Luka Ruzic

Separate neural representations for physical pain and social rejection

Current theories suggest that physical pain and social rejection share common neural mechanisms, largely by virtue of overlapping functional magnetic resonance imaging (fMRI) activity. Here we challenge this notion by identifying distinct multivariate fMRI patterns unique to pain and rejection. Sixty participants experience painful heat and warmth and view photos of ex-partners and friends on separate trials. FMRI pattern classifiers discriminate pain and rejection from their respective control conditions in out-of-sample individuals with 92% and 80% accuracy. The rejection classifier performs at chance on pain, and vice versa. Pain- and rejection-related representations are uncorrelated within regions thought to encode pain affect (for example, dorsal anterior cingulate) and show distinct functional connectivity with other regions in a separate resting-state data set (N = 91). These findings demonstrate that separate representations underlie pain and rejection despite common fMRI activity at the gross anatomical level. Rather than co-opting pain circuitry, rejection involves distinct affective representations in humans.

Attentional Control Activation Relates to Working Memory in Attention-Deficit/Hyperactivity Disorder

BACKGROUND Attentional control difficulties in individuals with attention-deficit/hyperactivity disorder (ADHD) might reflect poor working memory (WM) ability, especially because WM ability and attentional control rely on similar brain regions. The current study examined whether WM ability might explain group differences in brain activation between adults with ADHD and normal control subjects during attentional demand. METHODS Participants were 20 adults with ADHD combined subtype with no comorbid psychiatric or learning disorders and 23 control subjects similar in age, IQ, and gender. The WM measures were obtained from the Wechsler Adult Intelligence Scale-III and Wechsler Memory Scale-Revised. Brain activation was assessed with functional magnetic resonance imaging (fMRI) while performing a Color-Word Stroop task. RESULTS Group differences in WM ability explained a portion of the activation in left dorsolateral prefrontal cortex (DLPFC), which has been related to the creation and maintenance of an attentional set for task-relevant information. In addition, greater WM ability predicted increased activation of brain regions related to stimulus-driven attention and response selection processes in the ADHD group but not in the control group. CONCLUSIONS The inability to maintain an appropriate task set in young adults with combined type ADHD, associated with decreased activity in left DLPFC, might in part be due to poor WM ability. Furthermore, in individuals with ADHD, higher WM ability might relate to increased recruitment of stimulus-driven attention and response selection processes, perhaps as a compensatory strategy.

Cognitive control in adolescence: neural underpinnings and relation to self-report behaviors.

Background Adolescence is commonly characterized by impulsivity, poor decision-making, and lack of foresight. However, the developmental neural underpinnings of these characteristics are not well established. Methodology/Principal Findings To test the hypothesis that these adolescent behaviors are linked to under-developed proactive control mechanisms, the present study employed a hybrid block/event-related functional Magnetic Resonance Imaging (fMRI) Stroop paradigm combined with self-report questionnaires in a large sample of adolescents and adults, ranging in age from 14 to 25. Compared to adults, adolescents under-activated a set of brain regions implicated in proactive top-down control across task blocks comprised of difficult and easy trials. Moreover, the magnitude of lateral prefrontal activity in adolescents predicted self-report measures of impulse control, foresight, and resistance to peer pressure. Consistent with reactive compensatory mechanisms to reduced proactive control, older adolescents exhibited elevated transient activity in regions implicated in response-related interference resolution. Conclusions/Significance Collectively, these results suggest that maturation of cognitive control may be partly mediated by earlier development of neural systems supporting reactive control and delayed development of systems supporting proactive control. Importantly, the development of these mechanisms is associated with cognitive control in real-life behaviors.

The neural basis of sustained and transient attentional control in young adults with ADHD.

Differences in neural activation during performance on an attentionally demanding Stroop task were examined between 23 young adults with ADHD carefully selected to not be co-morbid for other psychiatric disorders and 23 matched controls. A hybrid blocked/single-trial design allowed for examination of more sustained vs. more transient aspects of attentional control. Our results indicated neural dysregulation across a wide range of brain regions including those involved in overall arousal, top-down attentional control, response selection, and inhibition. Furthermore, this dysregulation was most notable in lateral regions of DLPFC for sustained attentional control and in medial areas for transient aspects of attentional control. Because of the careful selection and matching of our two groups, these results provide strong evidence that the neural systems of attentional control are dysregulated in young adults with ADHD and are similar to dysregulations seen in children and adolescents with ADHD.

Inhibitory Control of Memory Retrieval and Motor Processing Associated with the Right Lateral Prefrontal Cortex: Evidence from Deficits in Individuals with ADHD.

Studies of inhibitory control have focused on inhibition of motor responses. Individuals with ADHD consistently show reductions in inhibitory control and exhibit reduced activity of rLPFC activity compared to controls when performing such tasks. Recently these same brain regions have been implicated in the inhibition of memory retrieval. The degree to which inhibition of motor responses and inhibition of memory retrieval might involve overlapping systems has been relatively unexplored. The current study examined whether inhibitory difficulties in ADHD extend to inhibitory control over memory retrieval. During fMRI 16 individuals with ADHD and 16 controls performed the Think/No-Think (TNT) task. Behaviorally, the Stop Signal Reaction Time task (SSRT) was used to assess inhibitory control over motor responses. To link both of these measures to behavior, the severity of inattentive and hyperactive symptomatology was also assessed. Behaviorally, ADHD individuals had specific difficulty in inhibiting, but not in elaborating/increasing memory retrieval, which was correlated with symptom severity and longer SSRT. Additionally, ADHD individuals showed reduced activity in rLPFC during the TNT, as compared to control individuals. Moreover, unlike controls, in whom the correlation between activity of the rMFG and hippocampus predicts inhibitory success, no such correlation was observed for ADHD individuals. Moreover, decreased activity in rIFG in individuals with ADHD predicted a decrease in the ability to inhibit motor responses. These results suggest that inhibitory functions of rLPFC include control over both memory and motoric processes. They also suggest that inhibitory deficits in individuals with ADHD extend to the memory domain.

Somatic and vicarious pain are represented by dissociable multivariate brain patterns

Understanding how humans represent others’ pain is critical for understanding pro-social behavior. ‘Shared experience’ theories propose common brain representations for somatic and vicarious pain, but other evidence suggests that specialized circuits are required to experience others’ suffering. Combining functional neuroimaging with multivariate pattern analyses, we identified dissociable patterns that predicted somatic (high versus low: 100%) and vicarious (high versus low: 100%) pain intensity in out-of-sample individuals. Critically, each pattern was at chance in predicting the other experience, demonstrating separate modifiability of both patterns. Somatotopy (upper versus lower limb: 93% accuracy for both conditions) was also distinct, located in somatosensory versus mentalizing-related circuits for somatic and vicarious pain, respectively. Two additional studies demonstrated the generalizability of the somatic pain pattern (which was originally developed on thermal pain) to mechanical and electrical pain, and also demonstrated the replicability of the somatic/vicarious dissociation. These findings suggest possible mechanisms underlying limitations in feeling others’ pain, and present new, more specific, brain targets for studying pain empathy. DOI: http://dx.doi.org/10.7554/eLife.15166.001

Symptom-correlated brain regions in young adults with combined-type ADHD: Their organization, variability, and relation to behavioral performance

Attention Deficit Hyperactivity Disorder (ADHD) is a widely diagnosed psychiatric disorder of childhood that may continue to manifest itself during adulthood. Across adults and children, inattention appears to be the most developmentally stable symptomatology of ADHD. To determine the neural systems that may be linked to such symptoms, the association between brain activation in a group of young adults in the face of an attentional challenge (the Stroop task) and inattentive symptoms was examined with functional magnetic resonance imaging. The results implicated a broad array of brain regions that are linked to behaviors compromised in ADHD, including executive function/cognitive control (prefrontal cortex, dorsal striatum), reward and motivational circuitry (ventral striatum), and stimulus representation and timing (posterior cortex and cerebellum). Also implicating these regions as being important for the manifestation of ADHD symptoms, the variability in the size of the BOLD signal across individuals was significantly higher for the ADHD group than for the control group, and variability across the time series in individuals with ADHD was linked to symptom severity and behavioral performance. The results suggest that a diverse set of brain structures is linked to ADHD symptoms and that the variability of activation within these regions may contribute to compromised attentional control.

Relationship between intelligence and the size and composition of the corpus callosum

We investigated the relationship between the morphology of the corpus callosum (CC) and IQ in a healthy sample of individuals in their late teens and early twenties. The relationship between the area of the CC, measured at the midline, and IQ showed regional differences. We observed that a higher estimated performance IQ was associated with smaller area in the posterior regions of the CC, a finding that differs from a positive association previously observed in a somewhat older adult sample. In contrast, higher estimated verbal IQ was associated with decreased fractional anisotropy of the genu, an anterior portion of the CC. Age effects were also observed such that older age was associated with larger CC area. Our results suggest that CC morphology is related to cognitive performance, which may have implications for clinical populations in whom CC morphology is atypical.

Brain Predictors of Individual Differences in Placebo Responding

Abstract Placebo responses are highly variable across individuals. Explaining this variability is one of the keys to understanding endogenous regulatory processes, and is critical for measuring and controlling placebo effects in all kinds of studies. In this chapter, we review literature on the personality and brain correlates of individual differences in placebo analgesia. An emerging brain literature has used functional magnetic resonance imaging (fMRI), opioid binding, dopamine binding, and structural brain imaging to predict the magnitude of individual placebo responses. Brain predictors in prefrontal cortices and ventral striatum/nucleus accumbens are relatively consistent across studies and methodologies, showing promise for understanding the neural bases of placebo analgesia. However, most studies use voxel-wise correlation maps to relate brain measures and placebo analgesia, which do not provide unbiased measures of predictive accuracy. Thus, the utility of these brain measures remains to be determined by larger-scale studies using appropriate analytic methods. Finally, we address an apparent paradox in the placebo literature: placebo responses appear to be both related to stable person-level variables (e.g. brain structure, genetics, personality) and highly variable across situational contexts. We suggest that a resolution lies in recognizing that placebo responses, like many other psychologic phenomena, arise from person × situation interactions, and that both must be considered jointly in order to understand and predict who will be a placebo ‘responder’ in a given situation.

Frontal-brainstem pathways mediating placebo effects on social rejection

Placebo treatments can strongly affect clinical outcomes, but research on how they shape other life experiences and emotional well-being is in its infancy. We used fMRI in humans to examine placebo effects on a particularly impactful life experience, social pain elicited by a recent romantic rejection. We compared these effects with placebo effects on physical (heat) pain, which are thought to depend on pathways connecting prefrontal cortex and periaqueductal gray (PAG). Placebo treatment, compared with control, reduced both social and physical pain, and increased activity in the dorsolateral prefrontal cortex (dlPFC) in both modalities. Placebo further altered the relationship between affect and both dlPFC and PAG activity during social pain, and effects on behavior were mediated by a pathway connecting dlPFC to the PAG, building on recent work implicating opioidergic PAG activity in the regulation of social pain. These findings suggest that placebo treatments reduce emotional distress by altering affective representations in frontal-brainstem systems. SIGNIFICANCE STATEMENT Placebo effects are improvements due to expectations and the socio-medical context in which treatment takes place. Whereas they have been extensively studied in the context of somatic conditions such as pain, much less is known of how treatment expectations shape the emotional experience of other important stressors and life events. Here, we use brain imaging to show that placebo treatment reduces the painful feelings associated with a recent romantic rejection by recruiting a prefrontal-brainstem network and by shifting the relationship between brain activity and affect. Our findings suggest that this brain network may be important for nonspecific treatment effects across a wide range of therapeutic approaches and mental health conditions.