Brain white matter pathways of resilience to chronic back pain: a multisite validation.

Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have shown that brain characteristics can serve as robust predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over six- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~ 0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.

Methyl-CpG binding protein 2 expression is associated with symptom severity in patients with PTSD in a sex-dependent manner.

Traumatic events may lead to post-traumatic stress disorder (PTSD), with higher prevalence in women. Adverse childhood experiences (ACE) increase PTSD risk in adulthood. Epigenetic mechanisms play important roles in PTSD pathogenesis and a mutation in the methyl-CpG binding protein 2 (MECP2) in mice provide susceptibility to PTSD-like alterations, with sex-dependent biological signatures. The present study examined whether the increased risk of PTSD associated with ACE exposure is accompanied by reduced MECP2 blood levels in humans, with an influence of sex. MECP2 mRNA levels were analyzed in the blood of 132 subjects (58 women). Participants were interviewed to assess PTSD symptomatology, and asked to retrospectively report ACE. Among trauma-exposed women, MECP2 downregulation was associated with the intensification of PTSD symptoms linked to ACE exposure. MECP2 expression emerges as a potential contributor to post-trauma pathophysiology fostering novel studies on the molecular mechanisms underlying its potential sex-dependent role in PTSD onset and progression.

The association of spouse interactions and emotional learning in interference related to chronic back pain.

Social interactions affect individual behaviours, preferences, and attitudes. This is also critical in the context of experiencing pain and expressing pain behaviours, and may relate to learned emotional responses. In this respect, individual variability in the medial prefrontal cortex (mPFC), which is involved in adjusting an organism's behaviour to its environment by evaluating and interpreting information within the context of past experiences, is important. It is critical for selecting suitable behavioural responses within a social environment and may reinforce maladaptation in chronic pain. In our study, we used brain imaging during appetitive and aversive pavlovian conditioning in persons with chronic back pain (CBP), subacute back pain (SABP), and healthy controls (HC), together with information on spouse responses to pain behaviours. We also examined the relationship of these responses with pain-related interference in the patients. Our findings yielded a significant negative association between mPFC responses to appetitive and aversive learning in CBP. We also observed a significant negative association for mPFC responses during aversive learning and distracting spouse responses, and a significant positive association between mPFC responses during appetitive learning and solicitous spouse responses in CBP. Both significantly predicted pain-related interference in the CBP group (explained variance up to 53%). Significant associations were not found for SABP or HC. Our findings support an association between appetitive and aversive pavlovian learning, related brain circuits and spouse responses to pain in CBP, where appetitive and aversive learning processes seem to be differentially involved. This can inform prevention and early intervention in a mechanistic approach.

Altered frontolimbic activity during virtual reality-based contextual fear learning in patients with posttraumatic stress disorder.

BACKGROUND: Deficiency in contextual and enhanced responding in cued fear learning may contribute to the development of posttraumatic stress disorder (PTSD). We examined the responses to aversive Pavlovian conditioning with an unpredictable spatial context as conditioned stimulus compared to a predictable context. We hypothesized that the PTSD group would demonstrate less hippocampal and ventromedial prefrontal cortex (vmPFC) activation during acquisition and extinction of unpredictable contexts and an over-reactive amygdala response in the predictable contexts compared to controls. METHODS: A novel combined differential cue-context conditioning paradigm was applied using virtual reality with spatial contexts that required configural and cue processing. We assessed 20 patients with PTSD, 21 healthy trauma-exposed (TC) and 22 non-trauma-exposed (HC) participants using functional magnetic resonance imaging, skin conductance responses, and self-report measures. RESULTS: During fear acquisition, patients with PTSD compared to TC showed lower activity in the hippocampi in the unpredictable and higher activity in the amygdalae in the predictable context. During fear extinction, TC compared to patients and HC showed higher brain activity in the vmPFC in the predictable context. There were no significant differences in self-report or skin conductance responses. CONCLUSIONS: Our results suggest that patients with PTSD differ in brain activation from controls in regions such as the hippocampus, the amygdala, and the vmPFC in the processing of unpredictable and predictable contexts. Deficient encoding of more complex configurations might lead to a preponderance of cue-based predictions in PTSD. Exposure-based treatments need to focus on improving predictability of contextual processing and reducing enhanced cue reactivity.

Practical challenges of continuous real-time functional magnetic resonance imaging neurofeedback with multiband accelerated echo-planar imaging and short repetition times.

Continuous real-time functional magnetic resonance imaging (fMRI) neurofeedback is gaining increasing scientific attention in clinical neuroscience and may benefit from the short repetition times of modern multiband echoplanar imaging sequences. However, minimizing feedback delay can result in technical challenges. Here, we report a technical problem we experienced during continuous fMRI neurofeedback with multiband echoplanar imaging and short repetition times. We identify the possible origins of this problem, describe our current interim solution and provide openly available workflows and code to other researchers in case they wish to use a similar approach.

Low levels of Methyl-CpG binding protein 2 are accompanied by an increased vulnerability to the negative outcomes of stress exposure during childhood in healthy women.

Numerous mental illnesses arise following stressful events in vulnerable individuals, with females being generally more affected than males. Adverse childhood experiences are known to increase the risk of developing psychopathologies and DNA methylation was demonstrated to drive the long-lasting effects of early life stress and promote stress susceptibility. Methyl-CpG binding protein 2 (MECP2), an X-linked reader of the DNA methylome, is altered in many mental disorders of stress origin, suggesting MECP2 as a marker of stress susceptibility; previous works also suggest a link between MECP2 and early stress experiences. The present work explored whether a reduced expression of MECP2 is paralleled by an increased vulnerability to the negative outcomes of stress exposure during childhood. To this aim, blood MECP2 mRNA levels were analyzed in 63 people without history of mental disorders and traits pertaining to depressive and anxiety symptom clusters were assessed as proxies of the vulnerability to develop stress-related disorders; stress exposure during childhood was also evaluated. Using structural equation modeling, we demonstrate that reduced MECP2 expression is accompanied by symptoms of anxiety/depression in association with exposure to stress in early life, selectively in healthy women. These results suggest a gender-specific involvement of MECP2 in the maladaptive outcomes of childhood adversities, and shed new light on the complex biology underlying gender bias in stress susceptibility.

Ambulatory assessment for precision psychiatry: Foundations, current developments and future avenues.

Precision psychiatry stands to benefit from the latest digital technologies for assessment and analyses to tailor treatment towards individuals. Insights into dynamic psychological processes as they unfold in humans' everyday life can critically add value in understanding symptomatology and environmental stressors to provide individualized treatment where and when needed. Towards this goal, ambulatory assessment encompasses methodological approaches to investigate behavioral, physiological, and biological processes in humans' everyday life. It combines repeated assessments of symptomatology over time, e.g., via Ecological Momentary Assessment (e.g., smartphone-diaries), with monitoring of physical behavior, environmental characteristics (such as geolocations, social interactions) and physiological function via sensors, e.g., mobile accelerometers, global-positioning-systems, and electrocardiography. In this review, we expand on promises of ambulatory assessment in the investigation of mental states (e.g., real-life, dynamical and contextual perspective), on chances for precision psychiatry such as the prediction of courses of psychiatric disorders, detection of tipping points and critical windows of relapse, and treatment effects as exemplified by ongoing projects, and on future avenues of how ambulatory interventions can benefit personalized care for psychiatric patients (e.g., through real-time feedback in everyday life). Ambulatory assessment is a key contributor to precision psychiatry, opening up promising avenues in research, diagnoses, prevention and treatment.

Gamma Band Oscillations Reflect Sensory and Affective Dimensions of Pain.

Pain is a multidimensional process, which can be modulated by emotions; however, the mechanisms underlying this modulation are unknown. We used pictures with different emotional valence (negative, positive, and neutral) as primes and applied electrical painful stimuli as targets to healthy participants. We assessed pain intensity and unpleasantness ratings and recorded electroencephalograms (EEGs). We found that pain unpleasantness and not pain intensity ratings were modulated by emotion, with increased ratings for negative and decreased ratings for positive pictures. We also found two consecutive gamma band oscillations (GBOs) related to pain processing from time frequency analyses of the EEG signals. The early GBO had a cortical distribution contralateral to the painful stimulus and its amplitude was positively correlated with intensity and unpleasantness ratings, but not with prime valence. The late GBO had a centroparietal distribution and its amplitude was larger for negative compared to neutral and positive pictures. The emotional modulation effect (negative vs. positive) of the late GBO amplitude was positively correlated with pain unpleasantness. The early GBO might reflect the overall pain perception, possibly involving the thalamocortical circuit, while the late GBO might be related to the affective dimension of pain and top-down-related processes.

Structural white and gray matter differences in a large sample of patients with Posttraumatic Stress Disorder and a healthy and trauma-exposed control group: Diffusion tensor imaging and region-based morphometry.

Differences in structural white and gray matter in survivors of traumatic experiences have been related to the development and maintenance of Posttraumatic Stress Disorder (PTSD). However, there are very few studies on diffusion tensor imaging and region based morphometry comparing patients with PTSD to two control groups, namely healthy individuals with or without trauma experience. It is also unknown if differences in white and gray matter are associated. In this cross-sectional study, we examined white- and gray matter differences between 44 patients with PTSD, 49 trauma control and 61 healthy control subjects. We compared the groups applying Tract-Based Spatial Statistics (TBSS) for a whole brain white matter analysis as well as region of interest analyses for white and gray matter. First, trauma control subjects in comparison to patients with PTSD and healthy control subjects showed significantly a) higher fractional anisotropy (FA) in the left corticospinal tract and inferior fronto-occipital fasciculus than patients with PTSD, b) higher FA in the left inferior fronto-occipital-, right inferior- and right superior longitudinal fasciculi, c) higher FA in the forceps minor and d) higher volume of the left and right anterior insulae. Second, we show significant correlations between the FA in the forceps minor and the gray matter volume in the left and right anterior insulae. Third, the mean FA value in the forceps minor correlated negatively with symptom severity of PTSD and depression as well as trait anxiety, whereas the gray matter volume in the left anterior insula correlated negatively with symptom severity in PTSD. Our findings underline the importance of brain structures critically involved in emotion regulation and salience mapping. While previous studies associated these processes primarily to functional and task-based differences in brain activity, we argue that morphometrical white and gray matter differences could serve as targets in neuroscientifically-informed prevention and treatment interventions for PTSD.

Peripheral input and phantom limb pain: A somatosensory event-related potential study.

BACKGROUND: Following amputation, nearly all amputees report nonpainful phantom phenomena and many of them suffer from chronic phantom limb pain (PLP) and residual limb pain (RLP). The aetiology of PLP remains elusive and there is an ongoing debate on the role of peripheral and central mechanisms. Few studies have examined the entire somatosensory pathway from the truncated nerves to the cortex in amputees with PLP compared to those without PLP. The relationship among afferent input, somatosensory responses and the change in PLP remains unclear. METHODS: Transcutaneous electrical nerve stimulation was applied on the truncated median nerve, the skin of the residual limb and the contralateral homologous nerve in 22 traumatic upper-limb amputees (12 with and 10 without PLP). Using somatosensory event-related potentials, the ascending volley was monitored from the brachial plexus, the spinal cord, the brainstem and the thalamus to the primary somatosensory cortex. RESULTS: Peripheral input could evoke PLP in amputees with chronic PLP (7/12), but not in amputees without a history of PLP (0/10). The amplitudes of the somatosensory components were comparable between amputees with and without PLP. In addition, evoked potentials from the periphery through the spinal, subcortical and cortical segments were not significantly associated with PLP. CONCLUSIONS: Peripheral input can modulate PLP but seems insufficient to cause PLP. These findings suggest the multifactorial complexity of PLP and different mechanisms for PLP and RLP. SIGNIFICANCE: Peripheral afferent input plays a role in PLP and has been assumed to be sufficient to generate PLP. In this study we found no significant differences in the electrical potentials generated by peripheral stimulation from the truncated nerve and the skin of the residual limb in amputees with and without PLP. Peripheral input could enhance existing PLP but could not cause it. These findings indicate the multifactorial complexity of PLP and an important role of central processes in PLP.

White matter correlates of contextual pavlovian fear extinction and the role of anxiety in healthy humans.

Pavlovian contextual fear extinction is viewed as an important mechanism for behavioral adaptation in everyday life, including challenging situations of stress and anxiety. It has frequently been shown to relate to the function of brain areas like the hippocampus and medial prefrontal cortex (mPFC), while the role of structural properties, like white matter tracts in these regions, has been less studied. We employed diffusion tensor imaging to determine structural white matter connectivity (cingulum and uncinate fasciculus) correlates of contextual pavlovian fear extinction indicators measured through functional magnetic resonance imaging, skin conductance responses (SCRs) and self-reports of valence, arousal and contingency in 93 healthy individuals. Higher fractional anisotropy values in the hippocampal cingulum were significantly related to higher SCRs during extinction of contextual conditioned responses (explained variance: 11.2%) as an indicator of extinction deficits on the level of physiological arousal. However, FA was neither related to any of the other fear extinction measures, nor did we find associations with functional extinction responses in the hippocampus or mPFC. Trait anxiety was a significant moderator of the SCR-hippocampal cingulum association (explained variance: 32.09%). The data add evidence for a critical role of the hippocampal formation in contextual pavlovian extinction, and, together with the strong effect of trait anxiety, may have implications for the development of anxiety disorders where contextual extinction learning deficits are observed.

Resting-state connectivity alterations during transient global amnesia.

While the pathophysiology of transient global amnesia (TGA) is not understood, due to the specific nature of the clinical deficits, transient dysfunction in the medial temporal lobe, especially in the hippocampus, is assumed; however, concomitant disturbances in other brain regions and in executive function have been postulated. In this study, a cohort of 16 patients was prospectively recruited from the emergency department for resting-state functional MRI (fMRI) during the acute stage of TGA, as confirmed by a standardized neuropsychological assessment. Twenty age- and sex-matched controls, as well as twenty patients with a history of TGA, were recruited for comparison. Functional data were processed using independent component analysis (ICA), allowing the complete automatic (data-driven) identification of spontaneous network dynamics. We documented a severe disturbance in anterograde episodic long-term memory in all patients. Group-based ICA of resting-state data in acute TGA patients versus that of controls and patients with a past TGA episode demonstrated reduced FC mainly of structures belonging to the executive network (EN), but also the hippocampus, confirming its pathophysiological involvement in the disorder, as well as areas belonging to the salience network and other subcortical regions. No significant differences were found when comparing connectivity in patients with a history of TGA and controls. Our findings strengthen previous empirical and theoretical accounts of hippocampal and executive dysfunction in TGA. The disruption of frontal, parietal and insular control regions, together with disruption in the hippocampus, provides a new interpretation for the pathophysiology and neuropsychological profile of this neurological disorder on a large-scale network level.

Default mode network connectivity of fear- and anxiety-related cue and context conditioning.

Classical fear conditioning is an important mechanism to adequately respond and adapt to environmental threats and has been related to the development of fear and anxiety. Both cue and context conditioning have been studied but little is known about their relation to relevant resting state networks. The default mode network (DMN) has been reported to be involved in affective learning and described as facilitating a state of readiness in responding to environmental changes. We examined resting state brain connectivity patterns of the default mode network (DMN) in 119 healthy volunteers. Specifically, we carried out correlation analyses between the DMN and skin conductance responses (SCRs) as well as arousal, valence and contingency ratings during learning. In addition, we examined the role of trait anxiety. Two different DMN patterns were identified in which stronger connectivity was linked to lower differential SCRs during fear and anxiety learning. One was related to cue conditioning and involved the amygdala and the medial prefrontal cortex, and one was associated with context conditioning and included the hippocampal formation and sensorimotor areas. These results were replicated in an independent sample. Functional connectivity of the DMN with these key regions at rest was also predictive of trait anxiety but this association could not be replicated in the second sample. We showed that DMN connectivity is differently associated with cued versus contextual learning mechanisms. Uncovering individual differences in baseline network connectivity of the DMN with these key regions might lead to a better understanding of fear and anxiety. Such findings could indeed help to identify vulnerability factors linked to network alterations at rest with dysregulation of learning processes involved in the pathophysiology of stress and anxiety disorders.

Oxytocin differentially modulates pavlovian cue and context fear acquisition.

Fear acquisition and extinction have been demonstrated as core mechanisms for the development and maintenance of mental disorders, with different contributions of processing cues vs contexts. The hypothalamic peptide oxytocin (OXT) may have a prominent role in this context, as it has been shown to affect fear learning. However, investigations have focused on cue conditioning, and fear extinction. Its differential role for cue and context fear acquisition is still not known. In a randomized, double-blind, placebo (PLC)-controlled design, we administered an intranasal dose of OXT or PLC before the acquisition of cue and context fear conditioning in healthy individuals (n = 52), and assessed brain responses, skin conductance responses and self-reports (valence/arousal/contingency). OXT compared with PLC significantly induced decreased responses in the nucleus accumbens during early cue and context acquisition, and decreased responses of the anterior cingulate cortex and insula during early as well as increased hippocampal response during late context, but not cue acquisition. The OXT group additionally showed significantly higher arousal in late cue and context acquisition. OXT modulates various aspects of cue and context conditioning, which is relevant from a mechanism-based perspective and might have implications for the treatment of fear and anxiety.