Irene Perini - Academia.edu (original) (raw)
Papers by Irene Perini
Brain, 2021
Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 pr... more Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a the...
doi: 10.3389/fnhum.2013.00755 Facets and mechanisms of adaptive pain behavior: predictive regulat... more doi: 10.3389/fnhum.2013.00755 Facets and mechanisms of adaptive pain behavior: predictive regulation and action
Seeking pleasant touch: neural correlates of behavioral
Cerebral Cortex, 2020
The evidence that action shapes perception has become widely accepted, for example, in the domain... more The evidence that action shapes perception has become widely accepted, for example, in the domain of vision. However, the manner in which action-relevant factors might influence the neural dynamics of acute pain processing has remained underexplored, particularly the functional roles of anterior insula (AI) and midanterior cingulate cortex (mid-ACC), which are frequently implicated in acute pain. To address this, we examined a unique group of heterozygous carriers of the rare R221W mutation on the nerve growth factor (NGF) gene. R221W carriers show a congenitally reduced density of C-nociceptor afferent nerves in the periphery, but can nonetheless distinguish between painful and nonpainful stimulations. Despite this, carriers display a tendency to underreact to acute pain behaviorally, thus exposing a potential functional gap in the pain–action relationship and allowing closer investigation of how the brain integrates pain and action information. Heterozygous R221W carriers and matc...
Current topics in behavioral neurosciences, 2021
Socialization happens so regularly in humans that it can be perceived as an effortless activity. ... more Socialization happens so regularly in humans that it can be perceived as an effortless activity. However, it reflects a sophisticated behavior, pervaded by anticipation and emotion. The fast-paced social interplay, strongly mediated by facial expressions, can be considered one of the most frequent high-order motor acts within the human behavioral repertoire. The ability to adequately process social feedback is critical for appropriate socialization and affects well-being. The social difficulties often observed in psychiatric patients highlight the link between mental health and successful socialization and the importance of characterizing the behavioral and neural mechanisms of social interaction. This chapter will present some cross-species evidence on the cortical regions engaged during social interactions including facial expressions, and the impact of induced or perceived social stress on the experience of social interactions.
Biological psychiatry. Cognitive neuroscience and neuroimaging, 2020
BACKGROUND Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations worldwide. Emoti... more BACKGROUND Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations worldwide. Emotion dysregulation is believed to contribute to NSSI, but underlying mechanisms are less known. We combined psychophysiological and neural data with subjective self-report in close temporal proximity to examine the mechanisms underlying emotion processing in adolescents with NSSI relative to control adolescents without a psychiatric diagnosis. METHODS Thirty female adolescents with NSSI and 30 age-matched female control subjects were included in this case-control study. Participants were presented with negative affective pictures during a functional magnetic resonance imaging scan. In a separate facial electromyography session, the same participants were shown positive and negative affective images and also provided ratings of valence and arousal. RESULTS Participants with NSSI responded to affective images with greater positive (e.g., zygomatic) and greater negative (e.g., corrugator) rea...
Biological Psychiatry
BACKGROUND Alcohol addiction is associated with a high disease burden, and treatment options are ... more BACKGROUND Alcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging. METHODS This was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures. RESULTS Both craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 ± 0.8% vs. 10.6 ± 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex. CONCLUSIONS We provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity.
Francis Jennings has to his credit an impressive array of titles in colonial American studies, in... more Francis Jennings has to his credit an impressive array of titles in colonial American studies, including The Invasion of America and The Founders of America (on native peoples and the contact between them and European colonizers) and The AmbiguousIroquoisEmpire and Empire of Fortune (both of which treat Six Nations culture during the seventeenth and eighteenth centuries). To these well-known, densely constructed, and often-cited studies, Jennings is adding a study of Benjamin Franklin. In introductory matter to the volume, Jennings says that he had studied Franklin closely decades ago. In many ways, though, the major scholarly contribution of the volume-a discussion of Franklin's activities from the 1750s through the 1770s-seems a logical outgrowth of Jennings's earlier work on Six Nations culture and the conflicts between the Six Nations Iroquois and the Lenni Lenape (the Delaware) peoples during the middle of the eighteenth century, as both groups faced continued settlement by Europeans on their ancestral lands. Jennings assumes from the outset that his book is revisionary. Among the epigraphs is Harrison Salisbury's comment from Heroes of My Time, "I harbor deep distrust of obvious heroes." Jennings himself insists in the introduction that the events of Franklin's life "reveal the ego hidden so carefully behind his words" (p. 15), and he avers that "the long life of Benjamin Franklin requires some reassessment of the standard thought about the beginnings of the American Revolution" (p. 16). In "A Note on the Sources," he concludes: "My findings herein are strongly revisionist" (p. 204). Jennings's assertions are to some extent accurate, if overstated. Scholars of the past two decades or so have been reexamining the papers of the so-called "founders" in an effort to fill in gaps left by World War II and postwar historians who sought a predominantly "American" story and made of the founders important "American" heroes. If we find these earlier historians wanting at this stage in the century, it is nonetheless useful if we keep the era of the world wars in sight: midcentury historians had an eye to developing a nationalistic construct, perhaps, just as scholars today might wish to examine colonial history from a transnational and multiethnic perspective. Jennings's book seems to divide into two sections, the first examining Franklin's common-law marriage and activities in Philadelphia to about the 1750s (the first THE PENNSYLVANIA MAGAZINE OF HISTORY AND BIOGRAPHY Vol. CXXI, No. 4 (October 1997) 372 BOOK REVIEWS October eight chapters) and the latter examining the years from the assembly campaigns of the early 1750s through the era of the Revolution. In the first eight chapters, the major thrust of Jennings's revisionism is a filling in of the gaps Jennings finds in Franklin's autobiography. Thus Jennings features Israel Pemberton, Jr., who "is a nonperson in the Autobiography" and who in Jennings's view was "as active as Benjamin Franklin in Philadelphia's civic affairs outside the Assembly/' Pemberton's absence from Franklin's memoir indicates to Jennings that "the competition rankled Franklin, who could be generous to the Quakers who were deferential to himself' (p. 44). Likewise, with regard to his securing the post of deputy postmaster at Philadelphia, Franklin's not having mentioned the unneeded patronage of Thomas Penn's provincial chief justice William Allen is also taken by Jennings as a sign of Franklin's ego (pp. 38-39). Perhaps more surprisingly, Franklin's not mentioning in his memoir his friend James Logan's activities during the nefarious Walking Purchase land-grab-indeed, the omission of any mention whatsoever of the chicanery of the Penn descendants and Franklin's early friendship with them, for patronageis understood by Jennings to be a "trivialization" of "the struggle by Pennsylvanians against their feudal lord": 'The self-consciously wise Franklin of the Autobiography could not admit how he had been duped by Penn and, worse, had actually worked hard to support Penn's political machine" (pp. 57, 58). For the same reasons, according to Jennings, Franklin omitted talking about William Smith in faz Autobiography: "To mention him would have required Franklin to confess that Smith had used and made a fool of him, had outsmarted him, and such a confession would be intolerable" (p. 70). For the most part, the key aspects of these early chaptersthe discussion related to Pemberton and the sneaking nature of the Walking Purchase-are detailed in Jennings's earlier writings, though here the discussion centers on people with whom Franklin was in contact. The other matters of these chapters are well-known and much-discussed, often in more detail, by most Franklinists. Although Jennings's later chapters cover some of the same issues as chapters 6 through 8, they focus on two central issues: first, Franklin's growing personal antagonisms with the Penns and the assembly's distrust of the whole proprietary system; and, second, Franklin's developing disillusionment with royalism and his eventual prorebellion fervor, ultimately ending in his refusal to assist royalist son, William, and his wife, once William had been taken into custody. These later chapters offer, for the most part, a condensed version of Jennings's magisterial book, Empire of Fortune. Their contribution lies in their treatment, especially for a general reader, of the events in which Franklin was entangled during the decade just prior to the Revolutionary War. With specific regard to Franklin's place in the growing turmoil, these chapters trace several of the well-known issues in Franklin's dealings with friends and with the British government: Franklin's statement of utter contempt for Thomas Penn after Penn slurred his father William Penn's name; Franklin's initial 1997 BOOK REVIEWS 373 acceptance of stamp measures set out by parliament, his attempted land negotiations with a number of lords; his imperialist attitudes that denied the legitimacy of settlement claims by Germans, Irish, Scotch-Irish, and native peoples to lands held by the Penn proprietary. In terms of Franklin's life story, the revisionary nature of these later chapters is less apparent, and thus the tone Jennings takes toward Franklin seems a little less smug, although here, too, Jennings takes Franklin to task for what Jennings sees as Franklin's inability to abide Quakers. Broadly speaking, Jennings's book seems to have three key issues at stake. Ostensibly, Jennings says he is filling in the gaps that historians (popular historians, really-not specialists) have left open in their celebrations of Franklin and the American revolutionary past. But the book's effect is actually more expansive. Jennings is, first, critiquing New England-oriented history-writing and the New England historians' focus on, for instance, the Boston Tea Party, instead, Jennings posits the centrality of midcentury affairs in Pennsylvania, Virginia, and the Ohio territory, and the importance of the proprietary charter rights versus Crown prerogative that Franklin addressed during his life. Historians of the American Revolution, in seeking to establish the revolt on ideological grounds based on a Whig interpretation of charter rights and liberties, wrongly focus on the rhetoric that came out of New England and more suitably might stress the economic, ethnic, and land concerns of the Middle Atlantic. Jennings's close analysis of the entanglements Franklin faced indicates the importance of a largely revisioned history that would account for more general tendencies rather than a few selected incidents from New England. If only for this reason, the book is a useful revisionist study. Second, Jennings is establishing (in the discussion of the Pennsylvania proprietary problems and the border settlers) a set of issues that more narrowly depicts the causes of the Revolution as economic and social, more middle-brow, mercantile, and plebeian, rather than ideological, and he thus shows the day-today causes as of key importance, not the rhetoric of revolution for which famous men are celebrated. Third, Jennings is participating in a revision of the history of the Religious Society of Friends, based on his assumption that the Quakers have received negative attention because of their pacifist stance during the Revolution. While Jennings might be correct in his assessment that Quaker calumniators then and perhaps now have driven negative readings about Quakers of the era of the American Revolution, to some extent, he seems to overstate his case with regard to Franklin and the Quakers. It is hard to miss the humor of Franklin's Autobiography where Franklin points to the quietness and security of a meeting of the Religious Society of Friends by announcing that, having repaired to such a meeting upon his first arrival in Philadelphia, he promptly fell asleep. To Jennings, however, Franklin's "massive ego is revealed more complexly in his callous conduct toward Quakers" (p. 197). Yet Jennings himself has shown the key issues that were at stake. Franklin initially wanted Crown intervention that would force taxation of the 374 BOOK REVIEWS October proprietary lands, because the border areas needed defending. Quakers did not wish themselves to provide for the defense of English settlers, based on their peace testimony; this would be an alternate way to provide for defense while stopping proprietary prerogative. Crown intervention might have mandated test oaths which Quakers would not be able to take. Franklin, an imperialist, not a Quaker, evidently did not see the contradiction that might have eventuated for Quakers between the chartered liberties original to the William Penn tract grant and those "liberties" associated with British imperial policy. Many imperialists might not have seen the potential problems herein. In pushing the position that Franklin disliked Quakers, especially during the 1750s and through the...
The ability to generate and regulate emotional experiences is critical to psychological well-bein... more The ability to generate and regulate emotional experiences is critical to psychological well-being. Impairments in emotion regulatory processes have transdiagnostic associations with psychopathology. Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations, especially clinical adolescent populations, and often linked to emotion regulatory deficits. Clinical observations propose a role for NSSI behaviors in regulating affect, suggesting that these behaviors may arise when other emotion regulatory strategies are insufficient or inaccessible. Experimental evidence has begun to explore the psychophysiological and neural underpinnings of emotion processing in NSSI populations. Thus far, a primary focus has been the role of NSSI in regulation of affect in response to stressful or negative states or stimuli, often suggesting enhanced reactivity in such situations. However, recent evidence suggests that NSSI populations may also display heightened reactivity to positive or rewa...
CT afferents have been known for years, since 1939 when Zotterman suggested they might contribute... more CT afferents have been known for years, since 1939 when Zotterman suggested they might contribute to itch. But their study has been hampered because any low threshold tactile stimulus will also activate large numbers of Aβ afferents. To investigate the psychophysics of CT afferents has recently become possible through microneurography, allowing selective recording from groups of these nerves, (Loken et al., Nat Neurosci 12(5):547–548, 2009 and this volume), and through the study of two rare cohorts of people who have lost either large fibre afferents due to disease or have selective loss of C afferents themselves due to hereditary neuropathy. This chapter details this latter work, and though comparisons between those with neurological conditions and control subjects must always be done with caution, such work can allow some insights into the normal functioning of the CT system.
Neuropsychopharmacology
Social drinking is common, but it is unclear how moderate levels of alcohol influence decision ma... more Social drinking is common, but it is unclear how moderate levels of alcohol influence decision making. Most prior studies have focused on adverse long-term effects on cognitive and executive function in people with alcohol use disorders (AUD). Some studies have investigated the acute effects of alcohol on decision making in healthy people, but have predominantly used small samples and focused on a narrow selection of tasks related to personal decision making, e.g., delay or probability discounting. Here, we conducted a large (n = 264), preregistered randomized placebo-controlled study (RCT) using a parallel group design, to systematically assess the acute effects of alcohol on measures of decision making in both personal and social domains. We found a robust effect of a 0.6 g/kg dose of alcohol on both moral judgment and altruistic behavior, but no effects on several measures of risk taking or waiting impulsivity. These findings suggest that alcohol at low to moderate doses selectively moderates decision making in the social domain, and promotes utilitarian decisions over those dictated by rule-based ethical principles (deontological). This is consistent with existing theory that emphasizes the dual roles of shortsighted information processing and salient social cues in shaping decisions made under the influence of alcohol. A better understanding of these effects is important to understand altered social functioning during alcohol intoxication.
BackgroundCue reactivity is one of the most frequently used paradigms in functional magnetic reso... more BackgroundCue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). While there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participant characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work is difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting, and review the FDCR literature to assess the reporting of items that are deemed important.MethodsFifty-five FDCR scientists from around the world participated in this st...
Translational Psychiatry
An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affect... more An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affective touch is an important means of social interaction, and C-Tactile (CT) afferents are thought to play a key role in the peripheral detection and encoding of these stimuli. Exploring the neural and behavioral mechanisms for processing CT-optimal touch (~3 cm/s) may therefore provide useful insights into the pathophysiology of ASD. We examined the relationship between touch hedonics (i.e. the subjective pleasantness with which affective touch stimuli are perceived) and neural processing in the posterior superior temporal sulcus (pSTS). This region is less activated to affective touch in individuals with ASD, and, in typically developing individuals (TD), is correlated positively with touch pleasantness. TD and ASD participants received brushing stimuli at CT-optimal, and CT-non-optimal speeds during fMRI. Touch pleasantness and intensity ratings were collected, and affective touch awaren...
Frontiers in Psychiatry
Nonsuicidal self-injury disorder (NSSID) is a condition in need of further study, especially in a... more Nonsuicidal self-injury disorder (NSSID) is a condition in need of further study, especially in adolescent and clinical populations where it is particularly prevalent and studies are limited. Twenty-nine clinical self-injuring adolescents were included in the study. The Clinical Assessment of Nonsuicidal Self-Injury Disorder Index (CANDI) was used to assess prevalence of NSSID. The NSSID diagnosis criteria were met by 62.1% of adolescents. The impairment or distress criterion was least often met. Criteria B and C (assessing reasons for NSSI and cognitions/emotions prior to NSSI) were confirmed by 96-100% of all participants. Adolescents with NSSI in this clinical sample had several comorbidities and high levels of psychopathology. NSSID occurred both in combination with and independently of borderline personality disorder traits as well as suicide plans and attempts. Those with NSSID had a significantly higher cutting frequency than those not meeting full NSSID criteria. Other NSSI characteristics, comorbidity, psychopathology, and trauma experiences did not differ between groups. CANDI was a feasible tool to assess NSSID in adolescents. It is important to use structured measures to assess the validity of the NSSID diagnosis across development in both community and clinical samples. The clinical utility of the NSSID diagnosis is discussed.
Neuropsychopharmacology
Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicot... more Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatmentseeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.
Pain is an unpleasant but necessary sensory experience, which facilitates adaptive behaviours, su... more Pain is an unpleasant but necessary sensory experience, which facilitates adaptive behaviours, such as fear. Despite recent advances, the question of how the pain experience influences learning of the fear response is still debated1,2. Genetic disorders rendering patients congenitally unable to feel pain have been described, and are usually explained by defects in peripheral nociceptors3-5. It is not known how growing up without pain affects central emotional and motivational responses to aversive stimuli. The rare autosomal recessive Hereditary Sensory and Autonomic Neuropathy type V (HSAN V) is caused by a mutation in the nerve growth factor (NGF) gene (R100W). HSAN V homozygous patients display a congenital indifference to painful events, with deficits in peripheral nociceptors but without overt cognitive impairment6. In contrast, heterozygous carriers do not present with pain-related deficits and have been identified only through pedigree and genetic screening7,8. We exploited t...
EClinicalMedicine
Background: Interpersonal stress and perceived rejection have been clinically observed as common ... more Background: Interpersonal stress and perceived rejection have been clinically observed as common triggers of nonsuicidal self-injury (NSSI), with self-injury behavior regulating both affective and social experiences. We investigated whether the subjective interpretation of social interaction in a simulated online environment might be biased in the NSSI group, and the brain mechanisms underlying the experience. Methods: Thirty female adolescent patients with NSSI and thirty female age-matched controls were investigated in this case-control study. In our novel task that simulates interaction on current social media platforms, participants indicated whether they liked or disliked pictures of other players during a functional magnetic resonance imaging (fMRI) scan. Participants also viewed positive and negative feedback directed toward them by others. The task also assessed the subjective effects of the social interaction. Finally, subjects underwent a separate facial electromyography session, which measured facial expressions processing. Outcomes: Behaviorally, the NSSI group showed a negative bias in processing social feedback from others. A multi-voxel pattern analysis (MVPA) identified brain regions that robustly classified NSSI subjects and controls. Regions in which mutual activity contributed to the classification included dorsomedial prefrontal cortex and subgenual anterior cingulate cortex, a region implicated in mood control. In the NSSI group, multi-voxel classification scores correlated with behavioral sensitivity to negative feedback from others. Results remained significant after controlling for medication, symptoms of depression, and symptoms of borderline personality disorder. Interpretation: This study identified behavioral and neural signatures of adolescents with NSSI during social interaction in a simulated social media environment. These findings highlight the importance of understanding social information processing in this clinical population and can potentially advance treatment approaches.
Brain, 2021
Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 pr... more Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a the...
doi: 10.3389/fnhum.2013.00755 Facets and mechanisms of adaptive pain behavior: predictive regulat... more doi: 10.3389/fnhum.2013.00755 Facets and mechanisms of adaptive pain behavior: predictive regulation and action
Seeking pleasant touch: neural correlates of behavioral
Cerebral Cortex, 2020
The evidence that action shapes perception has become widely accepted, for example, in the domain... more The evidence that action shapes perception has become widely accepted, for example, in the domain of vision. However, the manner in which action-relevant factors might influence the neural dynamics of acute pain processing has remained underexplored, particularly the functional roles of anterior insula (AI) and midanterior cingulate cortex (mid-ACC), which are frequently implicated in acute pain. To address this, we examined a unique group of heterozygous carriers of the rare R221W mutation on the nerve growth factor (NGF) gene. R221W carriers show a congenitally reduced density of C-nociceptor afferent nerves in the periphery, but can nonetheless distinguish between painful and nonpainful stimulations. Despite this, carriers display a tendency to underreact to acute pain behaviorally, thus exposing a potential functional gap in the pain–action relationship and allowing closer investigation of how the brain integrates pain and action information. Heterozygous R221W carriers and matc...
Current topics in behavioral neurosciences, 2021
Socialization happens so regularly in humans that it can be perceived as an effortless activity. ... more Socialization happens so regularly in humans that it can be perceived as an effortless activity. However, it reflects a sophisticated behavior, pervaded by anticipation and emotion. The fast-paced social interplay, strongly mediated by facial expressions, can be considered one of the most frequent high-order motor acts within the human behavioral repertoire. The ability to adequately process social feedback is critical for appropriate socialization and affects well-being. The social difficulties often observed in psychiatric patients highlight the link between mental health and successful socialization and the importance of characterizing the behavioral and neural mechanisms of social interaction. This chapter will present some cross-species evidence on the cortical regions engaged during social interactions including facial expressions, and the impact of induced or perceived social stress on the experience of social interactions.
Biological psychiatry. Cognitive neuroscience and neuroimaging, 2020
BACKGROUND Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations worldwide. Emoti... more BACKGROUND Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations worldwide. Emotion dysregulation is believed to contribute to NSSI, but underlying mechanisms are less known. We combined psychophysiological and neural data with subjective self-report in close temporal proximity to examine the mechanisms underlying emotion processing in adolescents with NSSI relative to control adolescents without a psychiatric diagnosis. METHODS Thirty female adolescents with NSSI and 30 age-matched female control subjects were included in this case-control study. Participants were presented with negative affective pictures during a functional magnetic resonance imaging scan. In a separate facial electromyography session, the same participants were shown positive and negative affective images and also provided ratings of valence and arousal. RESULTS Participants with NSSI responded to affective images with greater positive (e.g., zygomatic) and greater negative (e.g., corrugator) rea...
Biological Psychiatry
BACKGROUND Alcohol addiction is associated with a high disease burden, and treatment options are ... more BACKGROUND Alcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging. METHODS This was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures. RESULTS Both craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 ± 0.8% vs. 10.6 ± 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex. CONCLUSIONS We provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity.
Francis Jennings has to his credit an impressive array of titles in colonial American studies, in... more Francis Jennings has to his credit an impressive array of titles in colonial American studies, including The Invasion of America and The Founders of America (on native peoples and the contact between them and European colonizers) and The AmbiguousIroquoisEmpire and Empire of Fortune (both of which treat Six Nations culture during the seventeenth and eighteenth centuries). To these well-known, densely constructed, and often-cited studies, Jennings is adding a study of Benjamin Franklin. In introductory matter to the volume, Jennings says that he had studied Franklin closely decades ago. In many ways, though, the major scholarly contribution of the volume-a discussion of Franklin's activities from the 1750s through the 1770s-seems a logical outgrowth of Jennings's earlier work on Six Nations culture and the conflicts between the Six Nations Iroquois and the Lenni Lenape (the Delaware) peoples during the middle of the eighteenth century, as both groups faced continued settlement by Europeans on their ancestral lands. Jennings assumes from the outset that his book is revisionary. Among the epigraphs is Harrison Salisbury's comment from Heroes of My Time, "I harbor deep distrust of obvious heroes." Jennings himself insists in the introduction that the events of Franklin's life "reveal the ego hidden so carefully behind his words" (p. 15), and he avers that "the long life of Benjamin Franklin requires some reassessment of the standard thought about the beginnings of the American Revolution" (p. 16). In "A Note on the Sources," he concludes: "My findings herein are strongly revisionist" (p. 204). Jennings's assertions are to some extent accurate, if overstated. Scholars of the past two decades or so have been reexamining the papers of the so-called "founders" in an effort to fill in gaps left by World War II and postwar historians who sought a predominantly "American" story and made of the founders important "American" heroes. If we find these earlier historians wanting at this stage in the century, it is nonetheless useful if we keep the era of the world wars in sight: midcentury historians had an eye to developing a nationalistic construct, perhaps, just as scholars today might wish to examine colonial history from a transnational and multiethnic perspective. Jennings's book seems to divide into two sections, the first examining Franklin's common-law marriage and activities in Philadelphia to about the 1750s (the first THE PENNSYLVANIA MAGAZINE OF HISTORY AND BIOGRAPHY Vol. CXXI, No. 4 (October 1997) 372 BOOK REVIEWS October eight chapters) and the latter examining the years from the assembly campaigns of the early 1750s through the era of the Revolution. In the first eight chapters, the major thrust of Jennings's revisionism is a filling in of the gaps Jennings finds in Franklin's autobiography. Thus Jennings features Israel Pemberton, Jr., who "is a nonperson in the Autobiography" and who in Jennings's view was "as active as Benjamin Franklin in Philadelphia's civic affairs outside the Assembly/' Pemberton's absence from Franklin's memoir indicates to Jennings that "the competition rankled Franklin, who could be generous to the Quakers who were deferential to himself' (p. 44). Likewise, with regard to his securing the post of deputy postmaster at Philadelphia, Franklin's not having mentioned the unneeded patronage of Thomas Penn's provincial chief justice William Allen is also taken by Jennings as a sign of Franklin's ego (pp. 38-39). Perhaps more surprisingly, Franklin's not mentioning in his memoir his friend James Logan's activities during the nefarious Walking Purchase land-grab-indeed, the omission of any mention whatsoever of the chicanery of the Penn descendants and Franklin's early friendship with them, for patronageis understood by Jennings to be a "trivialization" of "the struggle by Pennsylvanians against their feudal lord": 'The self-consciously wise Franklin of the Autobiography could not admit how he had been duped by Penn and, worse, had actually worked hard to support Penn's political machine" (pp. 57, 58). For the same reasons, according to Jennings, Franklin omitted talking about William Smith in faz Autobiography: "To mention him would have required Franklin to confess that Smith had used and made a fool of him, had outsmarted him, and such a confession would be intolerable" (p. 70). For the most part, the key aspects of these early chaptersthe discussion related to Pemberton and the sneaking nature of the Walking Purchase-are detailed in Jennings's earlier writings, though here the discussion centers on people with whom Franklin was in contact. The other matters of these chapters are well-known and much-discussed, often in more detail, by most Franklinists. Although Jennings's later chapters cover some of the same issues as chapters 6 through 8, they focus on two central issues: first, Franklin's growing personal antagonisms with the Penns and the assembly's distrust of the whole proprietary system; and, second, Franklin's developing disillusionment with royalism and his eventual prorebellion fervor, ultimately ending in his refusal to assist royalist son, William, and his wife, once William had been taken into custody. These later chapters offer, for the most part, a condensed version of Jennings's magisterial book, Empire of Fortune. Their contribution lies in their treatment, especially for a general reader, of the events in which Franklin was entangled during the decade just prior to the Revolutionary War. With specific regard to Franklin's place in the growing turmoil, these chapters trace several of the well-known issues in Franklin's dealings with friends and with the British government: Franklin's statement of utter contempt for Thomas Penn after Penn slurred his father William Penn's name; Franklin's initial 1997 BOOK REVIEWS 373 acceptance of stamp measures set out by parliament, his attempted land negotiations with a number of lords; his imperialist attitudes that denied the legitimacy of settlement claims by Germans, Irish, Scotch-Irish, and native peoples to lands held by the Penn proprietary. In terms of Franklin's life story, the revisionary nature of these later chapters is less apparent, and thus the tone Jennings takes toward Franklin seems a little less smug, although here, too, Jennings takes Franklin to task for what Jennings sees as Franklin's inability to abide Quakers. Broadly speaking, Jennings's book seems to have three key issues at stake. Ostensibly, Jennings says he is filling in the gaps that historians (popular historians, really-not specialists) have left open in their celebrations of Franklin and the American revolutionary past. But the book's effect is actually more expansive. Jennings is, first, critiquing New England-oriented history-writing and the New England historians' focus on, for instance, the Boston Tea Party, instead, Jennings posits the centrality of midcentury affairs in Pennsylvania, Virginia, and the Ohio territory, and the importance of the proprietary charter rights versus Crown prerogative that Franklin addressed during his life. Historians of the American Revolution, in seeking to establish the revolt on ideological grounds based on a Whig interpretation of charter rights and liberties, wrongly focus on the rhetoric that came out of New England and more suitably might stress the economic, ethnic, and land concerns of the Middle Atlantic. Jennings's close analysis of the entanglements Franklin faced indicates the importance of a largely revisioned history that would account for more general tendencies rather than a few selected incidents from New England. If only for this reason, the book is a useful revisionist study. Second, Jennings is establishing (in the discussion of the Pennsylvania proprietary problems and the border settlers) a set of issues that more narrowly depicts the causes of the Revolution as economic and social, more middle-brow, mercantile, and plebeian, rather than ideological, and he thus shows the day-today causes as of key importance, not the rhetoric of revolution for which famous men are celebrated. Third, Jennings is participating in a revision of the history of the Religious Society of Friends, based on his assumption that the Quakers have received negative attention because of their pacifist stance during the Revolution. While Jennings might be correct in his assessment that Quaker calumniators then and perhaps now have driven negative readings about Quakers of the era of the American Revolution, to some extent, he seems to overstate his case with regard to Franklin and the Quakers. It is hard to miss the humor of Franklin's Autobiography where Franklin points to the quietness and security of a meeting of the Religious Society of Friends by announcing that, having repaired to such a meeting upon his first arrival in Philadelphia, he promptly fell asleep. To Jennings, however, Franklin's "massive ego is revealed more complexly in his callous conduct toward Quakers" (p. 197). Yet Jennings himself has shown the key issues that were at stake. Franklin initially wanted Crown intervention that would force taxation of the 374 BOOK REVIEWS October proprietary lands, because the border areas needed defending. Quakers did not wish themselves to provide for the defense of English settlers, based on their peace testimony; this would be an alternate way to provide for defense while stopping proprietary prerogative. Crown intervention might have mandated test oaths which Quakers would not be able to take. Franklin, an imperialist, not a Quaker, evidently did not see the contradiction that might have eventuated for Quakers between the chartered liberties original to the William Penn tract grant and those "liberties" associated with British imperial policy. Many imperialists might not have seen the potential problems herein. In pushing the position that Franklin disliked Quakers, especially during the 1750s and through the...
The ability to generate and regulate emotional experiences is critical to psychological well-bein... more The ability to generate and regulate emotional experiences is critical to psychological well-being. Impairments in emotion regulatory processes have transdiagnostic associations with psychopathology. Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations, especially clinical adolescent populations, and often linked to emotion regulatory deficits. Clinical observations propose a role for NSSI behaviors in regulating affect, suggesting that these behaviors may arise when other emotion regulatory strategies are insufficient or inaccessible. Experimental evidence has begun to explore the psychophysiological and neural underpinnings of emotion processing in NSSI populations. Thus far, a primary focus has been the role of NSSI in regulation of affect in response to stressful or negative states or stimuli, often suggesting enhanced reactivity in such situations. However, recent evidence suggests that NSSI populations may also display heightened reactivity to positive or rewa...
CT afferents have been known for years, since 1939 when Zotterman suggested they might contribute... more CT afferents have been known for years, since 1939 when Zotterman suggested they might contribute to itch. But their study has been hampered because any low threshold tactile stimulus will also activate large numbers of Aβ afferents. To investigate the psychophysics of CT afferents has recently become possible through microneurography, allowing selective recording from groups of these nerves, (Loken et al., Nat Neurosci 12(5):547–548, 2009 and this volume), and through the study of two rare cohorts of people who have lost either large fibre afferents due to disease or have selective loss of C afferents themselves due to hereditary neuropathy. This chapter details this latter work, and though comparisons between those with neurological conditions and control subjects must always be done with caution, such work can allow some insights into the normal functioning of the CT system.
Neuropsychopharmacology
Social drinking is common, but it is unclear how moderate levels of alcohol influence decision ma... more Social drinking is common, but it is unclear how moderate levels of alcohol influence decision making. Most prior studies have focused on adverse long-term effects on cognitive and executive function in people with alcohol use disorders (AUD). Some studies have investigated the acute effects of alcohol on decision making in healthy people, but have predominantly used small samples and focused on a narrow selection of tasks related to personal decision making, e.g., delay or probability discounting. Here, we conducted a large (n = 264), preregistered randomized placebo-controlled study (RCT) using a parallel group design, to systematically assess the acute effects of alcohol on measures of decision making in both personal and social domains. We found a robust effect of a 0.6 g/kg dose of alcohol on both moral judgment and altruistic behavior, but no effects on several measures of risk taking or waiting impulsivity. These findings suggest that alcohol at low to moderate doses selectively moderates decision making in the social domain, and promotes utilitarian decisions over those dictated by rule-based ethical principles (deontological). This is consistent with existing theory that emphasizes the dual roles of shortsighted information processing and salient social cues in shaping decisions made under the influence of alcohol. A better understanding of these effects is important to understand altered social functioning during alcohol intoxication.
BackgroundCue reactivity is one of the most frequently used paradigms in functional magnetic reso... more BackgroundCue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). While there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participant characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work is difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting, and review the FDCR literature to assess the reporting of items that are deemed important.MethodsFifty-five FDCR scientists from around the world participated in this st...
Translational Psychiatry
An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affect... more An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affective touch is an important means of social interaction, and C-Tactile (CT) afferents are thought to play a key role in the peripheral detection and encoding of these stimuli. Exploring the neural and behavioral mechanisms for processing CT-optimal touch (~3 cm/s) may therefore provide useful insights into the pathophysiology of ASD. We examined the relationship between touch hedonics (i.e. the subjective pleasantness with which affective touch stimuli are perceived) and neural processing in the posterior superior temporal sulcus (pSTS). This region is less activated to affective touch in individuals with ASD, and, in typically developing individuals (TD), is correlated positively with touch pleasantness. TD and ASD participants received brushing stimuli at CT-optimal, and CT-non-optimal speeds during fMRI. Touch pleasantness and intensity ratings were collected, and affective touch awaren...
Frontiers in Psychiatry
Nonsuicidal self-injury disorder (NSSID) is a condition in need of further study, especially in a... more Nonsuicidal self-injury disorder (NSSID) is a condition in need of further study, especially in adolescent and clinical populations where it is particularly prevalent and studies are limited. Twenty-nine clinical self-injuring adolescents were included in the study. The Clinical Assessment of Nonsuicidal Self-Injury Disorder Index (CANDI) was used to assess prevalence of NSSID. The NSSID diagnosis criteria were met by 62.1% of adolescents. The impairment or distress criterion was least often met. Criteria B and C (assessing reasons for NSSI and cognitions/emotions prior to NSSI) were confirmed by 96-100% of all participants. Adolescents with NSSI in this clinical sample had several comorbidities and high levels of psychopathology. NSSID occurred both in combination with and independently of borderline personality disorder traits as well as suicide plans and attempts. Those with NSSID had a significantly higher cutting frequency than those not meeting full NSSID criteria. Other NSSI characteristics, comorbidity, psychopathology, and trauma experiences did not differ between groups. CANDI was a feasible tool to assess NSSID in adolescents. It is important to use structured measures to assess the validity of the NSSID diagnosis across development in both community and clinical samples. The clinical utility of the NSSID diagnosis is discussed.
Neuropsychopharmacology
Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicot... more Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatmentseeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.
Pain is an unpleasant but necessary sensory experience, which facilitates adaptive behaviours, su... more Pain is an unpleasant but necessary sensory experience, which facilitates adaptive behaviours, such as fear. Despite recent advances, the question of how the pain experience influences learning of the fear response is still debated1,2. Genetic disorders rendering patients congenitally unable to feel pain have been described, and are usually explained by defects in peripheral nociceptors3-5. It is not known how growing up without pain affects central emotional and motivational responses to aversive stimuli. The rare autosomal recessive Hereditary Sensory and Autonomic Neuropathy type V (HSAN V) is caused by a mutation in the nerve growth factor (NGF) gene (R100W). HSAN V homozygous patients display a congenital indifference to painful events, with deficits in peripheral nociceptors but without overt cognitive impairment6. In contrast, heterozygous carriers do not present with pain-related deficits and have been identified only through pedigree and genetic screening7,8. We exploited t...
EClinicalMedicine
Background: Interpersonal stress and perceived rejection have been clinically observed as common ... more Background: Interpersonal stress and perceived rejection have been clinically observed as common triggers of nonsuicidal self-injury (NSSI), with self-injury behavior regulating both affective and social experiences. We investigated whether the subjective interpretation of social interaction in a simulated online environment might be biased in the NSSI group, and the brain mechanisms underlying the experience. Methods: Thirty female adolescent patients with NSSI and thirty female age-matched controls were investigated in this case-control study. In our novel task that simulates interaction on current social media platforms, participants indicated whether they liked or disliked pictures of other players during a functional magnetic resonance imaging (fMRI) scan. Participants also viewed positive and negative feedback directed toward them by others. The task also assessed the subjective effects of the social interaction. Finally, subjects underwent a separate facial electromyography session, which measured facial expressions processing. Outcomes: Behaviorally, the NSSI group showed a negative bias in processing social feedback from others. A multi-voxel pattern analysis (MVPA) identified brain regions that robustly classified NSSI subjects and controls. Regions in which mutual activity contributed to the classification included dorsomedial prefrontal cortex and subgenual anterior cingulate cortex, a region implicated in mood control. In the NSSI group, multi-voxel classification scores correlated with behavioral sensitivity to negative feedback from others. Results remained significant after controlling for medication, symptoms of depression, and symptoms of borderline personality disorder. Interpretation: This study identified behavioral and neural signatures of adolescents with NSSI during social interaction in a simulated social media environment. These findings highlight the importance of understanding social information processing in this clinical population and can potentially advance treatment approaches.