Parallel buprenorphine phMRI responses in conscious rodents and healthy human subjects.

Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial µ-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development.

Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine.

Buprenorphine (BUP) is a partial agonist at µ-, δ- and ORL1 (opioid receptor-like)/nociceptin receptors and antagonist at the κ-opioid receptor site. BUP is known to have both analgesic as well as antihyperalgesic effects via its central activity, and is used in the treatment of moderate to severe chronic pain conditions. Recently, it was shown that intravenous (IV) administration of 0.2mg/70 kg BUP modulates the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to acute noxious stimuli in healthy human subjects. The present study extends these observations by investigating the effects of BUP dose and route of administration on central nervous system (CNS) pain circuitry. Specifically, the modulation of evoked pain BOLD responses and resting state functional connectivity was measured following IV (0.1 and 0.2mg/70 kg) and sublingual (SL) (2mg) BUP administration in healthy human subjects. While 0.1mg/70 kg IV BUP is sub-analgesic, both 0.2mg/70 kg IV BUP and 2.0mg SL BUP are analgesic doses of the drug. Evoked BOLD responses were clearly modulated in a dose-dependent manner. The analgesic doses of BUP by both routes of administration yielded a potentiation in limbic/mesolimbic circuitry and attenuation in sensorimotor/sensory-discriminative circuitry. In addition, robust decreases in functional connectivity between the putamen and the sensorimotor/sensory-discriminative structures were observed at the two analgesic doses subsequent to measuring the maximum plasma BUP concentrations (C(max)). The decreases in functional connectivity within the sensorimotor/sensory-discriminative circuitry were also observed to be dose-dependent in the IV administration cohorts. These reproducible and consistent functional CNS measures at clinically effective doses of BUP demonstrate the potential of evoked pain fMRI and resting-state functional connectivity as objective tools that can inform the process of dose selection. Such methods may be useful during early clinical phase evaluation of potential analgesics in drug development.

Performance on patterned string problems by common marmosets (Callithrix jacchus).

This experiment examined the performance of common marmosets (Callithrix jacchus) on a series of patterned string problems to assess the marmosets' understanding of means-ends relationships. One marmoset, Jet, was exposed to a series of problems that were ordered in terms of perceived difficulty during two testings that were separated by 1 year. In the second testing, Jet received problems that had been used during the first testing along with three new problems. Each of the new problems was designed to be an exemplar of the type of problem that Jet had experienced difficulty with in the first testing. A second marmoset, Peaches, was tested on the same set of problems given to Jet in the second testing. Results indicated that the marmosets' performance on these problems fell into three categories. In one category, some problems were solved without evidence of trial-and-error learning. In a second category, there were problems in which the marmosets responded at chance levels initially but evidenced improvement as a function of extended testing. In a third category, some problems appeared to be virtually unsolvable even with extended testing. Taken together, these results indicate that the marmosets were able to learn the means-ends connection between pulling a string and obtaining food. This learning was best characterized as a trial-and-error process for some problem forms, while for others there appeared to be rapid learning that did not require extensive practice. The instances of rapid learning may be the result of the application of a simple spatial proximity rule in which the marmosets chose the string that was closest to an imaginary line drawn between the marmoset and the reinforcer.

Migraine attacks the Basal Ganglia.

BACKGROUND: With time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month). The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human) brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF) to a matched (gender, age, age of onset and type of medication) group of patients whose migraine episodes progressed (HF). RESULTS: In comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain. CONCLUSIONS: Supported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine.

Alterations in brain structure and functional connectivity in prescription opioid-dependent patients.

A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n=10); from a larger study on prescription opioid dependent patients (n=133)] and matched healthy individuals (n=10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.

Characteristics of implicit chaining in cotton-top tamarins (Saguinus oedipus).

In human cognition there has been considerable interest in observing the conditions under which subjects learn material without explicit instructions to learn. In the present experiments, we adapted this issue to nonhumans by asking what subjects learn in the absence of explicit reinforcement for correct responses. Two experiments examined the acquisition of sequence information by cotton-top tamarins (Saguinus oedipus) when such learning was not demanded by the experimental contingencies. An implicit chaining procedure was used in which visual stimuli were presented serially on a touchscreen. Subjects were required to touch one stimulus to advance to the next stimulus. Stimulus presentations followed a pattern, but learning the pattern was not necessary for reinforcement. In Experiment 1 the chain consisted of five different visual stimuli that were presented in the same order on each trial. Each stimulus could occur at any one of six touchscreen positions. In Experiment 2 the same visual element was presented serially in the same five locations on each trial, thereby allowing a behavioral pattern to be correlated with the visual pattern. In this experiment two new tests, a Wild-Card test and a Running-Start test, were used to assess what was learned in this procedure. Results from both experiments indicated that tamarins acquired more information from an implicit chain than was required by the contingencies of reinforcement. These results contribute to the developing literature on nonhuman analogs of implicit learning.

Achieving Mental Health Equity: Children and Adolescents.

This article briefly reviews the influences of protective and risk factors of child and adolescent mental health, and explores promising practices and outcomes of evidence-based programs designed to improve the mental health of youth, and the barriers for accessing quality and evidence-based child and adolescent mental health service delivery systems. The authors provide recommendations for individual practice improvements and policy, funding, and organizational practice improvements that will support mental health equity in child and adolescent populations.

To adapt or not to adapt: the question of domain-general cognitive control.

What do perceptually bistable figures, sentences vulnerable to misinterpretation and the Stroop task have in common? Although seemingly disparate, they all contain elements of conflict or ambiguity. Consequently, in order to monitor a fluctuating percept, reinterpret sentence meaning, or say "blue" when the word RED is printed in blue ink, individuals must regulate attention and engage cognitive control. According to the Conflict Monitoring Theory (Botvinick, Braver, Barch, Carter, & Cohen, 2001), the detection of conflict automatically triggers cognitive control mechanisms, which can enhance resolution of subsequent conflict, namely, "conflict adaptation." If adaptation reflects the recruitment of domain-general processes, then conflict detection in one domain should facilitate conflict resolution in an entirely different domain. We report two novel findings: (i) significant conflict adaptation from a syntactic to a non-syntactic domain and (ii) from a perceptual to a verbal domain, providing strong evidence that adaptation is mediated by domain-general cognitive control.

Imaging drugs with and without clinical analgesic efficacy.

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with µ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.