Placebo-Induced Improvements: How Therapeutic Rituals Affect the Patient's Brain

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Methylphenidate Normalizes Fronto-Striatal Underactivation During Interference Inhibition in Medication-Naïve Boys with Attention-Deficit Hyperactivity Disorder

Youth with attention deficit hyperactivity disorder (ADHD) have deficits in interference inhibition, which can be improved with the indirect catecholamine agonist methylphenidate (MPH). Functional magnetic resonance imaging was used to investigate the effects of a single dose of MPH on brain activation during interference inhibition in medication-naïve ADHD boys. Medication-naïve boys with ADHD were scanned twice, in a randomized, double-blind design, under either a single clinical dose of MPH or placebo, while performing a Simon task that measures interference inhibition and controls for the oddball effect of low-frequency appearance of incongruent trials. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of healthy age-matched comparison boys. During incongruent trials compared with congruent–oddball trials, boys with ADHD under placebo relative to controls showed reduced brain activation in typical areas of interference inhibition, including right inferior prefrontal cortex, left striatum and thalamus, mid-cingulate/supplementary motor area, and left superior temporal lobe. MPH relative to placebo upregulated brain activation in right inferior prefrontal and premotor cortices. Under the MPH condition, patients relative to controls no longer showed the reduced activation in right inferior prefrontal and striato-thalamic regions. Effect size comparison, furthermore, showed that these normalization effects were significant. MPH significantly normalized the fronto-striatal underfunctioning in ADHD patients relative to controls during interference inhibition, but did not affect medial frontal or temporal dysfunction. MPH therefore appears to have a region-specific upregulation effect on fronto-striatal activation

Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications”,

Drug addiction encompasses a relapsing cycle of intoxication, bingeing, withdrawal and craving that results in excessive drug use despite adverse consequences (FIG. 1). Drugs that are abused by humans increase dopamine in the reward circuit and this is believed to underlie their rewarding effects. Therefore, most clinical studies in addiction have focused on the midbrain dopamine areas (the ventral tegmental area and substantia nigra) and the basal ganglia structures to which they project (the ventral striatum, where the nucleus accumbens is located, and the dorsal striatum), which are known to be involved in reward, conditioning and habit formation On the basis of imaging findings and emerging preclinical studies 5,6 , we proposed 10 years ago that disrupted function of the PFC leads to a syndrome of impaired response inhibition and salience attribution (iRISA) in addiction Here we review imaging studies into the role of the PFC in addiction from the past decade, integrating them into the iRISA model with the aim to gain a greater understanding of the dysfunction of the PFC in addiction. Specifically, this is the first systematic evaluation of the role of distinct regions within the functionally heterogeneous PFC in the neuropsychological mechanisms that putatively underlie the relapsing cycle of addiction. We review positron emission tomography (PET) and functional MRI (fMRI) studies focusing on regions of the PFC that have been implicated in addiction. These include the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) (see R E V I E W S Non-contingent administration Administration of a certain drug that is not dependent on the subject's behaviour. Fixed-rate self-administration Self-administration of a certain drug on a ratio between drug delivery and behaviour that is fixed by an experimenter (for example, after emission of a certain number of responses or after a certain time has elapsed following the previous response). into the executive function of the PFC we refer the reader to other reviews Direct effects of drug exposure Here, we review studies that assessed the effects of stimulant and non-stimulant drugs on PFC activity 18 Fluorodyoxyglucose PET (PET FDG) study, administration of the stimulant drug methylphenidate (MPH) to active cocaine users increased whole-brain glucose metabolism 14 . Here, the left lateral OFC showed greater metabolism in response to unexpected than to expected MPH; the opposite pattern to that of the BOLD effect in the above study 13 possibly reflects the different temporal sensitivity of the imaging modalities (see below). Stimulant drugs also increase PFC activity in laboratory animals. For example, regional cerebral blood flow (rCBF) in drug-naive rhesus monkeys increased in DLPFC after non-contingent administration and in ACC during a simple fixed-rate self-administration of cocain

Neuropsychological Effects of Placebo Stimulants in College Students

The past 15 years has seen increases in the nonmedical use of prescription stimulants (NMUPS; e.g., Adderall, Ritalin, Focalin) across college students with rates reported between 6 and 34 percent. Many underestimate or ignore the serious side effects associated with stimulant medication. Furthermore, stimulant medications used to treat ADHD are classified as Schedule II drugs by the Drug Enforcement Agency as they provide beneficial outcomes when used as a prescription medication, but have a high potential risk for abuse, rendering the diversion and unprescribed use illegal. There is also the ethical dilemma that arises when students have access to prescription stimulants to use nonmedically for the purpose of cognitive enhancement. The present study measured the effect a placebo stimulant and one’s personal expectancies have on subjective physiological changes and academic enhancement. Undergraduate college students (N = 305) participated in a two-phase study. Phase I involved completing an online survey to gather distal study variables and screen participants for medical exclusionary criteria that precludes them from obtaining a stimulant prescription. Phase II required students to attend an in-person session in which they completed various physiological and neuropsychological measures (e.g., Physical Symptom Checklist, Digit Span, Passage Comprehension). Students were randomized to receive 30 milligrams of a placebo stimulant medication (experimental) or no medication (control). Following a 30-minute absorption period, participants completed another set of physiological and neuropsychological measures. A repeated measures-MANCOVA revealed no significant differences between groups from time 1 to 2 despite positive symptom changes in the experimental group. Expectancies moderated performance on some neuropsychological tasks. Future research should include more participants with a history of NMUPS and stimulant medication in addition to placebo

The placebo effect: from concepts to genes

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioural, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, observational, and social cues are centrally integrated to change behaviours and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioural, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximise treatment outcomes in clinical settings

The placebo effect: from concepts to genes

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioural, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, observational, and social cues are centrally integrated to change behaviours and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioural, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximise treatment outcomes in clinical settings

Prediction of the clinical response to psychostimulant by the basal and reactive salivary cortisol in children with ADHD

Le trouble du déficit de l’attention/hyperactivité (TDA/H) est un des troubles comportementaux le plus commun chez les enfants. TDAH a une étiologie complexe et des traitements efficaces. Le médicament le plus prescrit est le méthylphénidate, un psychostimulant qui bloque le transporteur de la dopamine et augmente la disponibilité de la dopamine dans la fente synaptique. Des études précliniques et cliniques suggèrent que le cortisol peut potentialiser les effets de la dopamine. Un dysfonctionnement du système hypothalamo-hypophyso-surrénalien (HHS) est associé avec plusieurs maladies psychiatriques comme la dépression, le trouble bipolaire, et l’anxiété. Nous avons fait l’hypothèse que le cortisol influence l’efficacité du traitement des symptômes du TDAH par le méthylphénidate. L’objectif de cette étude est de mesurer les niveaux de cortisol le matin au réveil et en réponse à une prise de sang dans un échantillon d’enfants diagnostiqué avec TDAH âgé de 8 ans. Le groupe était randomisé dans un protocole en chassé croisé et en double aveugle avec trois doses de méthylphénidate et un placebo pour une période de quatre semaines. Les enseignants et les parents ont répondu aux questionnaires SWAN et à une échelle d’évaluation des effets secondaires. Les résultats ont démontrés qu’un niveau de cortisol élevé au réveil prédit les sujets qui ne répondent pas au traitement du TDAH, si on se fie aux rapports des parents. En plus, la réactivité au stress élevé suggère un bénéfice additionnel d’une dose élevée de méthylphénidate selon les enseignants. Aussi, les parents rapportent une association entre la présence de troubles anxieux co-morbide avec le TDAH et une meilleure réponse à une dose élevée. Cette étude suggère qu’une forte réactivité de l’axe HHS améliore la réponse clinique à des doses élevées, mais qu’une élévation chronique du niveau de cortisol pourrait être un marqueur pour les non répondeurs. Les résultats de cette étude doivent être considérés comme préliminaires et nécessitent des tests plus approfondis des interactions possibles entre les médicaments utilisés pour traiter le TDAH et l’axe HHS.ADHD is the most common behavioural disorder in children with complex aetiology and efficacious treatments. The most prescribed medication for ADHD is methylphenidate, a psychostimulant that blocks the dopamine transporter and increases dopamine availability in the synaptic cleft. Preclinical and clinical studies show that cortisol may enhance dopamine effects. Dysregulation of the hypothalamic-pituitaryadrenal axis is also associated with many psychiatric disorders such as depression, bipolar disease, and anxiety. We hypothesized that cortisol has an influence on the efficacy of the treatment of ADHD symptoms with methylphenidate. The objective of this study was to measure the salivary level of cortisol in a sample of 8-year-old children with ADHD upon waking and in response to a venipuncture. The children were then randomized to three doses of methylphenidate and a placebo in a double-blind cross-over design. Teachers and parents rated the behaviour of the children using the SWAN and a side effect rating scale. The results showed that high morning cortisol is a good predictor of a nonresponder under active medication, as reported by parents. Also, the high stress reactivity group, but not the low stress reactivity group, demonstrated a greater benefit going to a higher dose of methylphenidate, according to teachers. In addition, parents demonstrated an association between anxiety comorbid disorders and a better response to a high dose of methylphenidate. This study suggests that a strong reactivity of the HPA axis improves the clinical response at high dose, but that chronically elevated cortisol might be a marker for non responders. The results of this study should be seen as preliminary and require further testing of the possible interactions between ADHD medication and HPA activity

Alcohol use in a polysubstance context : implications for understanding the mechanisms of alcohol reinforcement

Alcohol is frequently co-administered with other psychotropic substances, yet little is known about patterns of alcohol use in a simultaneous polysubstance context. In the present dissertation concomitant alcohol-drug administration is examined with an emphasis on delineating patterns of alcohol use when it is co-administered with psychostimulant drugs known to interact with neural mechanisms believed to be involved in mediating alcohol's ascending limb reinforcing effects: midbrain dopamine transmission.In two retrospective self-report studies polysubstance users reported on their simultaneous use of drugs and alcohol. Results revealed that alcohol was commonly co-administered with various abused substances, particularly with psychostimulant drugs that are known to increase dopamine neurotransmission, and there was an identifiable pattern of administration that was characterized by initial alcohol consumption preceding repeated intermingled alcohol-psychostimulant administrations which resulted in alcohol dose escalation.In a third study, the effects of administering the psychostimulant drug nicotine on alcohol intake was directly examined using a double-blind placebo controlled self-administration procedure. Nicotine was found to significantly increase alcohol ingestion.In a final study we examined the effect of decreasing dopamine neurotransmission on alcohol self-administration by using a dietary manipulation that depletes the nutritional precursors to dopamine. This procedure was found to decrease alcohol consumption, an effect that was especially evident in a subset of drinkers thought to be hypersensitive alcohol's ascending limb dopamine effects. Overall findings suggest that alcohol co-administration with psychostimulant drugs affects patterns of alcohol intake and that this may be the result of an interaction involving dopamine neurotransmission