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Tim Salomons

University of Reading, Psychology, Faculty Member

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Supervisors: Richard Davidson and Karen Davis
Phone: +44 (0118) 378 8524
Address: School of Psychology, Earley Gate, Whiteknights

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University of Nottingham

Università degli Studi di Torino

Arthur Coelho Araujo

Universidade Municipal de São Caetano do Sul (USCS)

Università degli Studi di Torino

Boston Children's Hospital

Harvard Medical School

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Papers by Tim Salomons

The " Pain Matrix " in Pain-Free Individuals

by Tim Salomons and Meng Liang

Human functional imaging provides a correlative picture of brain activity during pain. A particul... more Human functional imaging provides a correlative picture of brain activity during pain. A particular set of central nervous system structures (eg, the anterior cingulate cortex, thalamus, and insula) consistently respond to transient nociceptive stimuli causing pain. Activation of this so-called pain matrix or pain signature has been related to perceived pain intensity, both within and between individuals, 1,2

The integration of negative affect, pain and cognitive control in the cingulate cortex

by Alexander Shackman and Tim Salomons

It has been argued that emotion, pain and cognitive control are functionally segregated in distin... more It has been argued that emotion, pain and cognitive control are functionally segregated in distinct subdivisions of the cingulate cortex. However, recent observations encourage a fundamentally different view. Imaging studies demonstrate that negative affect, pain and cognitive control activate an overlapping region of the dorsal cingulate — the anterior midcingulate cortex (aMCC). Anatomical studies reveal that the aMCC constitutes a hub where information about reinforcers can be linked to motor centres responsible for expressing affect and executing goal-directed behaviour. Computational modelling and other kinds of evidence suggest that this intimacy reflects control processes that are common to all three domains. These observations compel a reconsideration of the dorsal cingulate's contribution to negative affect and pain.

Preserved emotional awareness of pain in a patient with extensive bilateral damage to the insula, anterior cingulate, and amygdala

Brain Structure and Function, 2015

Functional neuroimaging investigations of pain have discovered a reliable pattern of activation w... more Functional neuroimaging investigations of pain have discovered a reliable pattern of activation within limbic regions of a putative ''pain matrix'' that has been theorized to reflect the affective dimension of pain. To test this theory, we evaluated the experience of pain in a rare neurological patient with extensive bilateral lesions encompassing core limbic structures of the pain matrix, including the insula, anterior cingulate, and amygdala. Despite widespread damage to these regions, the patient's expression and experience of pain was intact, and at times excessive in nature. This finding was consistent across multiple pain measures including self-report, facial expression, vocalization, withdrawal reaction, and autonomic response. These results challenge the notion of a ''pain matrix'' and provide direct evidence that the insula, anterior cingulate, and amygdala are not necessary for feeling the suffering inherent to pain. The patient's heightened degree of pain affect further suggests that these regions may be more important for the regulation of pain rather than providing the decisive substrate for pain's conscious experience.

Neural Emotion Regulation Circuitry Underlying Anxiolytic Effects of Perceived Control over Pain

Journal of Cognitive Neuroscience, 2015

■ Anxiolytic effects of perceived control have been observed across species. In humans, neuroimag... more ■ Anxiolytic effects of perceived control have been observed across species. In humans, neuroimaging studies have suggested that perceived control and cognitive reappraisal reduce negative affect through similar mechanisms. An important limitation of extant neuroimaging studies of perceived control in terms of directly testing this hypothesis, however, is the use of within-subject designs, which confound participantsʼ affective response to controllable and uncontrollable stress. To compare neural and affective responses when participants were exposed to either uncontrollable or controllable stress, two groups of participants received an identical series of stressors (thermal pain stimuli). One group ("controllable") was led to believe they had behavioral control over the pain stimuli, whereas another ("uncontrollable") believed they had no con-trol. Controllable pain was associated with decreased state anxiety, decreased activation in amygdale, and increased activation in nucleus accumbens. In participants who perceived control over the pain, reduced state anxiety was associated with increased functional connectivity between each of these regions and ventral lateral/ventral medial pFC. The location of pFC findings is consistent with regions found to be critical for the anxiolytic effects of perceived control in rodents. Furthermore, interactions observed between pFC and both amygdala and nucleus accumbens are remarkably similar to neural mechanisms of emotion regulation through reappraisal in humans. These results suggest that perceived control reduces negative affect through a general mechanism involved in the cognitive regulation of emotion. ■

A brief cognitive-behavioural intervention for pain reduces secondary hyperalgesia

Repeated exposure to pain can result in sensitization of the central nervous system, enhancing su... more Repeated exposure to pain can result in sensitization of the central nervous system, enhancing subsequent pain and potentially leading to chronicity. The ability to reverse this sensitization in a top-down manner would be of tremendous clinical benefit, but the degree that this can be accomplished volitionally remains unknown. Here we investigated whether a brief ($5 min) cognitive-behavioural intervention could modify pain perception and reduce central sensitization (as reflected by secondary hyperalgesia). In each of 8 sessions, 2 groups of healthy human subjects received a series of painful thermal stimuli that resulted in secondary hyperalgesia. One group (regulate) was given brief painfocused cognitive training at each session, while the other group (control) received a non-pain-focused intervention. The intervention selectively reduced pain unpleasantness but not pain intensity in the regulate group. Furthermore, secondary hyperalgesia was significantly reduced in the regulate group compared with the control group. Reduction in secondary hyperalgesia was associated with reduced pain catastrophizing, suggesting that changes in central sensitization are related to changes in pain-related cognitions. Thus, we demonstrate that central sensitization can be modified volitionally by altering pain-related thoughts.

Anhedonia and Reward-Circuit Connectivity Distinguish Nonresponders from Responders to Dorsomedial Prefrontal Repetitive Transcranial Magnetic Stimulation in Major Depression

Biological Psychiatry, 2013

Background: Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeti... more

Resting state cortico-thalamic-striatal connectivity predicts response to dorsomedial prefrontal rTMS in major depressive disorder.

by Tim Salomons and Sidney Kennedy

Despite its high toll on society, there has been little recent improvement in treatment efficacy ... more Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD 17 ). We found that higher baseline cortico-cortical connectivity (dmPFCsubgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD 17 scores. We found that successful treatment was associated with increased dmPFCthalamic connectivity and decreased subgenual cingulate cortex-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks

Proceedings of the National Academy of Sciences, 2013

Human minds often wander away from their immediate sensory environment. It remains unknown whethe... more Human minds often wander away from their immediate sensory environment. It remains unknown whether such mind wandering is unsystematic or whether it lawfully relates to an individual's tendency to attend to salient stimuli such as pain and their associated brain structure/function. Studies of pain-cognition interactions typically examine explicit manipulation of attention rather than spontaneous mind wandering. Here we sought to better represent natural fluctuations in pain in daily life, so we assessed behavioral and neural aspects of spontaneous disengagement of attention from pain. We found that an individual's tendency to attend to pain related to the disruptive effect of pain on his or her cognitive task performance. Next, we linked behavioral findings to neural networks with strikingly convergent evidence from functional magnetic resonance imaging during pain coupled with thought probes of mind wandering, dynamic resting state activity fluctuations, and diffusion MRI. We found that (i) pain-induced default mode network (DMN) deactivations were attenuated during mind wandering away from pain; (ii) functional connectivity fluctuations between the DMN and periaqueductal gray (PAG) dynamically tracked spontaneous attention away from pain; and (iii) across individuals, stronger PAG-DMN structural connectivity and more dynamic resting state PAG-DMN functional connectivity were associated with the tendency to mind wander away from pain. These data demonstrate that individual tendencies to mind wander away from pain, in the absence of explicit manipulation, are subserved by functional and structural connectivity within and between default mode and antinociceptive descending modulation networks.

Beyond metaphor: contrasting mechanisms of social and physical pain

Trends in Cognitive Sciences, 2013

Physical pain can be clearly distinguished from other states of distress. In recent years, howeve... more Physical pain can be clearly distinguished from other states of distress. In recent years, however, the notion that social distress is experienced as physically painful has permeated the scientific literature and popular media. This conclusion is based on the overlap of brain regions that respond to nociceptive input and sociocultural distress. Here we challenge the assumption that underlies this conclusion -that physical pain can be easily inferred from a particular pattern of activated brain regions -by showing that patterns of activation commonly presumed to constitute the 'pain matrix' are largely unspecific to pain. We then examine recent analytical advances that may improve the specificity of imaging for parsing pain from a broad range of perceptually unique human experiences.

Connectivity-based parcellation of the human frontal polar cortex

Brain Structure and Function, 2014

The frontal pole corresponds to Brodmann area (BA) 10, the largest single architectonic area in t... more The frontal pole corresponds to Brodmann area (BA) 10, the largest single architectonic area in the human frontal lobe. Generally, BA10 is thought to contain two or three subregions that subserve broad functions such as multitasking, social cognition, attention, and episodic memory. However, there is a substantial debate about the functional and structural heterogeneity of this large frontal region. Previous connectivity-based parcellation studies have identified two or three subregions in the human frontal pole. Here, we used diffusion tensor imaging to assess structural connectivity of BA10 in 35 healthy subjects and delineated subregions based on this connectivity. This allowed us to determine the correspondence of structurally based subregions with the scheme previously defined functionally. Three subregions could be defined in each subject. However, these three subregions were not spatially consistent between subjects. Therefore, we accepted a solution with two subregions that encompassed the lateral and medial frontal pole. We then examined resting-state functional connectivity of the two subregions and found significant differences between their connectivities. The medial cluster was connected to nodes of the default-mode network, which is implicated in internally focused, self-related thought, and social cognition. The lateral cluster was connected to nodes of the executive control network, associated with directed attention and working memory. These findings support the concept that there are two major anatomical subregions of the frontal pole related to differences in functional connectivity.

Abnormal gray matter aging in chronic pain patients

Brain Research, 2012

Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent ... more Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent studies indicate that age-related GM changes are not uniform across the brain and may vary according to health status. Therefore the aims of this study were to determine whether chronic pain in temporomandibular disorder (TMD) is associated with abnormal GM aging in focal cortical regions associated with nociceptive processes, and the degree to which the cumulative effects of pain contributes to age effects. We found that patients have accelerated whole brain GM atrophy, compared to pain-free controls. We also identified three aberrant patterns of GM aging in five focal brain regions: 1) in the thalamus, GM volume correlated with age in the TMD patients but not in the control group; 2) in the anterior mid-and pregenual cingulate cortex (aMCC/pgACC), the TMD patients showed agerelated cortical thinning, whereas the controls had age-related cortical thickening; and 3) in the dorsal striatum and the premotor cortex (PMC). Interestingly, the controls but not the patients showed age-related GM reductions. Finally, a result of particular note is that after accounting for the effects of TMD duration, age remained as a significant predictor of GM in the PMC and dorsal striatum. Thus, abnormal GM aging in TMD may be due to the progressive impact of TMD-related factors in pain-related regions, as well as inherent Keywords: Aging Chronic pain Cortical thickness analysis Voxel-based morphometry Temporomandibular disorder MRI B R A I N R E S E A R C H 1 4 5 6 ( 2 0 1 2 ) 8 2 -9 3 A v a i l a b l e o n l i n e a t w w w . s c i e n c e d i r e c t . c o m w w w . e l s e v i e r . c o m / l o c a t e / b r a i n r e s factors in motor regions, in patients with TMD. This study is the first to show that chronic pain is associated with abnormal GM aging in focal cortical regions associated with pain and motor processes.

The validation of an active control intervention for Mindfulness Based Stress Reduction (MBSR)

Behaviour Research and Therapy, 2012

D.G. MacCoon). 1 Abbreviations: MBSR ¼ Mindfulness Based Stress Reduction; HEP ¼ Health Enhanceme... more D.G. MacCoon). 1 Abbreviations: MBSR ¼ Mindfulness Based Stress Reduction; HEP ¼ Health Enhancement Program. 2 A recent study by Raison and colleagues (Pace et al., 2008) also uses an active control condition but focuses on compassion meditation rather than the mindfulness meditation taught in MBSR.

White matter brain and trigeminal nerve abnormalities in temporomandibular disorder

Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly underst... more Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly understood. Recent imaging studies reported functional and gray matter abnormalities in brain areas implicated in sensorimotor, modulatory, and cognitive function in TMD, but it is not known whether there are white matter (WM) abnormalities along the trigeminal nerve (CNV) or in the brain. Here, we used diffusion tensor imaging, and found that, compared to healthy controls, TMD patients had 1) lower fractional anisotropy (FA) in both CNVs; 2) a negative correlation between FA of the right CNV and pain duration; and 3) diffuse abnormalities in the microstructure of WM tracts related to sensory, motor, cognitive, and pain functions, with a highly significant focal abnormality in the corpus callosum. Using probabilistic tractography, we found that the corpus callosum in patients had a higher connection probability to the frontal pole, and a lower connection probability to the dorsolateral prefrontal cortex, compared to controls. Finally, we found that 1) FA in tracts adjacent to the ventrolateral prefrontal cortex and tracts coursing through the thalamus negatively correlated with pain intensity; 2) FA in the internal capsule negatively correlated with pain intensity and unpleasantness; and 3) decreases in brain FA were associated with increases in mean diffusivity and radial diffusivity, markers of inflammation and oedema. These data provide novel evidence for CNV microstructural abnormalities that may be caused by increased nociceptive activity, accompanied by abnormalities along central WM pathways in TMD.

Altered anterior insula activation during anticipation and experience of painful stimuli in expert meditators

NeuroImage, 2013

Experientially opening oneself to pain rather than avoiding it is said to reduce the mind's tende... more Experientially opening oneself to pain rather than avoiding it is said to reduce the mind's tendency toward avoidance or anxiety which can further exacerbate the experience of pain. This is a central feature of mindfulness-based therapies. Little is known about the neural mechanisms of mindfulness on pain. During a meditation practice similar to mindfulness, functional magnetic resonance imaging was used in expert meditators (>10,000 h of practice) to dissociate neural activation patterns associated with pain, its anticipation, and habituation. Compared to novices, expert meditators reported equal pain intensity, but less unpleasantness. This difference was associated with enhanced activity in the dorsal anterior insula (aI), and the anterior mid-cingulate (aMCC) the so-called 'salience network', for experts during pain. This enhanced activity during pain was associated with reduced baseline activity before pain in these regions and the amygdala for experts only. The reduced baseline activation in left aI correlated with lifetime meditation experience. This pattern of low baseline activity coupled with high response in aIns and aMCC was associated with enhanced neural habituation in amygdala and pain-related regions before painful stimulation and in the pain-related regions during painful stimulation. These findings suggest that cultivating experiential openness down-regulates anticipatory representation of aversive events, and increases the recruitment of attentional resources during pain, which is associated with faster neural habituation.

Perceived helplessness is associated with individual differences in the central motor output system

European Journal of Neuroscience, 2012

Learned helplessness is a maladaptive response to uncontrollable stress characterized by impaired... more Learned helplessness is a maladaptive response to uncontrollable stress characterized by impaired motor escape responses, reduced motivation and learning deficits. There are important individual differences in the likelihood of becoming helpless following exposure to uncontrollable stress but little is known about the neural mechanisms underlying these individual differences. Here we used structural MRI to measure gray and white matter in individuals with chronic pain, a population at high risk for helplessness due to prolonged exposure to a poorly controlled stressor (pain). Given that self-reported helplessness is predictive of treatment outcomes in chronic pain, understanding such differences might provide valuable clinical insight. We found that the magnitude of selfreported helplessness correlated with cortical thickness in the supplementary motor area (SMA) and midcingulate cortex, regions implicated in cognitive aspects of motor behavior. We then examined the white matter connectivity of these regions and found that fractional anisotropy of connected white matter tracts along the corticospinal tract was associated with helplessness and mediated the relationship between SMA cortical thickness and helplessness. These data provide novel evidence that links individual differences in the motor output pathway with perceived helplessness over a chronic and poorly controlled stressor.

Turning on the alarm: The neural mechanisms of the transition from innocuous to painful sensation

NeuroImage, 2012

The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affec... more The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain. Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44-49°C) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid-cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings. These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum.

Neural response to emotional stimuli associated with successful antidepressant treatment and behavioral activation

Journal of Affective Disorders, 2013

Background: Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently ... more Background: Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states. Aim: To identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/ olanzapine combination treatment during an affective processing task. Methods: Twenty-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated for 6 weeks with fluoxetine (40-60 mg/day) and olanzapine (5-12.5 mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week. Results: There was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression-17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioral drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings. Conclusions: Treatment with fluoxetine/olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response to affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.

Does Meditation Reduce Pain through a Unique Neural Mechanism?

Journal of Neuroscience, 2011

Fear avoidance and neuroimaging: Falsification or just failure to confirm?

PAIN, 2012

Amygdalar Function Reflects Common Individual Differences in Emotion and Pain Regulation Success

Journal of Cognitive Neuroscience, 2012

■ Although the co-occurrence of negative affect and pain is well recognized, the mechanism underl... more ■ Although the co-occurrence of negative affect and pain is well recognized, the mechanism underlying their association is unclear. To examine whether a common self-regulatory ability impacts the experience of both emotion and pain, we integrated neuroimaging, behavioral, and physiological measures obtained from three assessments separated by substantial temporal intervals. Our results demonstrated that individual differences in emotion regulation ability, as indexed by an objective measure of emotional state, corrugator electromyography, predicted selfreported success while regulating pain. In both emotion and pain paradigms, the amygdala reflected regulatory success. Notably, we found that greater emotion regulation success was associated with greater change of amygdalar activity following pain regulation. Furthermore, individual differences in degree of amygdalar change following emotion regulation were a strong predictor of pain regulation success, as well as of the degree of amygdalar engagement following pain regulation. These findings suggest that common individual differences in emotion and pain regulatory success are reflected in a neural structure known to contribute to appraisal processes. ■

The " Pain Matrix " in Pain-Free Individuals

by Tim Salomons and Meng Liang

Human functional imaging provides a correlative picture of brain activity during pain. A particul... more Human functional imaging provides a correlative picture of brain activity during pain. A particular set of central nervous system structures (eg, the anterior cingulate cortex, thalamus, and insula) consistently respond to transient nociceptive stimuli causing pain. Activation of this so-called pain matrix or pain signature has been related to perceived pain intensity, both within and between individuals, 1,2

The integration of negative affect, pain and cognitive control in the cingulate cortex

by Alexander Shackman and Tim Salomons

It has been argued that emotion, pain and cognitive control are functionally segregated in distin... more It has been argued that emotion, pain and cognitive control are functionally segregated in distinct subdivisions of the cingulate cortex. However, recent observations encourage a fundamentally different view. Imaging studies demonstrate that negative affect, pain and cognitive control activate an overlapping region of the dorsal cingulate — the anterior midcingulate cortex (aMCC). Anatomical studies reveal that the aMCC constitutes a hub where information about reinforcers can be linked to motor centres responsible for expressing affect and executing goal-directed behaviour. Computational modelling and other kinds of evidence suggest that this intimacy reflects control processes that are common to all three domains. These observations compel a reconsideration of the dorsal cingulate's contribution to negative affect and pain.

Preserved emotional awareness of pain in a patient with extensive bilateral damage to the insula, anterior cingulate, and amygdala

Brain Structure and Function, 2015

Functional neuroimaging investigations of pain have discovered a reliable pattern of activation w... more Functional neuroimaging investigations of pain have discovered a reliable pattern of activation within limbic regions of a putative ''pain matrix'' that has been theorized to reflect the affective dimension of pain. To test this theory, we evaluated the experience of pain in a rare neurological patient with extensive bilateral lesions encompassing core limbic structures of the pain matrix, including the insula, anterior cingulate, and amygdala. Despite widespread damage to these regions, the patient's expression and experience of pain was intact, and at times excessive in nature. This finding was consistent across multiple pain measures including self-report, facial expression, vocalization, withdrawal reaction, and autonomic response. These results challenge the notion of a ''pain matrix'' and provide direct evidence that the insula, anterior cingulate, and amygdala are not necessary for feeling the suffering inherent to pain. The patient's heightened degree of pain affect further suggests that these regions may be more important for the regulation of pain rather than providing the decisive substrate for pain's conscious experience.

Neural Emotion Regulation Circuitry Underlying Anxiolytic Effects of Perceived Control over Pain

Journal of Cognitive Neuroscience, 2015

■ Anxiolytic effects of perceived control have been observed across species. In humans, neuroimag... more ■ Anxiolytic effects of perceived control have been observed across species. In humans, neuroimaging studies have suggested that perceived control and cognitive reappraisal reduce negative affect through similar mechanisms. An important limitation of extant neuroimaging studies of perceived control in terms of directly testing this hypothesis, however, is the use of within-subject designs, which confound participantsʼ affective response to controllable and uncontrollable stress. To compare neural and affective responses when participants were exposed to either uncontrollable or controllable stress, two groups of participants received an identical series of stressors (thermal pain stimuli). One group ("controllable") was led to believe they had behavioral control over the pain stimuli, whereas another ("uncontrollable") believed they had no con-trol. Controllable pain was associated with decreased state anxiety, decreased activation in amygdale, and increased activation in nucleus accumbens. In participants who perceived control over the pain, reduced state anxiety was associated with increased functional connectivity between each of these regions and ventral lateral/ventral medial pFC. The location of pFC findings is consistent with regions found to be critical for the anxiolytic effects of perceived control in rodents. Furthermore, interactions observed between pFC and both amygdala and nucleus accumbens are remarkably similar to neural mechanisms of emotion regulation through reappraisal in humans. These results suggest that perceived control reduces negative affect through a general mechanism involved in the cognitive regulation of emotion. ■

A brief cognitive-behavioural intervention for pain reduces secondary hyperalgesia

Repeated exposure to pain can result in sensitization of the central nervous system, enhancing su... more Repeated exposure to pain can result in sensitization of the central nervous system, enhancing subsequent pain and potentially leading to chronicity. The ability to reverse this sensitization in a top-down manner would be of tremendous clinical benefit, but the degree that this can be accomplished volitionally remains unknown. Here we investigated whether a brief ($5 min) cognitive-behavioural intervention could modify pain perception and reduce central sensitization (as reflected by secondary hyperalgesia). In each of 8 sessions, 2 groups of healthy human subjects received a series of painful thermal stimuli that resulted in secondary hyperalgesia. One group (regulate) was given brief painfocused cognitive training at each session, while the other group (control) received a non-pain-focused intervention. The intervention selectively reduced pain unpleasantness but not pain intensity in the regulate group. Furthermore, secondary hyperalgesia was significantly reduced in the regulate group compared with the control group. Reduction in secondary hyperalgesia was associated with reduced pain catastrophizing, suggesting that changes in central sensitization are related to changes in pain-related cognitions. Thus, we demonstrate that central sensitization can be modified volitionally by altering pain-related thoughts.

Anhedonia and Reward-Circuit Connectivity Distinguish Nonresponders from Responders to Dorsomedial Prefrontal Repetitive Transcranial Magnetic Stimulation in Major Depression

Biological Psychiatry, 2013

Background: Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeti... more

Resting state cortico-thalamic-striatal connectivity predicts response to dorsomedial prefrontal rTMS in major depressive disorder.

by Tim Salomons and Sidney Kennedy

Despite its high toll on society, there has been little recent improvement in treatment efficacy ... more Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD 17 ). We found that higher baseline cortico-cortical connectivity (dmPFCsubgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD 17 scores. We found that successful treatment was associated with increased dmPFCthalamic connectivity and decreased subgenual cingulate cortex-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks

Proceedings of the National Academy of Sciences, 2013

Human minds often wander away from their immediate sensory environment. It remains unknown whethe... more Human minds often wander away from their immediate sensory environment. It remains unknown whether such mind wandering is unsystematic or whether it lawfully relates to an individual's tendency to attend to salient stimuli such as pain and their associated brain structure/function. Studies of pain-cognition interactions typically examine explicit manipulation of attention rather than spontaneous mind wandering. Here we sought to better represent natural fluctuations in pain in daily life, so we assessed behavioral and neural aspects of spontaneous disengagement of attention from pain. We found that an individual's tendency to attend to pain related to the disruptive effect of pain on his or her cognitive task performance. Next, we linked behavioral findings to neural networks with strikingly convergent evidence from functional magnetic resonance imaging during pain coupled with thought probes of mind wandering, dynamic resting state activity fluctuations, and diffusion MRI. We found that (i) pain-induced default mode network (DMN) deactivations were attenuated during mind wandering away from pain; (ii) functional connectivity fluctuations between the DMN and periaqueductal gray (PAG) dynamically tracked spontaneous attention away from pain; and (iii) across individuals, stronger PAG-DMN structural connectivity and more dynamic resting state PAG-DMN functional connectivity were associated with the tendency to mind wander away from pain. These data demonstrate that individual tendencies to mind wander away from pain, in the absence of explicit manipulation, are subserved by functional and structural connectivity within and between default mode and antinociceptive descending modulation networks.

Beyond metaphor: contrasting mechanisms of social and physical pain

Trends in Cognitive Sciences, 2013

Physical pain can be clearly distinguished from other states of distress. In recent years, howeve... more Physical pain can be clearly distinguished from other states of distress. In recent years, however, the notion that social distress is experienced as physically painful has permeated the scientific literature and popular media. This conclusion is based on the overlap of brain regions that respond to nociceptive input and sociocultural distress. Here we challenge the assumption that underlies this conclusion -that physical pain can be easily inferred from a particular pattern of activated brain regions -by showing that patterns of activation commonly presumed to constitute the 'pain matrix' are largely unspecific to pain. We then examine recent analytical advances that may improve the specificity of imaging for parsing pain from a broad range of perceptually unique human experiences.

Connectivity-based parcellation of the human frontal polar cortex

Brain Structure and Function, 2014

The frontal pole corresponds to Brodmann area (BA) 10, the largest single architectonic area in t... more The frontal pole corresponds to Brodmann area (BA) 10, the largest single architectonic area in the human frontal lobe. Generally, BA10 is thought to contain two or three subregions that subserve broad functions such as multitasking, social cognition, attention, and episodic memory. However, there is a substantial debate about the functional and structural heterogeneity of this large frontal region. Previous connectivity-based parcellation studies have identified two or three subregions in the human frontal pole. Here, we used diffusion tensor imaging to assess structural connectivity of BA10 in 35 healthy subjects and delineated subregions based on this connectivity. This allowed us to determine the correspondence of structurally based subregions with the scheme previously defined functionally. Three subregions could be defined in each subject. However, these three subregions were not spatially consistent between subjects. Therefore, we accepted a solution with two subregions that encompassed the lateral and medial frontal pole. We then examined resting-state functional connectivity of the two subregions and found significant differences between their connectivities. The medial cluster was connected to nodes of the default-mode network, which is implicated in internally focused, self-related thought, and social cognition. The lateral cluster was connected to nodes of the executive control network, associated with directed attention and working memory. These findings support the concept that there are two major anatomical subregions of the frontal pole related to differences in functional connectivity.

Abnormal gray matter aging in chronic pain patients

Brain Research, 2012

Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent ... more Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent studies indicate that age-related GM changes are not uniform across the brain and may vary according to health status. Therefore the aims of this study were to determine whether chronic pain in temporomandibular disorder (TMD) is associated with abnormal GM aging in focal cortical regions associated with nociceptive processes, and the degree to which the cumulative effects of pain contributes to age effects. We found that patients have accelerated whole brain GM atrophy, compared to pain-free controls. We also identified three aberrant patterns of GM aging in five focal brain regions: 1) in the thalamus, GM volume correlated with age in the TMD patients but not in the control group; 2) in the anterior mid-and pregenual cingulate cortex (aMCC/pgACC), the TMD patients showed agerelated cortical thinning, whereas the controls had age-related cortical thickening; and 3) in the dorsal striatum and the premotor cortex (PMC). Interestingly, the controls but not the patients showed age-related GM reductions. Finally, a result of particular note is that after accounting for the effects of TMD duration, age remained as a significant predictor of GM in the PMC and dorsal striatum. Thus, abnormal GM aging in TMD may be due to the progressive impact of TMD-related factors in pain-related regions, as well as inherent Keywords: Aging Chronic pain Cortical thickness analysis Voxel-based morphometry Temporomandibular disorder MRI B R A I N R E S E A R C H 1 4 5 6 ( 2 0 1 2 ) 8 2 -9 3 A v a i l a b l e o n l i n e a t w w w . s c i e n c e d i r e c t . c o m w w w . e l s e v i e r . c o m / l o c a t e / b r a i n r e s factors in motor regions, in patients with TMD. This study is the first to show that chronic pain is associated with abnormal GM aging in focal cortical regions associated with pain and motor processes.

The validation of an active control intervention for Mindfulness Based Stress Reduction (MBSR)

Behaviour Research and Therapy, 2012

D.G. MacCoon). 1 Abbreviations: MBSR ¼ Mindfulness Based Stress Reduction; HEP ¼ Health Enhanceme... more D.G. MacCoon). 1 Abbreviations: MBSR ¼ Mindfulness Based Stress Reduction; HEP ¼ Health Enhancement Program. 2 A recent study by Raison and colleagues (Pace et al., 2008) also uses an active control condition but focuses on compassion meditation rather than the mindfulness meditation taught in MBSR.

White matter brain and trigeminal nerve abnormalities in temporomandibular disorder

Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly underst... more Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly understood. Recent imaging studies reported functional and gray matter abnormalities in brain areas implicated in sensorimotor, modulatory, and cognitive function in TMD, but it is not known whether there are white matter (WM) abnormalities along the trigeminal nerve (CNV) or in the brain. Here, we used diffusion tensor imaging, and found that, compared to healthy controls, TMD patients had 1) lower fractional anisotropy (FA) in both CNVs; 2) a negative correlation between FA of the right CNV and pain duration; and 3) diffuse abnormalities in the microstructure of WM tracts related to sensory, motor, cognitive, and pain functions, with a highly significant focal abnormality in the corpus callosum. Using probabilistic tractography, we found that the corpus callosum in patients had a higher connection probability to the frontal pole, and a lower connection probability to the dorsolateral prefrontal cortex, compared to controls. Finally, we found that 1) FA in tracts adjacent to the ventrolateral prefrontal cortex and tracts coursing through the thalamus negatively correlated with pain intensity; 2) FA in the internal capsule negatively correlated with pain intensity and unpleasantness; and 3) decreases in brain FA were associated with increases in mean diffusivity and radial diffusivity, markers of inflammation and oedema. These data provide novel evidence for CNV microstructural abnormalities that may be caused by increased nociceptive activity, accompanied by abnormalities along central WM pathways in TMD.

Altered anterior insula activation during anticipation and experience of painful stimuli in expert meditators

NeuroImage, 2013

Experientially opening oneself to pain rather than avoiding it is said to reduce the mind's tende... more Experientially opening oneself to pain rather than avoiding it is said to reduce the mind's tendency toward avoidance or anxiety which can further exacerbate the experience of pain. This is a central feature of mindfulness-based therapies. Little is known about the neural mechanisms of mindfulness on pain. During a meditation practice similar to mindfulness, functional magnetic resonance imaging was used in expert meditators (>10,000 h of practice) to dissociate neural activation patterns associated with pain, its anticipation, and habituation. Compared to novices, expert meditators reported equal pain intensity, but less unpleasantness. This difference was associated with enhanced activity in the dorsal anterior insula (aI), and the anterior mid-cingulate (aMCC) the so-called 'salience network', for experts during pain. This enhanced activity during pain was associated with reduced baseline activity before pain in these regions and the amygdala for experts only. The reduced baseline activation in left aI correlated with lifetime meditation experience. This pattern of low baseline activity coupled with high response in aIns and aMCC was associated with enhanced neural habituation in amygdala and pain-related regions before painful stimulation and in the pain-related regions during painful stimulation. These findings suggest that cultivating experiential openness down-regulates anticipatory representation of aversive events, and increases the recruitment of attentional resources during pain, which is associated with faster neural habituation.

Perceived helplessness is associated with individual differences in the central motor output system

European Journal of Neuroscience, 2012

Learned helplessness is a maladaptive response to uncontrollable stress characterized by impaired... more Learned helplessness is a maladaptive response to uncontrollable stress characterized by impaired motor escape responses, reduced motivation and learning deficits. There are important individual differences in the likelihood of becoming helpless following exposure to uncontrollable stress but little is known about the neural mechanisms underlying these individual differences. Here we used structural MRI to measure gray and white matter in individuals with chronic pain, a population at high risk for helplessness due to prolonged exposure to a poorly controlled stressor (pain). Given that self-reported helplessness is predictive of treatment outcomes in chronic pain, understanding such differences might provide valuable clinical insight. We found that the magnitude of selfreported helplessness correlated with cortical thickness in the supplementary motor area (SMA) and midcingulate cortex, regions implicated in cognitive aspects of motor behavior. We then examined the white matter connectivity of these regions and found that fractional anisotropy of connected white matter tracts along the corticospinal tract was associated with helplessness and mediated the relationship between SMA cortical thickness and helplessness. These data provide novel evidence that links individual differences in the motor output pathway with perceived helplessness over a chronic and poorly controlled stressor.

Turning on the alarm: The neural mechanisms of the transition from innocuous to painful sensation

NeuroImage, 2012

The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affec... more The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain. Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44-49°C) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid-cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings. These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum.

Neural response to emotional stimuli associated with successful antidepressant treatment and behavioral activation

Journal of Affective Disorders, 2013

Background: Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently ... more Background: Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states. Aim: To identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/ olanzapine combination treatment during an affective processing task. Methods: Twenty-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated for 6 weeks with fluoxetine (40-60 mg/day) and olanzapine (5-12.5 mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week. Results: There was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression-17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioral drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings. Conclusions: Treatment with fluoxetine/olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response to affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.

Does Meditation Reduce Pain through a Unique Neural Mechanism?

Journal of Neuroscience, 2011

Fear avoidance and neuroimaging: Falsification or just failure to confirm?

PAIN, 2012

Amygdalar Function Reflects Common Individual Differences in Emotion and Pain Regulation Success

Journal of Cognitive Neuroscience, 2012

■ Although the co-occurrence of negative affect and pain is well recognized, the mechanism underl... more ■ Although the co-occurrence of negative affect and pain is well recognized, the mechanism underlying their association is unclear. To examine whether a common self-regulatory ability impacts the experience of both emotion and pain, we integrated neuroimaging, behavioral, and physiological measures obtained from three assessments separated by substantial temporal intervals. Our results demonstrated that individual differences in emotion regulation ability, as indexed by an objective measure of emotional state, corrugator electromyography, predicted selfreported success while regulating pain. In both emotion and pain paradigms, the amygdala reflected regulatory success. Notably, we found that greater emotion regulation success was associated with greater change of amygdalar activity following pain regulation. Furthermore, individual differences in degree of amygdalar change following emotion regulation were a strong predictor of pain regulation success, as well as of the degree of amygdalar engagement following pain regulation. These findings suggest that common individual differences in emotion and pain regulatory success are reflected in a neural structure known to contribute to appraisal processes. ■