Individual differences in the effects of perceived controllability on pain perception: critical role of the prefrontal cortex

The degree to which perceived controllability alters the way a stressor is experienced varies greatly among individuals. We used functional magnetic resonance imaging to examine the neural activation associated with individual differences in the impact of perceived controllability on self-reported pain perception. Subjects with greater activation in response to uncontrollable (UC) rather than controllable (C) pain in the pregenual anterior cingulate cortex (pACC), periaqueductal gray (PAG), and posterior insula/SII reported higher levels of pain during the UC versus C conditions. Conversely, subjects with greater activation in the ventral lateral prefrontal cortex (VLPFC) in anticipation of pain in the UC versus C conditions reported less pain in response to UC versus C pain. Activation in the VLPFC was significantly correlated with the acceptance and denial subscales of the COPE inventory [Carver, C. S., Scheier, M. F., & Weintraub, J. K. Assessing coping strategies: A theoretically based approach. Journal of Personality and Social Psychology, 56, 267–283, 1989], supporting the interpretation that this anticipatory activation was associated with an attempt to cope with the emotional impact of uncontrollable pain. A regression model containing the two prefrontal clusters (VLPFC and pACC) predicted 64% of the variance in pain rating difference, with activation in the two additional regions (PAG and insula/SII) predicting almost no additional variance. In addition to supporting the conclusion that the impact of perceived controllability on pain perception varies highly between individuals, these findings suggest that these effects are primarily top-down, driven by processes in regions of the prefrontal cortex previously associated with cognitive modulation of pain and emotion regulation.

Individual Differences in Amygdala and Ventromedial Prefrontal Cortex Activity are Associated with Evaluation Speed and Psychological Well-being

Using functional magnetic resonance imaging, we examined whether individual differences in amygdala activation in response to negative relative to neutral information are related to differences in the speed with which such information is evaluated, the extent to which such differences are associated with medial prefrontal cortex function, and their relationship with measures of trait anxiety and psychological well-being (PWB). Results indicated that faster judgments of negative relative to neutral information were associated with increased left and right amygdala activation. In the prefrontal cortex, faster judgment time was associated with relative decreased activation in a cluster in the ventral anterior cingulate cortex (ACC, BA 24). Furthermore, people who were slower to evaluate negative versus neutral information reported higher PWB. Importantly, higher PWB was strongly associated with increased activation in the ventral ACC for negative relative to neutral information. Individual differences in trait anxiety did not predict variation in judgment time or in amygdala or ventral ACC activity. These findings suggest that people high in PWB effectively recruit the ventral ACC when confronted with potentially aversive stimuli, manifest reduced activity in subcortical regions such as the amygdala, and appraise such information as less salient as reflected in slower evaluative speed.

A Functional Magnetic Resonance Imaging Predictor of Treatment Response to Venlafaxine in Generalized Anxiety Disorder

Background: Functional magnetic resonance imaging (fMRI) holds promise as a noninvasive means of identifying neural responses that can be used to predict treatment response before beginning a drug trial. Imaging paradigms employing facial expressions as presented stimuli have been shown to activate the amygdala and anterior cingulate cortex (ACC). Here, we sought to determine whether pretreatment amygdala and rostral ACC (rACC) reactivity to facial expressions could predict treatment outcomes in patients with generalized anxiety disorder (GAD).Methods: Fifteen subjects (12 female subjects) with GAD participated in an open-label venlafaxine treatment trial. Functional magnetic resonance imaging responses to facial expressions of emotion collected before subjects began treatment were compared with changes in anxiety following 8 weeks of venlafaxine administration. In addition, the magnitude of fMRI responses of subjects with GAD were compared with that of 15 control subjects (12 female subjects) who did not have GAD and did not receive venlafaxine treatment.Results The magnitude of treatment response was predicted by greater pretreatment reactivity to fearful faces in rACC and lesser reactivity in the amygdala. These individual differences in pretreatment rACC and amygdala reactivity within the GAD group were observed despite the fact that 1) the overall magnitude of pretreatment rACC and amygdala reactivity did not differ between subjects with GAD and control subjects and 2) there was no main effect of treatment on rACC-amygdala reactivity in the GAD group.Conclusions: These findings show that this pattern of rACC-amygdala responsivity could prove useful as a predictor of venlafaxine treatment response in patients with GAD.

Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate.

We argue that impulsiveness is characterized by compromised timing functions such as premature motor timing, decreased tolerance to delays, poor temporal foresight and steeper temporal discounting. A model illustration for the association between impulsiveness and timing deficits is the impulsiveness disorder of attention-deficit hyperactivity disorder (ADHD). Children with ADHD have deficits in timing processes of several temporal domains and the neural substrates of these compromised timing functions are strikingly similar to the neuropathology of ADHD. We review our published and present novel functional magnetic resonance imaging data to demonstrate that ADHD children show dysfunctions in key timing regions of prefrontal, cingulate, striatal and cerebellar location during temporal processes of several time domains including time discrimination of milliseconds, motor timing to seconds and temporal discounting of longer time intervals. Given that impulsiveness, timing abnormalities and more specifically ADHD have been related to dopamine dysregulation, we tested for and demonstrated a normalization effect of all brain dysfunctions in ADHD children during time discrimination with the dopamine agonist and treatment of choice, methylphenidate. This review together with the new empirical findings demonstrates that neurocognitive dysfunctions in temporal processes are crucial to the impulsiveness disorder of ADHD and provides first evidence for normalization with a dopamine reuptake inhibitor.

Individual differences in some (but not all) medial prefrontal regions reflect cognitive demand while regulating unpleasant emotion.

The present study investigated the premise that individual differences in autonomic physiology could be used to specify the nature and consequences of information processing taking place in medial prefrontal regions during cognitive reappraisal of unpleasant pictures. Neural (blood oxygenation level-dependent functional magnetic resonance imaging) and autonomic (electrodermal [EDA], pupil diameter, cardiac acceleration) signals were recorded simultaneously as twenty-six older people (ages 64–66 years) used reappraisal to increase, maintain, or decrease their responses to unpleasant pictures. EDA was higher when increasing and lower when decreasing compared to maintaining. This suggested modulation of emotional arousal by reappraisal. By contrast, pupil diameter and cardiac acceleration were higher when increasing and decreasing compared to maintaining. This suggested modulation of cognitive demand. Importantly, reappraisal-related activation (increase, decrease > maintain) in two medial prefrontal regions (dorsal medial frontal gyrus and dorsal cingulate gyrus) was correlated with greater cardiac acceleration (increase, decrease > maintain) and monotonic changes in EDA (increase > maintain > decrease). These data indicate that these two medial prefrontal regions are involved in the allocation of cognitive resources to regulate unpleasant emotion, and that they modulate emotional arousal in accordance with the regulatory goal. The emotional arousal effects were mediated by the right amygdala. Reappraisal-related activation in a third medial prefrontal region (subgenual anterior cingulate cortex) was not associated with similar patterns of change in any of the autonomic measures, thus highlighting regional specificity in the degree to which cognitive demand is reflected in medial prefrontal activation during reappraisal.

Atypical neural self-representation in autism

The 'self' is a complex multidimensional construct deeply embedded and in many ways defined by our relations with the social world. Individuals with autism are impaired in both self-referential and other-referential social cognitive processing. Atypical neural representation of the self may be a key to understanding the nature of such impairments. Using functional magnetic resonance imaging we scanned adult males with an autism spectrum condition and age and IQ-matched neurotypical males while they made reflective mentalizing or physical judgements about themselves or the British Queen. Neurotypical individuals preferentially recruit the middle cingulate cortex and ventromedial prefrontal cortex in response to self compared with other-referential processing. In autism, ventromedial prefrontal cortex responded equally to self and other, while middle cingulate cortex responded more to other-mentalizing than self-mentalizing. These atypical responses occur only in areas where self-information is preferentially processed and does not affect areas that preferentially respond to other-referential information. In autism, atypical neural self-representation was also apparent via reduced functional connectivity between ventromedial prefrontal cortex and areas associated with lower level embodied representations, such as ventral premotor and somatosensory cortex. Furthermore, the magnitude of neural self-other distinction in ventromedial prefrontal cortex was strongly related to the magnitude of early childhood social impairments in autism. Individuals whose ventromedial prefrontal cortex made the largest distinction between mentalizing about self and other were least socially impaired in early childhood, while those whose ventromedial prefrontal cortex made little to no distinction between mentalizing about self and other were the most socially impaired in early childhood. These observations reveal that the atypical organization of neural circuitry preferentially coding for self-information is a key mechanism at the heart of both self-referential and social impairments in autism.

Shared neural circuits for mentalizing about the self and others

Although many examples exist for shared neural representations of self and other, it is unknown how such shared representations interact with the rest of the brain. Furthermore, do high-level inference-based shared mentalizing representations interact with lower level embodied/simulation-based shared representations? We used functional neuroimaging (fMRI) and a functional connectivity approach to assess these questions during high-level inference-based mentalizing. Shared mentalizing representations in ventromedial prefrontal cortex, posterior cingulate/precuneus, and temporo-parietal junction (TPJ) all exhibited identical functional connectivity patterns during mentalizing of both self and other. Connectivity patterns were distributed across low-level embodied neural systems such as the frontal operculum/ventral premotor cortex, the anterior insula, the primary sensorimotor cortex, and the presupplementary motor area. These results demonstrate that identical neural circuits are implementing processes involved in mentalizing of both self and other and that the nature of such processes may be the integration of low-level embodied processes within higher level inference-based mentalizing.

Microglial activation correlates with severity in Huntington disease: a clinical and PET study

Background: Huntington disease ( HD) is characterized by the progressive death of medium spiny dopamine receptor bearing striatal GABAergic neurons. In addition, microglial activation in the areas of neuronal loss has recently been described in postmortem studies. Activated microglia are known to release neurotoxic cytokines, and these may contribute to the pathologic process. Methods: To evaluate in vivo the involvement of microglia activation in HD, the authors studied patients at different stages of the disease using [ C-11]( R)-PK11195 PET, a marker of microglia activation, and [ C-11] raclopride PET, a marker of dopamine D2 receptor binding and hence striatal GABAergic cell function. Results: In HD patients, a significant increase in striatal [ C-11]( R)-PK11195 binding was observed, which significantly correlated with disease severity as reflected by the striatal reduction in [ C-11] raclopride binding, the Unified Huntington's Disease Rating Scale score, and the patients' CAG index. Also detected were significant increases in microglia activation in cortical regions including prefrontal cortex and anterior cingulate. Conclusions: These [ C-11]( R)-PK11195 PET findings show that the level of microglial activation correlates with Huntington disease ( HD) severity. They lend support to the view that microglia contribute to the ongoing neuronal degeneration in HD and indicate that [ C-11]( R)-PK11195 PET provides a valuable marker when monitoring the efficacy of putative neuroprotecting agents in this relentlessly progressive genetic disorder.

How does the brain mediate interpretation of incongruent auditory emotions? The neural response to prosody in the presence of conflicting lexico-semantic cues

We frequently encounter conflicting emotion cues. This study examined how the neural response to emotional prosody differed in the presence of congruent and incongruent lexico-semantic cues. Two hypotheses were assessed: (i) decoding emotional prosody with conflicting lexico-semantic cues would activate brain regions associated with cognitive conflict (anterior cingulate and dorsolateral prefrontal cortex) or (ii) the increased attentional load of incongruent cues would modulate the activity of regions that decode emotional prosody (right lateral temporal cortex). While the participants indicated the emotion conveyed by prosody, functional magnetic resonance imaging data were acquired on a 3T scanner using blood oxygenation level-dependent contrast. Using SPM5, the response to congruent cues was contrasted with that to emotional prosody alone, as was the response to incongruent lexico-semantic cues (for the 'cognitive conflict' hypothesis). The right lateral temporal lobe region of interest analyses examined modulation of activity in this brain region between these two contrasts (for the 'prosody cortex' hypothesis). Dorsolateral prefrontal and anterior cingulate cortex activity was not observed, and neither was attentional modulation of activity in right lateral temporal cortex activity. However, decoding emotional prosody with incongruent lexico-semantic cues was strongly associated with left inferior frontal gyrus activity. This specialist form of conflict is therefore not processed by the brain using the same neural resources as non-affective cognitive conflict and neither can it be handled by associated sensory cortex alone. The recruitment of inferior frontal cortex may indicate increased semantic processing demands but other contributory functions of this region should be explored.

The BOLD response during Stroop task-like inhibition paradigms: effects of task difficulty and task-relevant modality

Previous studies of the Stroop task propose two key mediators: the prefrontal and cingulate cortices but hints exist of functional specialization within these regions. This study aimed to examine the effect of task modality upon the prefrontal and cingulate response by examining the response to colour, number, and shape Stroop tasks whilst BOLD fMRI images were acquired on a Siemens 3 T MRI scanner. Behavioural analyses indicated facilitation and interference effects and a noticeable effect of task difficulty. Some modular effects of modality were observed in the prefrontal cortex that survived exclusion of task difficulty related activations. No effect of task-relevant information was observed in the anterior cingulate. Future comparisons of the mediation of selective attention need to consider the effects of task context and task difficulty. (c) 2005 Elsevier Inc. All rights reserved.

Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise

Recent brain imaging studies using functional magnetic resonance imaging (fMRI) have implicated insula and anterior cingulate cortices in the empathic response to another's pain. However, virtually nothing is known about the impact of the voluntary generation of compassion on this network. To investigate these questions we assessed brain activity using fMRI while novice and expert meditation practitioners generated a loving-kindness-compassion meditation state. To probe affective reactivity, we presented emotional and neutral sounds during the meditation and comparison periods. Our main hypothesis was that the concern for others cultivated during this form of meditation enhances affective processing, in particular in response to sounds of distress, and that this response to emotional sounds is modulated by the degree of meditation training. The presentation of the emotional sounds was associated with increased pupil diameter and activation of limbic regions (insula and cingulate cortices) during meditation (versus rest). During meditation, activation in insula was greater during presentation of negative sounds than positive or neutral sounds in expert than it was in novice meditators. The strength of activation in insula was also associated with self-reported intensity of the meditation for both groups. These results support the role of the limbic circuitry in emotion sharing. The comparison between meditation vs. rest states between experts and novices also showed increased activation in amygdala, right temporo-parietal junction (TPJ), and right posterior superior temporal sulcus (pSTS) in response to all sounds, suggesting, greater detection of the emotional sounds, and enhanced mentation in response to emotional human vocalizations for experts than novices during meditation. Together these data indicate that the mental expertise to cultivate positive emotion alters the activation of circuitries previously linked to empathy and theory of mind in response to emotional stimuli.

Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting

Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making.

The functional neuroanatomy of the evolving parent–infant relationship

Infant survival and the development of secure and cooperative relationships are central to the future of the species. In humans, this relies heavily on the evolving early parent–infant social and affective relationship. While much is known about the behavioural and psychological components of this relationship, relatively little is known about the underlying functional neuroanatomy. Affective and social neuroscience has helped to describe the main adult brain networks involved, but has so far engaged very little with developmental findings. In this review, we seek to highlight future avenues for research by providing a coherent framework for describing the parent–infant relationship over the first 18 months. We provide an outline of the evolving nature of the relationship, starting with basic orienting and recognition processes, and culminating in the infant's attainment of higher socio-emotional and cognitive capacities. Key social and affective interactions, such as communication, cooperative play and the establishment of specific attachments propel the development of the parent–infant relationship. We summarise our current knowledge of the developing infant brain in terms of structure and function, and how these relate to the emergent abilities necessary for the formation of a secure and cooperative relationship with parents or other caregivers. Important roles have been found for brain regions including the orbitofrontal, cingulate, and insular cortices in parent–infant interactions, but it has become clear that much more information is needed about the developmental time course and connectivity of these regions.

Electrophysiological correlates of spatial orienting towards angry faces: a source localization study

The goal of this study was to examine behavioral and electrophysiological correlates of involuntary orienting toward rapidly presented angry faces in non-anxious, healthy adults using a dot-probe task in conjunction with high-density event-related potentials and a distributed source localization technique. Consistent with previous studies, participants showed hypervigilance toward angry faces, as indexed by facilitated response time for validly cued probes following angry faces and an enhanced P1 component. An opposite pattern was found for happy faces suggesting that attention was directed toward the relatively more threatening stimuli within the visual field (neutral faces). Source localization of the P1 effect for angry faces indicated increased activity within the anterior cingulate cortex, possibly reflecting conflict experienced during invalidly cued trials. No modulation of the early C1 component was found for affect or spatial attention. Furthermore, the face-sensitive N170 was not modulated by emotional expression. Results suggest that the earliest modulation of spatial attention by face stimuli is manifested in the P1 component, and provide insights about mechanisms underlying attentional orienting toward cues of threat and social disapproval.

Age-related changes in the functional neuroanatomy of overt speech production

Alterations of existing neural networks during healthy aging, resulting in behavioral deficits and changes in brain activity, have been described for cognitive, motor, and sensory functions. To investigate age-related changes in the neural circuitry underlying overt non-lexical speech production, functional MRI was performed in 14 healthy younger (21–32 years) and 14 healthy older individuals (62–84 years). The experimental task involved the acoustically cued overt production of the vowel /a/ and the polysyllabic utterance /pataka/. In younger and older individuals, overt speech production was associated with the activation of a widespread articulo-phonological network, including the primary motor cortex, the supplementary motor area, the cingulate motor areas, and the posterior superior temporal cortex, similar in the /a/ and /pataka/ condition. An analysis of variance with the factors age and condition revealed a significant main effect of age. Irrespective of the experimental condition, significantly greater activation was found in the bilateral posterior superior temporal cortex, the posterior temporal plane, and the transverse temporal gyri in younger compared to older individuals. Significantly greater activation was found in the bilateral middle temporal gyri, medial frontal gyri, middle frontal gyri, and inferior frontal gyri in older vs. younger individuals. The analysis of variance did not reveal a significant main effect of condition and no significant interaction of age and condition. These results suggest a complex reorganization of neural networks dedicated to the production of speech during healthy aging.