Orbitofrontal Cortex and the Early Processing of Visual Novelty in Healthy Aging

Event-related potential (ERP) studies have previously found that scalp topographies of attention-related ERP components show frontal shifts with age, suggesting an increased need for compensatory frontal activity to assist with top-down facilitation of attention. However, the precise neural time course of top-down attentional control in aging is not clear. In this study, 20 young (mean: 22 years) and 14 older (mean: 64 years) adults completed a three-stimulus visual oddball task while high-density ERPs were acquired. Colorful, novel distracters were presented to engage early visual processing. Relative to young controls, older participants exhibited elevations in occipital early posterior positivity (EPP), approximately 100 ms after viewing colorful distracters. Neural source models for older adults implicated unique patterns of orbitofrontal cortex (BA 11) activity during early visual novelty processing (100 ms), which was positively correlated with subsequent activations in primary visual cortex (BA 17). Older adult EPP amplitudes and OFC activity were associated with performance on tests of complex attention and executive function. These findings are suggestive of age-related, compensatory neural changes that may driven by a combination of weaker cortical efficiency and increased need for top-down control over attention. Accordingly, enhanced early OFC activity during visual attention may serve as an important indicator of frontal lobe integrity in healthy aging

An investigation into aripiprazole's partial D(2) agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers

Rationale: Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory. Objectives: We probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole’s prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole’s unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone. Method: A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning. Results: Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d’) and speeded reaction times. In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d’ and additionally had reduced errors of commission compared with placebo. Conclusion: Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade

Colocalized Structural and Functional Changes in the Cortex of Patients with Trigeminal Neuropathic Pain

Background: Recent data suggests that in chronic pain there are changes in gray matter consistent with decreased brain volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has evaluated cortical thickness in relation to specific functional changes in evoked pain. In this study we sought to investigate structural (gray matter thickness) and functional (blood oxygenation dependent level – BOLD) changes in cortical regions of precisely matched patients with chronic trigeminal neuropathic pain (TNP) affecting the right maxillary (V2) division of the trigeminal nerve. The model has a number of advantages including the evaluation of specific changes that can be mapped to known somatotopic anatomy. Methodology/Principal Findings: Cortical regions were chosen based on sensory (Somatosensory cortex (SI and SII), motor (MI) and posterior insula), or emotional (DLPFC, Frontal, Anterior Insula, Cingulate) processing of pain. Both structural and functional (to brush-induced allodynia) scans were obtained and averaged from two different imaging sessions separated by 2–6 months in all patients. Age and gender-matched healthy controls were also scanned twice for cortical thickness measurement. Changes in cortical thickness of TNP patients were frequently colocalized and correlated with functional allodynic activations, and included both cortical thickening and thinning in sensorimotor regions, and predominantly thinning in emotional regions. Conclusions: Overall, such patterns of cortical thickness suggest a dynamic functionally-driven plasticity of the brain. These structural changes, which correlated with the pain duration, age-at-onset, pain intensity and cortical activity, may be specific targets for evaluating therapeutic interventions

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The Stroop task and attention deficits in schizophrenia: a critical evaluation of card and single-trial Stroop methodologies

The Stroop task, considered by many to be a paradigmatic measure of selective attention, has often been employed to investigate attention deficits in schizophrenia. Card and single-trial versions of this task have yielded different results. In this study both card and single-trial versions were administered to healthy controls (n = 24) and patients with schizophrenia (n = 55). No differences in reaction time (RT) interference were found on either version. On the single-trial version, patients showed greater RT facilitation and error rate interference, evidence for a deficit in selective attention. Methodologic and analytic issues that account for the mixed results from earlier card Stroop studies are addressed. It is concluded that single-trial versions provide greater sensitivity to selective attention pathology in schizophrenia. The Stroop task (Stroop, 1935) has been considered a paradigmatic measure of selective attention in neuropsychology and cognitive psychology for more than 60 years. The Stroop task requires participants to attend to a single dimension of a stimulus while simultaneously ignorin

Immediate Changes After Manual Therapy in Resting-State Functional Connectivity as Measured by Functional Magnetic Resonance Imaging in Participants With Induced Low Back Pain

AbstractObjectiveThe purposes of this study were to use functional magnetic resonance imaging to investigate the immediate changes in functional connectivity (FC) between brain regions that process and modulate the pain experience after 3 different types of manual therapies (MT) and to identify reductions in experimentally induced myalgia and changes in local and remote pressure pain sensitivity.MethodsTwenty-four participants (17 men; mean age ± SD, 21.6 ± 4.2 years) who completed an exercise-injury protocol to induce low back pain were randomized into 3 groups: chiropractic spinal manipulation (n = 6), spinal mobilization (n = 8), or therapeutic touch (n = 10). The primary outcome was the immediate change in FC as measured on functional magnetic resonance imaging between the following brain regions: somatosensory cortex, secondary somatosensory cortex, thalamus, anterior and posterior cingulate cortices, anterior and poster insula, and periaqueductal gray. Secondary outcomes were immediate changes in pain intensity, measured with a 101-point numeric rating scale, and pain sensitivity, measured with a handheld dynamometer. Repeated-measures analysis of variance models and correlation analyses were conducted to examine treatment effects and the relationship between within-person changes across outcome measures.ResultsChanges in FC were found between several brain regions that were common to all 3 MT interventions. Treatment-dependent changes in FC were also observed between several brain regions. Improvement was seen in pain intensity after all interventions (P < .05) with no difference between groups (P > .05). There were no observed changes in pain sensitivity, or an association between primary and secondary outcome measures.ConclusionThese results suggest that MTs (chiropractic spinal manipulation, spinal mobilization, and therapeutic touch) have an immediate effect on the FC between brain regions involved in processing and modulating the pain experience. This suggests that neurophysiologic changes after MT may be an underlying mechanism of pain relief