An fMRI study of unconditioned responses in post-traumatic stress disorder

Background: Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response. Results: Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD. Conclusions: Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased

An fMRI study of unconditioned responses in post-traumatic stress disorder

BACKGROUND: Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response. RESULTS: Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD. CONCLUSIONS: Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased

Transient and Persistent Pain Induced Connectivity Alterations in Pediatric Complex Regional Pain Syndrome

Evaluation of pain-induced changes in functional connectivity was performed in pediatric complex regional pain syndrome (CRPS) patients. High field functional magnetic resonance imaging was done in the symptomatic painful state and at follow up in the asymptomatic pain free/recovered state. Two types of connectivity alterations were defined: (1) Transient increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb vs. unaffected limb in the CRPS state, but with normalized connectivity patterns in the recovered state; and (2) Persistent increases in functional connectivity that identified regions with increased cold-induced functional connectivity in the affected limb as compared to the unaffected limb that persisted also in the recovered state (recovered affected limb versus recovered unaffected limb). The data support the notion that even after symptomatic recovery, alterations in brain systems persist, particularly in amygdala and basal ganglia systems. Connectivity analysis may provide a measure of temporal normalization of different circuits/regions when evaluating therapeutic interventions for this condition. The results add emphasis to the importance of early recognition and management in improving outcome of pediatric CRPS

Nocebo Effect in Randomized Clinical Trials of Antidepressants in Children and Adolescents: Systematic Review and Meta-Analysis

Objective:: To compare the incidence of adverse events between active and placebo arms of randomized clinical trials in depressive children and adolescents (C&A) with antidepressant treatments, in order to look for similarities in both groups that allow to establish a possible nocebo effect. Methods:: Systematic search strategy (January 1974–March 2013) in electronic databases, conference abstracts, and reference list of systematic reviews and included studies to identify parallel randomized placebo-controlled trials of antidepressants in C&A (<19 years) with major depressive disorder, and one or more interventions of any orally administered antidepressant. The pooled adverse events were calculated based on a fixed-effect model and statistical analysis involved the risk ratio (RR) of adverse events, with 95% confidence intervals (95% CI). Results:: Sixteen studies were included in the review, of which seven studies with a sample of 1911 patients had data to include in the meta-analysis. There was similar risk for the incidence of adverse events between non-active and active group (global RR 1.04, 95% CI: 0.97–1.11). Conclusion:: Depressive C&A allocated to placebo or active group had similar risk to develop adverse events. These similarities in both groups are attributed to the nocebo effect. It is of note that defining “nocebo” effects is challenging in clinical populations because adverse effects may be attributed to the intervention or may be manifestation of the disease itself. The inclusion of a no-treatment arm may be warranted. Nocebo effects are likely when adverse events of placebo mimic the adverse events of active treatment, as was the case here

Elevated [11C]-D-Deprenyl Uptake in Chronic Whiplash Associated Disorder Suggests Persistent Musculoskeletal Inflammation

There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer 11C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that 11C-D-deprenyl is a promising tracer for these purposes

Imaging Chronic Pain and Inflammation : Positron Emission Tomography Studies of Whiplash Associated Disorder

This thesis is on chronic neck pain after a rear impact car injury, so called whiplash associated disorder (WAD). Three empirical studies using positron emission tomography (PET) with different radioligands have been performed. The first study evaluated resting state regional cerebral blood flow (rCBF) in WAD patients and in healthy, pain-free controls, by use of oxygen-15 labeled water. Patients had heightened resting rCBF bilaterally in the posterior parahippocampal and the posterior cingulate gyri, in the right thalamus and in the right medial prefrontal gyrus. Attenuated tempero-occipital blood flow was also observed in the patient group as compared to healthy controls. Alterations in rCBF were related to patients’ neck disability ratings. Study I suggests an involvement of the posterior cingulate, the parahippocampal and the medial prefrontal gyri in WAD. This altered resting state neural activity may be linked to an increased self-relevant evaluation of pain and stress. The second study evaluated central expression of the neurokinin-1 (NK1) receptor in WAD patients and healthy controls. Using a carbon-11 labeled specific NK1 antagonist, the receptor availability was measured. Patients displayed lowered NK1 receptor availability in the insula, anterior cingulate, frontal lobe, hippocampus, amygdala and in the periaqueductal gray matter, consistent with results from animal models of chronic pain. NK1 receptor availability was most reduced in the ventromedial orbitofrontal cortex, where attenuations were linearly related to patients fear and avoidance of movement. Thirdly, carbon-11 labeled D-deprenyl was used to investigate the presence of locally inflamed soft tissue in the cervical neck in WAD patients. Although the retention mechanism of [11C]D-deprenyl is not known, the results suggest that WAD patients have chronic inflammatory processes in the neck, most commonly in the adipose tissue at the spineous process of the second vertebra. In summary, this thesis provides evidence for altered central blood flow and receptor characteristics in WAD patients. Further, WAD patients may also have signs of persistent peripheral tissue damage. Both central and peripheral pain mechanisms have been demonstrated and visualized in patients with whiplash associated disorder

The risk of being bitten by a dog is higher on hot, sunny, and smoggy days

Abstract Humans commit more violent crimes when temperature and air pollution is higher. Here, we investigate if also the day-to-day rates of dogs biting humans is influenced by environmental factors. 69,525 reports of dogs biting humans, sourced from public records on animal control requests and from ER records, were analyzed. The impact of temperature and air pollutants were evaluated with a zero-inflated Poisson generalized additive model, while controlling for regional and calendar effects. Exposure–response curves were used to assess the association between outcome and major exposure variables. We find that the rates of dogs biting humans increases with increasing temperature and ozone, but not PM2.5 exposure. We also observed that higher UV irradiation levels were related to higher rats of dog bites. We conclude that dogs, or the interactions between humans and dogs, are more hostile on hot, sunny, and smoggy days, indicating that the societal burden of extreme heat and air pollution also includes the costs of animal aggression

Spinal cord atrophy after spinal cord injury - A systematic review and meta-analysis

Cervical spinal cord atrophy occurs after spinal cord injury. The atrophy and how level of injury affects atrophy differs between studies. A systematic review and metaanalysis were done after systematic searches of PubMed, CINAHL, APA PsycInfo and Web of Science. English language original studies analyzing MRI cervical spinal cord cross-sectional area in adults with spinal cord injury were included. Atrophy and correlation between injury level and atrophy were estimated with random-effects models, standardized mean differences, and 95% confidence intervals. 24 studies were identified. 13/24 studies had low risk of bias. Cord atrophy meta-analysis of 18 articles corresponded to a standardized mean difference of -1.48 (95% CI -1.78 to -1.19) with moderate to large interstudy heterogeneity. Logarithmic time since injury influenced heterogeneity. Longitudinal atrophy was best described by a logarithmic model, indicating that rate of spinal atrophy decreases over time. Meta-correlation of eight studies indicated more severe atrophy in more rostral injuries (0.41, 95% CI 0.20-0.59). Larger and preferably longitudinal studies, data sharing, and standardized protocols are warranted

Aversive Stimuli and Functional Networks of Fear Learning in PTSD : 734

Background: One characteristic of post traumatic stress disorder is an inability to adapt to a safe environment i.e. to change behavior when predictions of adverse outcomes are not met. Recent studies have also indicated that PTSD patients have altered pain processing, with hyperactivation of the putamen and insula to aversive stimuli (Geuze et al, 2007). The present study examined neuronal responses to aversive and predicted aversive events. Methods: Twenty-four trauma exposed non-PTSD controls and nineteen subjects with PTSD underwent fMRI imaging during a partial reinforcement fear conditioning paradigm, with a mild electric shock as the unconditioned stimuli (UCS). Three conditions were analyzed: actual presentations of the UCS, events when a UCS was expected, but omitted (CS+), and events when the UCS was neither expected nor delivered (CS-). Results: The UCS evoked significant alterations in the pain matrix consisting of the brainstem, the midbrain, the thalamus, the insula, the anterior and middle cingulate and the contralateral somatosensory cortex. PTSD subjects displayed bilaterally elevated putamen activity to the electric shock, as compared to controls. In trials when USC was expected, but omitted, significant activations were observed in the brainstem, the midbrain, the anterior insula and the anterior cingulate. PTSD subjects displayed similar activations, but also elevated activations in the amygdala and the posterior insula. Conclusions: These results indicate altered fear and safety learning in PTSD, and neuronal activations are further explored in terms of functional connectivity using psychophysiological interaction analyses