Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials.

Fundamental aspects of human behavior operate outside of conscious awareness. Yet, theories of conditioned responses in humans, such as placebo and nocebo effects on pain, have a strong emphasis on conscious recognition of contextual cues that trigger the response. Here, we investigated the neural pathways involved in nonconscious activation of conditioned pain responses, using functional magnetic resonance imaging in healthy participants. Nonconscious compared with conscious activation of conditioned placebo analgesia was associated with increased activation of the orbitofrontal cortex, a structure with direct connections to affective brain regions and basic reward processing. During nonconscious nocebo, there was increased activation of the thalamus, amygdala, and hippocampus. In contrast to previous assumptions about conditioning in humans, our results show that conditioned pain responses can be elicited independently of conscious awareness and our results suggest a hierarchical activation of neural pathways for nonconscious and conscious conditioned responses. Demonstrating that the human brain has a nonconscious mechanism for responding to conditioned cues has major implications for the role of associative learning in behavioral medicine and psychiatry. Our results may also open up for novel approaches to translational animal-to-human research since human consciousness and animal cognition is an inherent paradox in all behavioral science.

Blinding protects against bias but the success of blinding is seldom assessed and reported in clinical trials including studies of acupuncture where blinding represents a major challenge. Recently, needles with the potential for double-blinding were developed, so we tested if acupuncture can be double-blinded in a randomized study of sixty-seven patients with acute pain ≥ 3 (0-10 scale following third molar removal) who received active acupuncture with a penetrating needle or placebo acupuncture with a non-penetrating needle. To test if acupuncture was administered double-blind, patients and acupuncturists were asked about perceived treatment allocation at the end of the study. To test if there were clues which led to identification of the treatment, deep dull pain associated with needle application and rotation (termed "de qi" in East Asian medicine), and patients' pain levels were assessed. Perceived treatment allocation depended on actual group allocation (p < 0.015) for both patients and acupuncturists, indicating that the needles were not successful in double-blinding. Up to 68% of patients and 83% of acupuncturists correctly identified the treatment, but for patients the distribution was not far from 50/50. Also, there was a significant interaction between actual or perceived treatment and the experience of de qi (p = 0.027), suggesting that the experience of de qi and possible non-verbal clues contributed to correct identification of the treatment. Yet, of the patients who perceived the treatment as active or placebo, 50% and 23%, respectively, reported de qi. Patients' acute pain levels did not influence the perceived treatment. In conclusion, acupuncture treatment was not fully double-blinded which is similar to observations in pharmacological studies. Still, the non-penetrating needle is the only needle that allows some degree of practitioner blinding. The study raises questions about alternatives to double-blind randomized clinical trials in the assessment of acupuncture treatment.

Side effects are frequent in pharmacological pain management, potentially preceding analgesia and limiting drug tolerability. Discussing side effects is part of informed consent, yet can favor nocebo effects. This study aimed to test whether a positive suggestion regarding side effects, which could act as reminders of the medication having been absorbed, might favor analgesia in a clinical interaction model. Sixty-six healthy males participated in a study "to validate pupillometry as an objective measure of analgesia". Participants were unknowingly randomized double-blind to positive vs control information about side effects embedded in a video regarding the study drugs. Sequences of moderately painful heat stimuli applied before and after treatment with diclofenac and atropine served to evaluate analgesia. Atropine was deceptively presented as a co-analgesic, but used to induce side effects. Adverse events (AE) were collected with the General Assessment of Side Effects (GASE) questionnaire prior to the second induced pain sequence. Debriefing fully informed participants regarding the purpose of the study and showed them the two videos.The combination of medication led to significant analgesia, without a between-group difference. Positive information about side effects increased the attribution of AE to the treatment compared to the control information. The total GASE score was correlated with analgesia, i.e., the more AEs reported, the stronger the analgesia. Interestingly, there was a significant between-groups difference on this correlation: the GASE score and analgesia correlated only in the positive information group. This provides evidence for a selective link between AEs and pain relief in the group who received the suggestion that AEs could be taken as a sign "that help was on the way". During debriefing, 65% of participants said they would prefer to receive the positive message in a clinical context. Although the present results cannot be translated immediately to clinical pain conditions, they do indicate the importance of testing this type of modulation in a clinical context.

To determine the placebo component of treatment responses in patients with intellectual disability (ID).

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP.

Large placebo responses in randomized clinical trials may keep effective medication from reaching the market. Primary outcome measures of clinical trials have shifted from patient-reported to objective outcomes, partly because response to randomized placebo treatment is thought to be greater in subjective compared with objective outcomes. However, a direct comparison of placebo response in subjective and objective outcomes in the same patient population is missing.

Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes.

Electroacupuncture (EA) is currently one of the most popular acupuncture modalities. However, the continuous stimulation characteristic of EA treatment presents challenges to the use of conventional functional Magnetic Resonance Imaging (fMRI) approaches for the investigation of neural mechanisms mediating treatment response because of the requirement for brief and intermittent stimuli in event related or block designed task paradigms. A relatively new analysis method, functional connectivity fMRI (fcMRI), has great potential for studying continuous treatment modalities such as EA. In a previous study, we found that, compared with sham acupuncture, EA can significantly reduce Periaqueductal Gray (PAG) activity when subsequently evoked by experimental pain. Given the PAG's important role in mediating acupuncture analgesia, in this study we investigated functional connectivity with the area of the PAG we previously identified and how that connectivity was affected by genuine and sham EA.

Although meta-analyses have shown that placebo responses are large in Major Depressive Disorder (MDD) trials; the placebo response of devices such as repetitive transcranial magnetic stimulation (rTMS) has not been systematically assessed. We proposed to assess placebo responses in two categories of MDD trials: pharmacological (antidepressant drugs) and non-pharmacological (device- rTMS) trials.

Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

The goal of this study was to determine the neural correlates of successful doctor-patient interactions. We performed an experimental neuroimaging study where medical doctors (MDs) performed a treatment task while their brain activation pattern was measured, using functional magnetic resonance imaging (fMRI). MDs (25-37 years old) first performed a standardized clinical exam of a "professional patient". Unbeknownst to the doctors, the professional patient was a confederate that rated the doctors' clinical examination using the Consultation And Relational Empathy (CARE) questionnaire, a standardized protocol assessing a clinician's social interaction during a consultation. After the clinical exam, MDs were placed inside a brain scanner and the patient was placed on a chair next to the MD. MDs performed a treatment task where an analgesic device was used to alleviate the patient's pain (experimentally induced), while the MD's brain activity was measured with fMRI. MDs rated their own empathic concern (equivalent of compassion) and personal distress using the Interpersonal Reactivity Index questionnaire. The patient's rating of CARE was robustly related to the MD's own ratings of trait empathic concern and to compassion-related and reward-related activation of medial frontal brain regions during treatment. In contrast, there was no relation with MD's personal distress, nor with activation in regions associated with the aversive component of experiencing empathy. We conclude that a patient's positive experience of a medical examination is reflected in doctors' empathic concern and reward-related brain activations during treatment, suggesting that compassion and pleasure are key factors for successful doctor-patient interactions.

Cystinosis is a rare autosomal recessive disorder caused by intracellular cystine accumulation. Proximal tubulopathy (Fanconi syndrome) is one of the first signs, leading to end-stage renal disease between the age of 12 and 16. Other symptoms occur later and encompass endocrinopathies, distal myopathy and deterioration of the central nervous system. Treatment with cysteamine if started early can delay the progression of the disease. Little is known about the neurological impairment which occurs later. The goal of the present study was to find a possible neuroanatomical dysmorphic pattern that could help to explain the cognitive profile of cystinosis patients. We also performed a detailed review of the literature on neurocognitive complications associated with cystinosis.

The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a duplication of 24 base pairs (c.429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA). In this study, we first present ARX expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although ARX expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 ARX patients carrying c.429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that ARX patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip. As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in ARX dup24 patients is very likely the anatomical substrate of this developmental form of LKA.

Chronic itch, a highly debilitating condition, has received relatively little attention in the neuroimaging literature. Recent studies suggest that brain regions supporting itch in chronic itch patients encompass sensorimotor and salience networks, and corticostriatal circuits involved in motor preparation for scratching. However, how these different brain areas interact with one another in the context of itch is still unknown. We acquired BOLD fMRI scans in 14 atopic dermatitis patients to investigate resting-state functional connectivity before and after allergen-induced itch exacerbated the clinical itch perception in these patients. A seed-based analysis revealed decreased functional connectivity from baseline resting state to the evoked-itch state between several itch-related brain regions, particularly the insular and cingulate cortices and basal ganglia, where decreased connectivity was significantly correlated with increased levels of perceived itch. In contrast, evoked itch increased connectivity between key nodes of the frontoparietal control network (superior parietal lobule and dorsolateral prefrontal cortex), where higher increase in connectivity was correlated with a lesser increase in perceived itch, suggesting that greater interaction between nodes of this executive attention network serves to limit itch sensation via enhanced top-down regulation. Overall, our results provide the first evidence of itch-dependent changes in functional connectivity across multiple brain regions.

The scientific basis for acupuncture meridians is unknown. Past studies have suggested that acupuncture meridians are physiologically characterized by low electrical impedance and anatomically associated with connective tissue planes. We are interested in seeing whether acupuncture meridians are associated with lower electrical impedance and whether ultrasound-derived measures--specifically echogenic collagenous bands--can account for these impedance differences.

Patients in the placebo arms of randomized controlled trials (RCT) often experience positive changes from baseline. While multiple theories concerning such "placebo effects" exist, peculiarly, none has been informed by actual interviews of patients undergoing placebo treatment. Here, we report on a qualitative study (n = 27) embedded within a RCT (n = 262) in patients with irritable bowel syndrome. Besides identical placebo acupuncture treatment in the RCT, the qualitative study patients also received an additional set of interviews at the beginning, midpoint, and end of the trial. Interviews of the 12 qualitative subjects who underwent and completed placebo treatment were transcribed. We found that patients (1) were persistently concerned with whether they were receiving placebo or genuine treatment; (2) almost never endorsed "expectation" of improvement but spoke of "hope" instead and frequently reported despair; (3) almost all reported improvement ranging from dramatic psychosocial changes to unambiguous, progressive symptom improvement to tentative impressions of benefit; and (4) often worried whether their improvement was due to normal fluctuations or placebo effects. The placebo treatment was a problematic perturbation that provided an opportunity to reconstruct the experiences of the fluctuations of their illness and how it disrupted their everyday life. Immersion in this RCT was a co-mingling of enactment, embodiment and interpretation involving ritual performance and evocative symbols, shifts in bodily sensations, symptoms, mood, daily life behaviors, and social interactions, all accompanied by self-scrutiny and re-appraisal. The placebo effect involved a spectrum of factors and any single theory of placebo--e.g. expectancy, hope, conditioning, anxiety reduction, report bias, symbolic work, narrative and embodiment--provides an inadequate model to explain its salubrious benefits.

Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment ("waitlist"), placebo treatment alone ("limited") and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

To assess the quantity and quality of randomised, sham-controlled studies of surgery and invasive procedures and estimate the treatment-specific and non-specific effects of those procedures.

Patients after organ transplantation or with chronic, inflammatory autoimmune diseases require lifelong treatment with immunosuppressive drugs, which have toxic adverse effects. Recent insight into the neurobiology of placebo responses shows that associative conditioning procedures can be employed as placebo-induced dose reduction strategies in an immunopharmacological regimen. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. Thus, 30 renal transplant patients underwent a taste-immune conditioning paradigm, in which immunosuppressive drugs (unconditioned stimulus) were paired with a gustatory stimulus [conditioned stimulus (CS)] during the learning phase. During evocation phase, after patients were reexposed to the CS, T cell proliferative capacity was significantly reduced in comparison with the baseline kinetics of T cell functions under routine drug intake (ƞp2 = 0.34). These data demonstrate, proof-of-concept, that learned immunosuppressive placebo responses can be used as a supportive, placebo-based, dose-reduction strategy to improve treatment efficacy in an ongoing immunopharmacological regimen.