Conditioning induced placebo-like and nocebo-like effects of thermal discomfort in adults but not in youth.

Introduction: Conditioning can be used to modulate the perception of pain, in the form of placebo and nocebo effects. Previous studies show inconsistent results as to whether adolescents show similar, weaker, or non-significant conditioned placebo and nocebo effects compared to effects found in adults. There are suggestions that such differences (if any) may dependent on the cues used in the thermal conditioning paradigms. Therefore, in this current study, we utilized novel, neutral 3D-shaped visual cues to implicitly induce conditioned placebo-like and nocebo-like effects in adolescents and adults. Methods: During the conditioning paradigm, distinct cues (Fribbles) were paired with low and high temperatures in 24 adults and 20 adolescents (mean age = 25.5 years). In the testing phase, these conditioned cues as well as a neutral (unconditioned) cue were presented with moderate temperatures. Results: Thermal discomfort of moderate temperatures was lower when presented with the conditioned low heat cue (placebo-like effect) and higher when thermal stimuli were presented with the high heat cue (nocebo-like effect) compared to the neutral cue. The effects were driven by adults, as neither the placebo-like nor the nocebo-like effect was significant in adolescents. The difference between adolescents and adults was not explained by differences in temperature or discomfort levels, as adults and adolescents had comparable calibrated temperatures and levels of discomfort during heat stimuli. Conclusion: Our findings suggest that thermal perception in adolescents is less influenced by conditioning to an engaging novel visual cue, compared to adults. Our work may have implications for better understanding the scope and limitations of conditioning as a key mechanism of placebo and nocebo effects in youth.

Conditioned Placebo- and Nocebo-Like Effects in Adolescents: The Role of Conscious Awareness, Sensory Discrimination, and Executive Function.

Background: Conditioning is a key mechanism of placebo and nocebo effects in adults. Little is known about the underlying mechanisms of placebo and nocebo effects in youth and how they might be influenced by conscious awareness and cognitive abilities. In this study, the role of conditioning on thermal perception in youth was investigated. Methods: Differences in thermal ratings were assessed in response to consciously and non-consciously perceived cues that were conditioned to either low or high heat. Furthermore, we tested whether executive function mediates the effect of conditioning on thermal perception. Thirty-five high-school students (14-17 years) completed an executive function task and underwent a sensory perception paradigm. In a conditioning phase, two distinct neutral faces (conditioned cues) were coupled to either a low or a high temperature stimulus delivered to participants' forearms. In a testing phase, the conditioned cues, and novel faces (non-conditioned control cues), were paired with identical moderate thermal stimuli. In this testing phase, for half of the participants cues were presented consciously (supraliminally) and for the other half non-consciously (subliminally). Results: We found a significant main effect of cue type on thermal ratings (p = 0.003) in spite of identical heat being administered following all cues. Post-hoc analyses indicated that the nocebo-like effect (conditioned high cue compared to control) was significant (p = 0.027); the placebo-like effect (conditioned low cue compared to control) was non-significant. No difference between cues presented supra- vs. subliminally and no significant interaction effects were found. The association between sensory discrimination and the magnitude of the nocebo-like effect was mediated by executive function. Conclusions: To our best knowledge, this is the first study establishing a relationship between thermal perception, nocebo effects, and executive function in youth. Our results may have important implications for understanding cognitive/ learning processes involved in nocebo effects.

Hallucination-Specific structure-function associations in schizophrenia.

Combining structural (sMRI) and functional magnetic resonance imaging (fMRI) data in schizophrenia patients with and without auditory hallucinations (9 SZ_AVH, 12 SZ_nAVH), 18 patients with bipolar disorder, and 22 healthy controls, we examined whether cortical thinning was associated with abnormal activity in functional brain networks associated with auditory hallucinations. Language-task fMRI data were combined with mean cortical thickness values from 148 brain regions in a constrained principal component analysis (CPCA) to identify brain structure-function associations predictable from group differences. Two components emerged from the multimodal analysis. The "AVH component" highlighted an association of frontotemporal and cingulate thinning with altered brain activity characteristic of hallucinations among patients with AVH. In contrast, the "Bipolar component" distinguished bipolar patients from healthy controls and linked increased activity in the language network with cortical thinning in the left occipital-temporal lobe. Our findings add to a body of evidence of the biological underpinnings of hallucinations and illustrate a method for multimodal data analysis of structure-function associations in psychiatric illness.

Processing Narratives Concerning Protected Values: A Cross-Cultural Investigation of Neural Correlates.

Narratives are an important component of culture and play a central role in transmitting social values. Little is known, however, about how the brain of a listener/reader processes narratives. A receiver's response to narration is influenced by the narrator's framing and appeal to values. Narratives that appeal to "protected values," including core personal, national, or religious values, may be particularly effective at influencing receivers. Protected values resist compromise and are tied with identity, affective value, moral decision-making, and other aspects of social cognition. Here, we investigated the neural mechanisms underlying reactions to protected values in narratives. During fMRI scanning, we presented 78 American, Chinese, and Iranian participants with real-life stories distilled from a corpus of over 20 million weblogs. Reading these stories engaged the posterior medial, medial prefrontal, and temporo-parietal cortices. When participants believed that the protagonist was appealing to a protected value, signal in these regions was increased compared with when no protected value was perceived, possibly reflecting the intensive and iterative search required to process this material. The effect strength also varied across groups, potentially reflecting cultural differences in the degree of concern for protected values.

Altered balance of functional brain networks in Schizophrenia.

Activity in dorsal attention (DAN) and frontoparietal (FPN) functional brain networks is linked to allocation of attention to external stimuli, and activity in the default-mode network (DMN) is linked to allocation of attention to internal representations. Tasks requiring attention to external stimuli shift activity to the DAN/FPN and away from the DMN, and optimal task performance depends on balancing DAN/FPN against DMN activity. The current functional magnetic resonance imaging (fMRI) study assessed the balance of DAN/FPN and DMN activity in 13 schizophrenia patients and 13 healthy controls while they were engaged in a task switching Stroop paradigm which demanded internally directed attention to task instructions. The typical pattern of reciprocity between the DAN/FPN and DMN was observed for healthy controls but not for patients, suggesting a reduction in the internally focussed thought important for maintenance of instructions and strategies in schizophrenia. The observed alteration in the balance between DAN/FPN and DMN in patients may reflect a general mechanism underlying multiple forms of cognitive impairment in schizophrenia, including global processing deficits such as cognitive inefficiency and impaired context processing.

Body language in the brain: constructing meaning from expressive movement.

This fMRI study investigated neural systems that interpret body language-the meaningful emotive expressions conveyed by body movement. Participants watched videos of performers engaged in modern dance or pantomime that conveyed specific themes such as hope, agony, lust, or exhaustion. We tested whether the meaning of an affectively laden performance was decoded in localized brain substrates as a distinct property of action separable from other superficial features, such as choreography, kinematics, performer, and low-level visual stimuli. A repetition suppression (RS) procedure was used to identify brain regions that decoded the meaningful affective state of a performer, as evidenced by decreased activity when emotive themes were repeated in successive performances. Because the theme was the only feature repeated across video clips that were otherwise entirely different, the occurrence of RS identified brain substrates that differentially coded the specific meaning of expressive performances. RS was observed bilaterally, extending anteriorly along middle and superior temporal gyri into temporal pole, medially into insula, rostrally into inferior orbitofrontal cortex, and caudally into hippocampus and amygdala. Behavioral data on a separate task indicated that interpreting themes from modern dance was more difficult than interpreting pantomime; a result that was also reflected in the fMRI data. There was greater RS in left hemisphere, suggesting that the more abstract metaphors used to express themes in dance compared to pantomime posed a greater challenge to brain substrates directly involved in decoding those themes. We propose that the meaning-sensitive temporal-orbitofrontal regions observed here comprise a superordinate functional module of a known hierarchical action observation network (AON), which is critical to the construction of meaning from expressive movement. The findings are discussed with respect to a predictive coding model of action understanding.

Reduced functional connectivity during controlled semantic integration in schizophrenia: A multivariate approach.

Impairment in controlled semantic association is a central feature of schizophrenia, and the goal of the current functional magnetic resonance imaging study was to identify the neural correlates of this impairment. Thirty people with schizophrenia and 30 healthy age- and gender-matched control subjects performed a task requiring participants to match word pairs that varied in semantic distance (distant vs. close). A whole-brain multivariate connectivity analysis revealed three functional brain networks of primary interest engaged by the task: two configurations of a multiple demands network, in which brain activity did not differ between groups, and a semantic integration network, in which coordinated activity was reduced in schizophrenia patients relative to healthy controls, for distantly relative to closely related word pairs. The hypoactivity during controlled semantic integration in schizophrenia reported here, combined with hyperactivity in automatic semantic association reported in the literature, suggests an imbalance between controlled integration and automatic association. This provides a biological basis for Bleuler's concept of schizophrenia as a "split mind" arising from an impaired ability to form coherent associations between semantic concepts.

Structurally-constrained relationships between cognitive states in the human brain.

The anatomical connectivity of the human brain supports diverse patterns of correlated neural activity that are thought to underlie cognitive function. In a manner sensitive to underlying structural brain architecture, we examine the extent to which such patterns of correlated activity systematically vary across cognitive states. Anatomical white matter connectivity is compared with functional correlations in neural activity measured via blood oxygen level dependent (BOLD) signals. Functional connectivity is separately measured at rest, during an attention task, and during a memory task. We assess these structural and functional measures within previously-identified resting-state functional networks, denoted task-positive and task-negative networks, that have been independently shown to be strongly anticorrelated at rest but also involve regions of the brain that routinely increase and decrease in activity during task-driven processes. We find that the density of anatomical connections within and between task-positive and task-negative networks is differentially related to strong, task-dependent correlations in neural activity. The space mapped out by the observed structure-function relationships is used to define a quantitative measure of separation between resting, attention, and memory states. We find that the degree of separation between states is related to both general measures of behavioral performance and relative differences in task-specific measures of attention versus memory performance. These findings suggest that the observed separation between cognitive states reflects underlying organizational principles of human brain structure and function.

Structural foundations of resting-state and task-based functional connectivity in the human brain.

Magnetic resonance imaging enables the noninvasive mapping of both anatomical white matter connectivity and dynamic patterns of neural activity in the human brain. We examine the relationship between the structural properties of white matter streamlines (structural connectivity) and the functional properties of correlations in neural activity (functional connectivity) within 84 healthy human subjects both at rest and during the performance of attention- and memory-demanding tasks. We show that structural properties, including the length, number, and spatial location of white matter streamlines, are indicative of and can be inferred from the strength of resting-state and task-based functional correlations between brain regions. These results, which are both representative of the entire set of subjects and consistently observed within individual subjects, uncover robust links between structural and functional connectivity in the human brain.

Attitudes trigger motor behavior through conditioned associations: neural and behavioral evidence.

It has long been argued that attitudes prepare the body to act. While early evidence suggested that evaluations (positive or negative) are rigidly linked to specific motor behaviors (approach or avoidant), recent behavioral evidence suggests that this linkage is context dependent. Here, we report that the neural circuitry mediating the relationship between evaluations and motor responses promotes flexibility in our embodiment of attitudes. In a behavioral study, stimulus-response relationships between evaluations and actions were rapidly conditioned. In a neuroimaging (functional magnetic resonance imaging) study, repetition suppression demonstrated that these relationships are formed in neural systems traditionally implicated in arbitrary sensorimotor mappings (i.e. the dorsal premotor cortex and posterior superior parietal lobule). These data provide the first neurophysiological evidence for attitude embodiment and demonstrate that relationships between evaluation and action are inherently malleable.

Decoding intention: a neuroergonomic perspective.

Decoding the intentions of other people based on non-linguistic cues such as their body movement is a major requirement of many jobs. Whether it is maintaining security at an airport or negotiating with locals in a foreign country, there is a need to maximize the effectiveness of training or real-time performance in this decoding process. This review considers the potential utility of neuroergonomic solutions, and in particular, of electroencephalographic (EEG) methods for augmenting action understanding. Focus is given to body movements and hand-object interactions, where there is a rapid growth in relevant science. The interpretation of EEG-based signals is reinforced by a consideration of functional magnetic resonance imaging experiments demonstrating underlying brain mechanisms that support goal oriented action. While no EEG method is currently implemented as a practical application for enhancing the understanding of unspoken intentions, there are a number of promising approaches that merit further development.

Brain responses to biological relevance.

This study examines whether orienting attention to biologically based social cues engages neural mechanisms distinct from those engaged by orienting to nonbiologically based nonsocial cues. Participants viewed a perceptually ambiguous stimulus presented centrally while performing a target detection task. By having participants alternate between viewing this stimulus as an eye in profile or an arrowhead, we were able to directly compare the neural mechanisms of attentional orienting to social and nonsocial cues while holding the physical stimulus constant. The functional magnetic resonance imaging results indicated that attentional orienting to both eye gaze and arrow cues engaged extensive dorsal and ventral fronto-parietal networks. Eye gaze cues, however, more vigorously engaged two regions in the ventral frontal cortex associated with attentional reorienting to salient or meaningful stimuli, as well as lateral occipital regions. An event-related potential study demonstrated that this enhanced occipital response was attributable to a higher-amplitude sensory gain effect for targets appearing at locations cued by eye gaze than for those cued by an arrowhead. These results endorse the hypothesis that differences in attention to social and nonsocial cues are quantitative rather than qualitative, running counter to current models that assume enhanced processing for social stimuli reflects the involvement of a unique network of brain regions. An intriguing implication of the present study is the possibility that our ability to orient volitionally and reflexively to socially irrelevant stimuli, including arrowheads, may have arisen as a useful by-product of a system that developed first, and foremost, to promote social orienting to stimuli that are biologically relevant.

Attentional orienting to graspable objects: what triggers the response?

We used event-related potentials to determine whether attentional orienting to graspable objects depends on the type of motor representation they implicitly activate - object and/or hand specific. Our paradigm was based on varying the visual hemifield location (left vs. right) of a task-irrelevant 'tool'. As our left-handed participants had object and hand-specific motor representations lateralized to their left and right cerebral hemispheres, respectively, the motor representation activated on each trial thus varied with the tool's hemifield. In question was whether attentional orienting would also vary with the tool's hemifield. Our ERP data, however, indicated that attention was drawn to the tool's location regardless of hemifield, suggesting that graspable objects can trigger attentional orienting via either an object or hand-specific motor representation.

Motor experience with graspable objects reduces their implicit analysis in visual- and motor-related cortex.

Motor-related regions of parietal and prefrontal cortices have been shown to selectively activate when observers passively view objects that afford manual grasping. Yet, it remains unknown whether these cortical responses depend on prior motor-related experience with the object being observed. To address this question, we asked participants to undergo fMRI scanning while viewing exemplars of two different categories of graspable objects: one associated with extensive motor experience (door knobs) and one associated with no self-reported motor experience (artificial rock climbing holds). Despite participants' lack of experience grasping climbing holds, these objects were found to generate a systematic response in several visuomotor-related regions of cortex-including left PMv and left AIP. Interestingly, however, the response to door knobs did not include activity in any motor-related regions, being limited instead to a comparatively small bilateral area of lateral occipital cortex, relative to the more spatially extensive response in occipital and temporal cortex that was observed for climbing holds. This result suggested that object-specific responses in both visual- and motor-related cortex may in fact negatively correlate with object-specific motor experience. To test this possibility, we repeated the experiment using participants having extensive self-reported experience grasping climbing holds (i.e., veteran indoor rock climbers). Consistent with our hypothesis, both climbing holds and door knobs generated activity limited to lateral occipital cortex. Taken together, these data support the proposal that repeated real-world motor experience with an object category may lead to reduced implicit analysis in both motor- and visual-related regions of cortex.

Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation.

RATIONALE: Working memory performance may be improved or decreased by amphetamine, depending on baseline working memory capacity and amphetamine dosage. This variable effect suggests an optimal range of monaminergic activity for working memory, either below or above which it is compromised. We directly tested this possibility with human participants by varying amphetamine dosage and measuring the efficiency of cortical processing in brain regions associated with working memory. OBJECTIVES: The modulation of cortical processing in a verbal working memory network by dextroamphetamine (D-amph) was examined using BOLD functional magnetic resonance imaging (fMRI) with healthy participants. The goal of the study was to test the hypothesis of an inverted U-shaped relationship between D-amph dose and processing efficiency of a verbal working memory system. METHODS: D-amph dosage was increased cumulatively every 2 h across four scanning sessions collected in a single day. The primary measure used for analyses in this study was the extent of activation in brain regions empirically defined as a working memory network. RESULTS: An inverted U-shaped relationship was observed between the amount of D-amph administered and working memory processing efficiency. This relationship was specific to brain areas functionally defined as working memory regions and to the encoding/maintenance phase (as opposed to the response phase) of the task. CONCLUSION: The results are consistent with the hypothesis that the neurochemical effects of amphetamine modulate the efficiency of a verbal working memory system. The effect of amphetamine on working memory in healthy individuals may provide insight regarding the working memory deficits seen in schizophrenia, given the overlap between neurochemical systems affected by amphetamine, and those disordered in schizophrenia.

Placing a tool in the spotlight: spatial attention modulates visuomotor responses in cortex.

Visual spatial attention has long been associated with facilitatory effects on visual perception. Here, we report that spatial attention can also modulate implicit visuomotor processing in dorsal regions of human cortex. Participants underwent fMRI scanning while performing a voluntary attentional orienting task that varied the category of a task-irrelevant object in the attended location (tool vs. non-tool). Data were then analyzed as a function of the attended location (left vs. right visual field) and the object category in that location. We found that the fMRI BOLD response in two visuomotor-related regions--the supplementary motor area (SMA) and the left inferior parietal lobule (IPL)--showed an interaction between the location of attention and the location of the tool in the bilateral display. Further, these responses were statistically distinct from those regions in dorsal cortex showing activity modulated only by the tool location or only by the attended location. While the effects of attending non-foveally within the visual field have been well documented in relation to visual perception, our findings support the proposal that voluntary visuospatial attention may also have consequences for the implicit planning of object-directed actions.