Adolescents' pain-related ontogeny shares a neural basis with adults' chronic pain in basothalamo-cortical organization.

During late adolescence, the brain undergoes ontogenic organization altering subcortical-cortical circuitry. This includes regions implicated in pain chronicity, and thus alterations in the adolescent ontogenic organization could predispose to pain chronicity in adulthood - however, evidence is lacking. Using resting-state functional magnetic resonance imaging from a large European longitudinal adolescent cohort and an adult cohort with and without chronic pain, we examined links between painful symptoms and brain connectivity. During late adolescence, thalamo-, caudate-, and red nucleus-cortical connectivity were positively and subthalamo-cortical connectivity negatively associated with painful symptoms. Thalamo-cortical connectivity, but also subthalamo-cortical connectivity, was increased in adults with chronic pain compared to healthy controls. Our results indicate a shared basis in basothalamo-cortical circuitries between adolescent painful symptomatology and adult pain chronicity, with the subthalamic pathway being differentially involved, potentially due to a hyperconnected thalamo-cortical pathway in chronic pain and ontogeny-driven organization. This can inform neuromodulation-based prevention and early intervention.

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.

Reduced tactile sensitivity is associated with mild cognitive impairment.

BACKGROUND: Sensory impairment has been related to age-associated cognitive decline. While these associations were investigated primarily in the auditory and visual domain, other senses such as touch have rarely been studied. Thus, it remains open whether these results are specific for particular sensory domains, or rather point to a fundamental role of sensory deficits in cognitive decline. METHODS: Data from 31 participants with mild cognitive impairment (MCI), 46 participants with frailty, and 23 non-clinical control participants (NCCs) were included. We assessed sensory function using visual acuity and contrast sensitivity, hearing threshold, and mechanical detection threshold. Cognitive function in participants with MCI was assessed using associative memory performance. Group differences on sensory thresholds were tested using analyses of covariance with age, sex, and years of education as covariates. Associations between measures within participants with MCI were evaluated using Spearman correlations. FINDINGS: We found a significant difference in mechanical detection threshold between the groups (p < 0.001, η2 = 0.18). Participants with MCI showed significantly reduced tactile sensitivity compared to participants with frailty and NCCs. In participants with MCI, lower associative memory performance was significantly related to reduced tactile sensitivity (rs = 0.39, p = 0.031) and auditory acuity (rs = 0.41, p = 0.022). INTERPRETATION: Our results indicate that reduced tactile sensitivity is related to cognitive decline. Prospective studies should investigate the age-related alterations of multimodal sensory processes and their contribution to dementia-related processes. FUNDING: Deutsche Forschungsgemeinschaft (FL 156/41-1) and a grant of the Hector-Stiftung II, Weinheim, Germany.

Refocusing of Attention on Positive Events Using Monitoring-Based Feedback and Microinterventions for Patients With Chronic Musculoskeletal Pain in the PerPAIN Randomized Controlled Trial: Protocol for a Microrandomized Trial.

BACKGROUND: Chronic musculoskeletal pain (CMSP) affects between 13% and 47% of the population, with a global growth rate of 20.3% within the last 15 years, suggesting that there is a high need for effective treatments. Pain diaries have long been a common tool in nonpharmacological pain treatment for monitoring and providing feedback on patients' symptoms in daily life. More recently, positive refocusing techniques have come to be used, promoting pain-free episodes and positive outcomes rather than focusing on managing the pain. OBJECTIVE: This study aims to evaluate the feasibility (ie, acceptability, intervention adherence, and fidelity) and initial signals of efficacy of the PerPAIN app, an ecological momentary intervention for patients with CMSP. The app comprises digitalized monitoring using the experience sampling method (ESM) and feedback. In addition, the patients receive 3 microinterventions targeted at refocusing of attention on positive events. METHODS: In a microrandomized trial, we will recruit 35 patients with CMSP who will be offered the app for 12 weeks. Participants will be prompted to fill out 4 ESM monitoring questionnaires a day assessing information on their current context and the proximal outcome variables: absence of pain, positive mood, and subjective activity. Participants will be randomized daily and weekly to receive no feedback, verbal feedback, or visual feedback on proximal outcomes assessed by the ESM. In addition, the app will encourage participants to complete 3 microinterventions based on positive psychology and cognitive behavioral therapy techniques. These microinterventions are prompts to report joyful moments and everyday successes or to plan pleasant activities. After familiarizing themselves with each microintervention individually, participants will be randomized daily to receive 1 of the 3 exercises or none. We will assess whether the 2 feedback types and the 3 microinterventions increase proximal outcomes at the following time point. The microrandomized trial is part of the PerPAIN randomized controlled trial (German Clinical Trials Register DRKS00022792) investigating a personalized treatment approach to enhance treatment outcomes in CMSP. RESULTS: Approval was granted by the Ethics Committee II of the University of Heidelberg on August 4, 2020. Recruitment for the microrandomized trial began in May 2021 and is ongoing at the time of submission. By October 10, 2022, a total of 24 participants had been enrolled in the microrandomized trial. CONCLUSIONS: This trial will provide evidence on the feasibility of the PerPAIN app and the initial signals of efficacy of the different intervention components. In the next step, the intervention would need to be further refined and investigated in a definitive trial. This ecological momentary intervention presents a potential method for offering low-level accessible treatment to a wide range of people, which could have substantial implications for public health by reducing disease burden of chronic pain in the population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43376.

Effects of an app-based sensorimotor training in promoting neuroplasticity and neuropsychological functioning in frailty: A randomized controlled trial.

BACKGROUND: Loss of sensorimotor stimulation and maladaptive plastic changes of the brain may play a major role in problematic aging phenomena such as frailty. However, it is not clear if interventions specifically targeting neuroplasticity can reverse or slow the development of frailty. OBJECTIVES: We compared the effect of a tablet-based neuroplasticity-oriented sensorimotor training (experimental group, EG) and a tablet-based relaxation training (control group, CG) on frailty and sensorimotor brain function. METHODS: Interventions consisted of daily 30 min sessions distributed over 90 days. Assessments took place at baseline, after 60 days, and after 90 days. A total of N = 48 frail older adults (EG: n = 24; CG: n = 24) were assigned to the two groups and reassessed after 60 days. Primary outcomes included frailty phenotype (FP) and frailty index (FI). Sensorimotor brain activity was evaluated using functional magnetic resonance imaging and single-pulse transcranial magnetic stimulation. RESULTS: After 60 days of training, both groups showed a reduction in the number of FP criteria (p < 0.001) with a trend towards a significant time-by-group interaction (p = 0.058) indicating a stronger reduction of frailty in the EG (p < 0.001) compared to the CG (p = 0.039). In addition, pain was significantly reduced in the EG but not the CG. No significant effects were found for measures of brain function. DISCUSSION: We provided initial evidence that a neuroplasticity-oriented sensorimotor training could be beneficial in counteracting frailty as well as chronic pain. Further studies are needed to determine the potentially underlying neuroplastic mechanisms and the influence of plasticity-related biomarkers as well as their clinical significance. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 (registered 11 September 2018).

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.

Chronotype, Longitudinal Volumetric Brain Variations Throughout Adolescence, and Depressive Symptom Development.

OBJECTIVE: Adolescence is a critical period for circadian rhythm, with a strong shift toward eveningness around age 14. Also, eveningness in adolescence has been found to predict later onset of depressive symptoms. However, no previous study has investigated structural variations associated with chronotype in early adolescence and how this adds to the development of depressive symptoms. METHOD: Assessment of 128 community-based adolescents (51% girls) at age 14 and 19 years was performed. Using whole-brain voxel-based morphometry, baseline (at age 14) regional gray matter volumes (GMVs), follow-up (at age 19) regional GMVs, and longitudinal changes (between 14 and 19) associated with Morningness/Eveningness Scale in Children score and sleep habits at baseline were measured. The association of GMV with depressive symptoms at 19 years was studied, and the role of potential clinical and genetic factors as mediators and moderators was assessed. RESULTS: Higher eveningness was associated with larger GMV in the right medial prefrontal cortex at ages 14 and 19 in the whole sample. GMV in this region related to depressive symptoms at age 19 in catechol-O-methyltransferase (COMT) Val/Val, but not in Met COMT, carriers. Larger GMV also was observed in the right fusiform gyrus at age 14, which was explained by later wake-up time during weekends. CONCLUSION: In adolescence, eveningness and its related sleep habits correlated with distinct developmental patterns. Eveningness was specifically associated with GMV changes in the medial prefrontal cortex; this could serve as a brain vulnerability factor for later self-reported depressive symptoms in COMT Val/Val carriers.

Stress-induced hyperalgesia instead of analgesia in patients with chronic musculoskeletal pain.

Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.

Sensory and motor correlates of frailty: dissociation between frailty phenotype and frailty index.

BACKGROUND: Frailty has been associated with a decline in sensory and motor function. However, given that different frailty measures were shown to overlap but also differ in their diagnostic properties, sensory and motor correlates of frailty might be different depending on the operationalization of frailty. Our objective was to identify sensory and motor determinants of frailty and compare the results between frailty phenotype (FP) and frailty index (FI). METHODS: Data from 44 pre-frail and frail subjects aged 65 and above were used. Frailty was measured using the FP and the FI. Sensory function in the visual, auditory, and tactile domain was assessed using visual acuity, absolute hearing threshold and mechanical detection threshold. Upper extremity motor performance was evaluated by the Purdue Pegboard Test and the Short Physical Performance Battery was used to assess lower extremity motor function. Multiple logistic regression models were employed to determine associations of sensory and motor function with frailty vs. pre-frailty for both frailty measures. RESULTS: The frailty measures were moderately correlated (0.497, p ≤ 0.01) and had a Kappa agreement of 0.467 (p = 0.002). Using the FP, frailty was significantly associated with reduced upper extremity motor function only (OR = 0.50, 95% CI 0.29-0.87, p = 0.014). Frailty as assessed by the FI was significantly related to higher hearing thresholds (OR = 1.21, 95% CI 1.02-1.43, p = 0.027) and reduced lower extremity performance (OR = 0.32, 95% CI 0.13-0.77, p = 0.012). CONCLUSION: Frailty is related to reduced performance in measures of sensory and motor function. However, traditional measures of frailty might be differentially sensitive to capture sensory and motor decline, possibly contributing to the much-observed discordance between the diagnostic instruments. This should be taken into account by researchers and clinicians when planning and evaluating therapeutic interventions for frailty. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 . Registered 11 September 2018 - Retrospectively registered.

Corticostriatal circuits in the transition to chronic back pain: The predictive role of reward learning.

Connectivity between the nucleus accumbens (NAc) and ventromedial prefrontal cortex (vmPFC) and reward learning independently predict the transition from acute to chronic back pain (CBP). However, how these predictors are related remains unclear. Using functional magnetic resonance imaging, we investigate NAc- and vmPFC-dependent reward learning in 50 patients with subacute back pain (SABP) and follow them over 6 months. Additionally, we compare 29 patients with CBP and 29 pain-free controls to characterize mechanisms of reward learning in the chronic stage. We find that the learning-related updating of the value of reinforcement (prediction error) in the NAc predicts the transition to chronicity. In CBP, compared with controls, vmPFC responses to this prediction error signal are decreased, but increased during a discriminative stimulus. Distinct processes of reward learning in the vmPFC and NAc characterize the development and maintenance of CBP. These could be targeted for the prevention and treatment of chronic pain.

Increased functional connectivity between limbic brain areas in healthy individuals with high versus low sensitivity to cold pain: A resting state fMRI study.

BACKGROUND: The representation of variability in sensitivity to pain by differences in neural connectivity patterns and its association with psychological factors needs further investigation. This study assessed differences in resting-state functional connectivity (rsFC) and its association to cognitive-affective aspects of pain in two groups of healthy subjects with low versus high sensitivity to pain (LSP vs. HSP). We hypothesized that HSP will show stronger connectivity in brain regions involved in the affective-motivational processing of pain and that this higher connectivity would be related to negative affective and cognitive evaluations of pain. METHODS: Forty-eight healthy subjects were allocated to two groups according to their tolerability to cold stimulation (cold pressor test, CPT, 1°C). Group LSP (N = 24) reached the cut-off time of 180±0 sec and group HSP tolerated the CPT for an average of 13±4.8 sec. Heat, cold and mechanical evoked pain were measured, as well as pain-catastrophizing (PCS), depression, anxiety and stress (DASS-21). All subjects underwent resting state fMRI. ROI-to-ROI analysis was performed. RESULTS: In comparison to the LSP, the HSP had stronger interhemispheric connectivity of the amygdala (p = 0.01) and between the amygdala and nucleus accumbens (NAc) (p = 0.01). Amygdala connectivity was associated with higher pain catastrophizing in the HSP only (p<0.01). CONCLUSIONS: These findings suggest that high sensitivity to pain may be reflected by neural circuits involved in affective and motivational aspects of pain. To what extent this connectivity within limbic brain structures relates to higher alertness and more profound withdrawal behavior to aversive events needs to be further investigated.

Promoting neuroplasticity and neuropsychological functioning in frailty through an app-based sensorimotor training: study protocol for a randomized trial.

BACKGROUND: Frailty is characterized by an age-related decline in multiple physiological systems, leading to a high vulnerability to stressors, adverse health outcomes, and low quality of life. Neuroscientific models of pathological aging emphasize the loss of sensorimotor stimulation and reduced neuromodulatory capacities as core processes in age-related cognitive and bodily decline, which may be associated with maladaptive plastic changes in the brain. We plan to increase sensorimotor stimulation in frail persons through a newly developed app-based training program and link the training trials to biological and psychological correlates of age-associated vulnerability and health indices. METHODS: We will conduct a randomized trial, applying an app-based sensorimotor home training (N = 30) in people suffering from frailty. An app-based relaxation training will serve as an active control condition (N = 30). Both interventions will last for 90 days each. The sensorimotor training includes unimodal and multimodal sensory discrimination tasks in the visual, auditory, and tactile domain, as well as sensorimotor precision tasks. The tasks will be implemented using an adaptive training algorithm and enriched with motivational components embedded in a virtual training environment. We expect a pre-post reduction of frailty status and associated functional decline related to refinement of representational maps within the sensorimotor system and improved sensorimotor function such as extremity function. Secondary analyses will study the influence of BDNF genotype as moderating variable. Additional outcomes will include measures of perceptual and cognitive functioning, quality of life as well as BDNF serum levels. Measurements will take place before training (baseline), after 60 days (assessment 1), and at the end of the training after 90 days (assessment 2). DISCUSSION: In our randomized trial, we aim to characterize a multidimensional concept of frailty and to target maladaptive behaviors and neuroplasticity using an app-based sensorimotor training. This type of intervention might provide further knowledge and new possibilities for preventing decline and preserving function in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 . Registered 11 September 2018 - Retrospectively registered. Protocol version: Version 4 revised (issue date: 19 May 2021).

Reward Enhances Pain Discrimination in Humans.

The notion that reward inhibits pain is a well-supported observation in both humans and animals, allowing suppression of pain reflexes to acquired rewarding stimuli. However, a blanket inhibition of pain by reward would also impair pain discrimination. In contrast, early counterconditioning experiments implied that reward might actually spare pain discrimination. To test this hypothesis, we investigated whether discriminative performance was enhanced or inhibited by reward. We found in adult human volunteers (N = 25) that pain-based discriminative ability is actually enhanced by reward, especially when reward is directly contingent on discriminative performance. Drift-diffusion modeling shows that this relates to an augmentation of the underlying sensory signal strength and is not merely an effect of decision bias. This enhancement of sensory-discriminative pain-information processing suggests that whereas reward can promote reward-acquiring behavior by inhibition of pain in some circumstances, it can also facilitate important discriminative information of the sensory input when necessary.

Case report: a giant arachnoid cyst masking Alzheimer's disease.

BACKGROUND: Intracranial arachnoid cysts are usually benign congenital findings of neuroimaging modalities, sometimes however, leading to focal neurological and psychiatric comorbidities. Whether primarily clinically silent cysts may become causally involved in cognitive decline in old age is neither well examined nor understood. CASE PRESENTATION: A 66-year old caucasian man presenting with a giant left-hemispheric frontotemporal cyst without progression of size, presented with slowly progressive cognitive decline. Neuropsychological assessment revealed an amnestic mild cognitive impairment (MCI) without further neurological or psychiatric symptoms. The patient showed mild medio-temporal lobe atrophy on structural MRI. Diffusion tensor and functional magnetic resonance imaging depicted a rather sustained function of the strongly suppressed left hemisphere. Amyloid-PET imaging was positive for increased amyloid burden and he was homozygous for the APOEε3-gene. A diagnosis of MCI due to Alzheimer's disease was given and a co-morbidity with a silent arachnoid cyst was assumed. To investigate, if a potentially reduced CSF flow due to the giant arachnoid cyst contributed to the early manifestation of AD, we reviewed 15 case series of subjects with frontotemporal arachnoid cysts and cognitive decline. However, no increased manifestation of neurodegenerative disorders was reported. CONCLUSIONS: With this case report, we illustrate the necessity of a systematic work-up for neurodegenerative disorders in patients with arachnoid cysts and emerging cognitive decline. We finally propose a modus operandi for the stratification and management of patients with arachnoid cysts potentially susceptive for cognitive dysfunction.

Hypothalamic-pituitary-adrenal axis feedback sensitivity in different states of back pain.

Pain normally signals a threat to bodily integrity and causes emotional distress. Acute pain serves a protective function, yet, when pain turns chronic, the protective function is lost. A chain of psychophysiological alterations including changes in the stress regulation system, apparent in dysfunctional activity and responsivity of the hypothalamic-pituitary-adrenal (HPA) axis, might be an important factor in this context. Moreover, maladaptive responses may be complicated by affective comorbid symptoms such as anxiety and depression, and alter nociceptive processing. However, the relationship among pain chronicity, stress regulation, and contributing components of comorbid symptomatology as well as somatosensory profiles has rarely been examined. In the present study, we obtained diurnal cortisol profiles at baseline and feedback regulation (following a dexamethasone suppression test (DST)) in subacute (SABP) and chronic (CBP) back pain patients and healthy control individuals (HC). We also assessed anxiety, depression and chronic stress levels and used quantitative sensory testing (QST) to detect sensory abnormalities. We found a hyper-suppression of cortisol following DST and thus enhanced negative stress feedback sensitivity in SABP compared to both CBP and HC. In SABP, DST-related cortisol levels were negatively associated with pain intensity, mediated by cold pain thresholds and anxiety. These data support a stress model of pain chronicity and suggest that stress responses might be indicators of individual vulnerability in the transition period of subacute pain.

Psychological, cognitive factors and contextual influences in pain and pain-related suffering as revealed by a combined qualitative and quantitative assessment approach.

Previous psychophysiological research suggests that pain measurement needs to go beyond the assessment of Pain Intensity and Unpleasantness by adding the evaluation of Pain-Related Suffering. Based on this three-dimensional approach, we attempted to elucidate who is more likely to suffer by identifying reasons that may lead individuals to report Pain and Pain-Related Suffering more than others. A sample of 24 healthy participants (age range 18-33) underwent four different sessions involving the evaluation of experimentally induced phasic and tonic pain. We applied two decision tree models to identify variables (selected from psychological questionnaires regarding pain and descriptors from post-session interviews) that provided a qualitative characterization of the degrees of Pain Intensity, Unpleasantness and Suffering and assessed the respective impact of contextual influences. The overall classification accuracy of the decision trees was 75% for Intensity, 77% for Unpleasantness and 78% for Pain-Related Suffering. The reporting of suffering was predominantly associated with fear of pain and active cognitive coping strategies, pain intensity with bodily competence conveying strength and resistance and unpleasantness with the degree of fear of pain and catastrophizing. These results indicate that the appraisal of the three pain dimensions was largely determined by stable psychological constructs. They also suggest that individuals manifesting higher active coping strategies may suffer less despite enhanced pain and those who fear pain may suffer even under low pain. The second decision tree model revealed that suffering did not depend on pain alone, but that the complex rating-related decision making can be shifted by situational factors (context, emotional and cognitive). The impact of coping and fear of pain on individual Pain-Related Suffering may highlight the importance of improving cognitive coping strategies in clinical settings.

Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity.

Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are two substances from cannabis sativa that have beenimplicated in the treatment of mental and neurological disorders. We concentrated on a previously validated neuroimaging phenotype, fronto-striatal connectivity across different striatal seeds, because of this loop's relevance to executive functioning, decision making, salience generation and motivation and its link to various neuropsychiatric conditions. Therefore, we studied the effect of THC and CBD on fronto-striatal circuitry by a seed-voxel connectivity approach using seeds from the caudate and the putamen. We conducted a cross-over pharmaco-fMRI study in 16 healthy male volunteers with placebo, 10 mg oral THC and 600 mg oral CBD. Resting state was measured in a 3 T scanner. CBD lead to an increase of fronto-striatal connectivity in comparison to placebo. In contrast to our expectation that THC and CBD show opposing effects, THC versus placebo did not show any significant effects, probably due to insufficient concentration of THC during scanning. The effect of CBD on enhancing fronto-striatal connectivity is of interest because it might be a neural correlate of its anti-psychotic effect in patients.

Impact of controllability on pain and suffering.

INTRODUCTION: Chronic pain and pain-related suffering are major health problems. The lack of controllability of experienced pain seems to greatly contribute to the extent of suffering. This study examined how controllability affects the perception of pain and pain-related suffering, and the modulation of this effect by beliefs and emotions such as locus of control of reinforcement, pain catastrophizing, and fear of pain. METHODS: Twenty-six healthy subjects received painful electric stimulation in both controllable and uncontrollable conditions. Visual analogue scales and the "Pictorial Representation of Illness and Self Measure" were used to assess pain intensity, unpleasantness, pain-related suffering, and the level of perceived control. We also investigated nonverbal indicators of pain and suffering such as heart rate, skin conductance, and corrugator electromyogram. RESULTS: Controllability selectively reduced the experience of pain-related suffering, but did not affect pain intensity or pain unpleasantness. This effect was modulated by chance locus of control but was unrelated to fear of pain or catastrophizing. Physiological responses were not affected by controllability. In a second sample of 25 participants, we varied the instruction. The effect of controllability on pain-related suffering was only present when instructions focused on the person being able to stop the pain. DISCUSSION: Our data suggest that the additional measure of pain-related suffering may be important in the assessment of pain and may be more susceptible to the effects of perceived control than pain intensity and unpleasantness. We also show that this effect depends on personal involvement.

Two innovative pharmaceutical forms of leuprorelin: results from 818 patients with advanced prostate cancer.

OBJECTIVES: This study set out to examine the efficacy and tolerability of two innovative implant forms of leuprorelin acetate in men with advanced hormone-dependent prostate cancer in everyday clinical practice. METHODS: Data were collected from 818 patients (from 273 centers across Germany) who were pretreated with slow-release luteinizing hormone-releasing hormone (LHRH) agonist formulations and who were about to be switched to the leuprorelin implants. Patients received three injections of 1- or 3-month leuprorelin implant and physicians were asked to complete a case report form specific to each of the three clinic visits. Documented parameters included laboratory measurements, such as testosterone and prostate-specific antigen (PSA) levels, adverse events, and patient- and physician-rated assessments of the therapy. RESULTS: Compared with baseline, a significant decrease in both testosterone and PSA levels were measured after the first and second injections of leuprorelin implant. These results were confirmed for both the 1-month and 3-month implants in separate analyses. Switching, without treatment interruption, from Trenantone® (Takeda Pharma GmBH, Aachen, Germany) to the leuprorelin implant resulted in a significant decrease in the mean serum testosterone concentrations (P < 0.05) and a nonsignificant increase in the proportion of patients reaching castrate testosterone levels, while the number of patients with PSA values ≤ 4 ng/mL significantly increased (P = 0.045). Similar results were obtained for patients previously treated with goserelin who switched to leuprorelin implant. For 94% of patients, treating physicians rated the efficacy of leuprorelin implant as "very good" or "good." Treatment with leuprorelin implant was well tolerated, with only 61 adverse events reported in 42 (5.1%) patients. Patients and physicians rated the tolerability of leuprorelin implant as "very good" or "good" in 95% and 91% of cases, respectively. CONCLUSIONS: These results confirm the efficacy, tolerability, and ease of use of the leuprorelin implants among a large population of men with advanced, hormone-dependent prostate cancer treated in a clinical practice setting.