Explore the vast range of titles available.

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify \"sham-susceptible\" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.

Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18]fluorodeoxyglucose before and after 6 weeks of treatment with L-T4 ( n =15) or placebo ( n =10) in 12 volumes of interest (VOIs): the bilateral thalamus, amygdala, hippocampus, dorsal striatum and ventral striatum, and midline cerebellar vermis and subgenual cingulate cortex. Radioactivity in the VOIs, normalized to whole-brain radioactivity was taken as a surrogate index of glucose metabolism, and markers of thyroid function were assayed. Changes in brain activity and their association with clinical response were assessed using statistical parametric mapping. Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P <0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores ( P <0.05 after Bonferroni correction). Placebo treatment was associated with a significant decrease in activity only in the right amygdala, and no region had a change in activity that was correlated with change in depression scores. The groups differed significantly in the relationship between the changes in depression scores and in activity in the thalamus bilaterally and the left ventral striatum. The findings provide evidence that administration of supraphysiologic thyroid hormone improves depressive symptoms in patients with bipolar disorder by modulating function in components of the anterior limbic network.

Rationale Mesocorticolimbic reactivity to alcohol-associated cues has been shown to be associated with relapse to renewed drinking and to be decreased by cue-exposure-based extinction training (CET). Evidence from preclinical studies suggests that the extinction of conditioned alcohol-seeking behavior might be facilitated by drugs increasing N -methyl- d -aspartate (NMDA) receptor-associated memory consolidation. Objectives In this study, we assessed the efficacy of CET treatment supplemented with the partial NMDA-receptor agonist d -cycloserine (DCS) at reducing mesolimbic cue reactivity (CR), craving, and relapse risk in alcoholism. Methods In a randomized, placebo-controlled, double-blind study, we recruited 76 recently detoxified abstinent alcohol-dependent patients. Thirty-two (16 DCS, 16 placebo) patients showed cue-induced ventral-striatal activation measured with functional magnetic resonance imaging (fMRI) prior to treatment and were thus included in the efficacy analyses. After inpatient detoxification, patients underwent nine sessions of CET spaced over 3 weeks, receiving either 50 mg DCS or placebo 1 h prior to each CET session. FMRI was conducted before treatment and 3 weeks after treatment onset. Results Following treatment with CET plus DCS, cue-induced brain activation in the ventral and dorsal striatum was decreased compared to treatment with CET plus placebo. Elevated posttreatment ventral striatal CR and increased craving (assessed using the Obsessive Compulsive Drinking Scale) were associated with increased relapse risk. Conclusions DCS was shown to augment the effect of CET for alcohol-dependent subjects. The interaction between craving and ventral-striatal CR on treatment outcome suggests that CET might be especially effective in patients exhibiting both high craving and elevated CR.

Supplementation of standard treatment with high-dose levothyroxine (L-T 4 ) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T 4 treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [ 18 F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T 4 (mean dose 320  μ g/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T 4 treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T 4 treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T 4 improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T 4 may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

The D2/D3 receptor agonist pramipexole has clinical efficacy as an antidepressant, but its neural mechanisms are unknown. We used 18FDG-PET to investigate the cerebral metabolic effects of pramipexole augmentation of mood stabilizers in bipolar II depression. Fifteen bipolar II depressed patients on mood stabilizers were imaged at baseline and following 6 wk of pramipexole (n=7) or placebo (n=8) augmentation. Relative to placebo, pramipexole treatment was associated with reductions in normalized metabolism in bilateral orbitofrontal cortex, left ventrolateral prefrontal cortex (PFC), and right anteromedial PFC. Voxel-wise analyses additionally showed decreased normalized metabolism in the left inferior parietal cortex and medial frontopolar cortical (BA 10P) area of the anteromedial PFC following pramipexole treatment. These pramipexole-induced effects on regional metabolism suggest a mechanism of antidepressant action distinct from that previously reported under serotonin reuptake inhibitor treatment and appear compatible with evidence that the central dopaminergic system plays a role in the pathophysiology of bipolar depression.

Chronic pain is a condition in which pain progresses from an acute to chronic state and persists beyond the healing process. Chronic pain impairs function and decreases patients’ quality of life. In recent years, efforts have been made to deepen our understanding of chronic pain and to develop better treatments to alleviate chronic pain. In this review, we summarize the results of previous studies, focusing on the mechanisms underlying chronic pain development and the identification of neural areas related to chronic pain. We review the association between chronic pain and negative affective states. Further, we describe the structural and functional changes in brain structures that accompany the chronification of pain and discuss various neurotransmitter families involved. Our review aims to provide guidance for the development of future therapeutic approaches that could be used in the management of chronic pain.

There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.

In the forced swim test (FST) rodents progressively show increased episodes of immobility if immersed in a beaker with water from where escape is not possible. In this test, a compound qualifies as a potential antidepressant if it prevents or delays the transition to this passive (energy conserving) behavioural style. In the past decade however the switch from active to passive “coping” was used increasingly to describe the phenotype of an animal that has been exposed to a stressful history and/or genetic modification. A PubMed analysis revealed that in a rapidly increasing number of papers (currently more than 2,000) stress-related immobility in the FST is labeled as a depression-like phenotype. In this contribution we will examine the different phases of information processing during coping with the forced swim stressor. For this purpose we focus on the action of corticosterone that is mediated by the closely related mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the limbic brain. The evidence available suggests a model in which we propose that the limbic MR-mediated response selection operates in complementary fashion with dopaminergic accumbens/prefrontal executive functions to regulate the transition between active and passive coping styles. Upon rescue from the beaker the preferred, mostly passive, coping style is stored in the memory via a GR-dependent action in the hippocampal dentate gyrus. It is concluded that the rodent’s behavioural response to a forced swim stressor does not reflect depression. Rather the forced swim experience provides a unique paradigm to investigate the mechanistic underpinning of stress coping and adaptation.

Issue Title: Dopamine - revisited

Serotonergic neurons project their axons pervasively throughout the brain and innervate various target fields in a space-filling manner, leading to tiled arrangements of their axon terminals to allow optimal allocation of serotonin among target neurons. Here we show that conditional deletion of the mouse protocadherin α (Pcdhα) gene cluster in serotonergic neurons disrupts local axonal tiling and global assembly of serotonergic circuitries and results in depression-like behaviors. Genetic dissection and expression profiling revealed that this role is specifically mediated by Pcdhαc2, which is the only Pcdhα isoform expressed in serotonergic neurons. We conclude that, in contrast to neurite self-avoidance, which requires single-cell identity mediated by Pcdh diversity, a single cell-type identity mediated by the common C-type Pcdh isoform is required for axonal tiling and assembly of serotonergic circuitries.