cortex of the dominant hemisphere in bilateral motor control. (C) 1999 Elsevier Science ireland Ltd. All rights reserved.

1999 - Cortical coding of temporal and intensive aspects of pain: Echo-planar fMRI studies [Articolo su rivista]
Baraldi, P.; Pagnoni, G.; Serafini, M.; Murari, C.; Nichelli, P.; Porro, C. A.

1999 - Neuroanatomical correlates of recognizing emotional faces [Articolo su rivista]
Tempini, M. L. G.; Pradelli, S.; Pagnoni, G.; Baraldi, P.; Serafini, M.; Porro, C. A.; Nicoletti, R.; Umilta, C.; Nichelli, P.

1998 - Cortical areas shared by contra- And ipsilateral sequential finger movements [Articolo su rivista]
Baraldi, P.; Porro, C. A.; Serafini, M.; Pagnoni, G.; Tavani, F.; Nichelli, P.