Neurophysiological effects of multiple mood episodes in bipolar disorder.

OBJECTIVES: Bipolar disorder is marked by progressive symptomatic changes, which have been linked with episode-related structural findings-particularly in the prefrontal cortex. However, few studies have examined neurofunctional and neurochemical effects of disease burden. In this study, we compared first- and multi-episode bipolar individuals. We hypothesized that the latter would demonstrate evidence of neurophysiological differences consistent with a model of progressive functional degradation of these networks. METHODS: First- and multi-episode manic bipolar subjects participated in functional magnetic resonance imaging (fMRI) including a continuous performance task with emotional distractors, and in single-voxel (1 H) magnetic resonance spectroscopy (MRS). A priori fMRI regions-of-interest (ROI) included structures comprising prefrontal-striatal-amygdala networks; (1 H)MRS voxels were placed within bilateral ventrolateral prefrontal (VLPFC) and anterior cingulate cortex (ACC). Both ROI and voxel-based brain activation in response to emotional stimuli, and neurochemical concentrations derived from (1 H)MRS were compared across bipolar groups. RESULTS: Multi-episode bipolar subjects showed relatively lower regional activation across prefrontal-striatal-amygdala networks, including bilateral VLPFC, orbitofrontal cortex, ACC, putamen, caudate, and amygdala. Exploratory whole-brain, voxel-based analysis suggested additional areas of lower activation extending into Brodmann area 22, posterior parietal regions, and right thalamus. Glutamate and N-acetylaspartate (NAA) concentrations were also relatively lower in the ACC of multi-episode subjects. CONCLUSIONS: Disease burden, exemplified by multiple affective episodes is associated with evidence of widespread decrements in affective network activity. Lower ACC NAA concentration is similarly consistent with a model of progressive functional deficits. These findings support the functional significance of previously observed progressive structural changes throughout these regions.

Enhanced neural activation with blueberry supplementation in mild cognitive impairment.

OBJECTIVES: Preclinical studies have shown that blueberry supplementation can improve cognitive performance and neural function in aged animals and have identified associations between anthocyanins and such benefits. Preliminary human trials also suggest cognitive improvement in older adults, although direct evidence of enhancement of brain function has not been demonstrated. In this study, we investigated the effect of blueberry supplementation on regional brain activation in older adults at risk for dementia. METHODS: In a randomized, double-blind, placebo-controlled trial we performed pre- and post-intervention functional magnetic resonance imaging during a working memory (WM) task to assess the effect of blueberry supplementation on blood oxygen level-dependent (BOLD) signal in older adults with mild cognitive impairment, a risk condition for dementia. RESULTS: Following daily supplementation for 16 weeks, blueberry-treated participants exhibited increased BOLD activation in the left pre-central gyrus, left middle frontal gyrus, and left inferior parietal lobe during WM load conditions (corrected P < 0.01). There was no clear indication of WM enhancement associated with blueberry supplementation. Diet records indicated no between-group difference in anthocyanin consumption external to the intervention. DISCUSSION: These data demonstrate, for the first time, enhanced neural response during WM challenge in blueberry-treated older adults with cognitive decline and are consistent with prior trials showing neurocognitive benefit with blueberry supplementation in this at-risk population.

Neural Function Before and After Mindfulness-Based Cognitive Therapy in Anxious Adolescents at Risk for Developing Bipolar Disorder.

OBJECTIVE: We sought to evaluate the neurophysiology of mindfulness-based cognitive therapy for children (MBCT-C) in youth with generalized, social, and/or separation anxiety disorder who were at risk for developing bipolar disorder. METHODS: Nine youth (mean age: 13 ± 2 years) with a generalized, social, and/or separation anxiety disorder and a parent with bipolar disorder completed functional magnetic resonance imaging (fMRI) while performing a continuous processing task with emotional and neutral distractors (CPT-END) prior to and following 12 weeks of MBCT-C. RESULTS: MBCT-C was associated with increases in activation of the bilateral insula, lentiform nucleus, and thalamus, as well as the left anterior cingulate while viewing emotional stimuli during the CPT-END, and decreases in anxiety were correlated with change in activation in the bilateral insula and anterior cingulate during the viewing of emotional stimuli (p < 0.05, uncorrected; p < 0.005 corrected; cluster size, 37 voxels). CONCLUSIONS: MBCT-C treatment in anxious youth with a familial history of bipolar disorder is associated with increased activation of brain structures that subserve interoception and the processing of internal stimuli-functions that are ostensibly improved by this treatment.

Age-dependent decreases of high energy phosphates in cerebral gray matter of patients with bipolar I disorder: a preliminary phosphorus-31 magnetic resonance spectroscopic imaging study.

OBJECTIVES: To identify abnormalities in high energy phosphate cerebral metabolism in euthymic bipolar disorder. METHODS: Phosphorus-31 magnetic resonance spectroscopic imaging ((31)P MRSI) data were acquired from the entire brain of 9 euthymic adults with bipolar disorder and 13 healthy adults. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP) in homogeneous gray and white matter were obtained by tissue regression analysis. RESULTS: Analyses of covariance revealed the effect of age to be significantly different between bipolar and healthy groups for concentrations of PCr (p=0.0018) and ATP (p=0.013) in gray matter. These metabolites were negatively correlated with age in gray matter in bipolar subjects while PCr was positively correlated with age in gray matter of healthy subjects. Additionally, age-corrected concentrations of PCr in gray matter were significantly elevated in bipolar subjects (p=0.0048). LIMITATIONS: Given that this cross-sectional study possessed a small sample and potentially confounding effects of medication status, we recommend a larger, longitudinal study to more robustly study relationships between bioenergetic impairment and duration of disease. CONCLUSIONS: Our results suggest bioenergetic impairment related to mitochondrial function may be progressive in multi-episode bipolar subjects as they age.

Mean diffusivity as a potential diffusion tensor biomarker of motor rehabilitation after electrical stimulation incorporating task specific exercise in stroke: a pilot study.

Changes in diffusion tensor imaging (DTI) values co-occur with neurological and functional changes after stroke. However, quantitative DTI metrics have not been examined in response to participation in targeted rehabilitative interventions in chronic stroke. The primary purpose of this pilot study was to examine whether changes in DTI metrics co-occur with paretic arm movement changes among chronic stroke patients participating in a regimen of electrical stimulation targeting the paretic arm. Three subjects exhibiting stable arm hemiparesis were administered 30-minute (n = 1) or 120-minute (n = 2) therapy sessions emphasizing paretic arm use during valued, functional tasks and incorporating an electrical stimulation device. These sessions occurred every weekday for 8 weeks. A fourth subject served as a treatment control, participating in a 30-minute home exercise regimen without electrical stimulation every weekday for 8 weeks. DTI and behavioral outcome measures were acquired at baseline and after intervention. DTI data were analyzed using a region of interest (ROI) approach, with ROIs chosen based on tract involvement in sensorimotor function or as control regions. Behavioral outcome measures were the Fugl-Meyer Scale (FM) and the Action Research Arm Test (ARAT). The treatment control subject exhibited gains in pinch and grasp, as shown by a 5-point increase on the ARAT. The subject who participated in 30-minute therapy sessions exhibited no behavioral gains. Subjects participating in 120-minute therapy sessions displayed consistent impairment reductions and distal movement changes. DTI changes were largest in subjects two and three, with mean diffusivity (MD) decreases in the middle cerebellar peduncle and posterior limb of the internal capsule following treatment. No changes in fractional anisotropy (FA) were observed for sensorimotor tracts. Our preliminary results suggest that active rehabilitative therapies augmented by electrical stimulation may induce positive behavioral changes which are underscored by DTI changes indicative of increased white matter tract integrity in regions specific to sensory-motor function.

Improved cognitive-cerebral function in older adults with chromium supplementation.

Insulin resistance is implicated in the pathophysiological changes associated with Alzheimer's disease, and pharmaceutical treatments that overcome insulin resistance improve memory function in subjects with mild cognitive impairment (MCI) and early Alzheimer's disease. Chromium (Cr) supplementation improves glucose disposal in patients with insulin resistance and diabetes. We sought to assess whether supplementation with Cr might improve memory and neural function in older adults with cognitive decline. In a placebo-controlled, double-blind trial, we randomly assigned 26 older adults to receive either chromium picolinate (CrPic) or placebo for 12 weeks. Memory and depression were assessed prior to treatment initiation and during the final week of treatment. We also performed functional magnetic resonance imaging (fMRI) scans on a subset of subjects. Although learning rate and retention were not enhanced by CrPic supplementation, we observed reduced semantic interference on learning, recall, and recognition memory tasks. In addition, fMRI indicated comparatively increased activation for the CrPic subjects in right thalamic, right temporal, right posterior parietal, and bifrontal regions. These findings suggest that supplementation with CrPic can enhance cognitive inhibitory control and cerebral function in older adults at risk for neurodegeneration.

Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study.

BACKGROUND: Emerging evidence suggests that docosahexaenoic acid (DHA, 22:6n-3), the principal omega-3 (n-3) fatty acid in brain gray matter, positively regulates cortical metabolic function and cognitive development. However, the effects of DHA supplementation on functional cortical activity in human subjects are unknown. OBJECTIVE: The objective was to determine the effects of DHA supplementation on functional cortical activity during sustained attention in human subjects. DESIGN: Healthy boys aged 8-10 y (n = 33) were randomly assigned to receive placebo or 1 of 2 doses of DHA (400 or 1200 mg/d) for 8 wk. Relative changes in cortical activation patterns during sustained attention at baseline and endpoint were determined by functional magnetic resonance imaging. RESULTS: At 8 wk, erythrocyte membrane DHA composition increased significantly from baseline in subjects who received low-dose (by 47%) or high-dose (by 70%) DHA but not in those who received placebo (-11%). During sustained attention, both DHA dose groups had significantly greater changes from baseline in activation of the dorsolateral prefrontal cortex than did the placebo group, and the low-dose and high-dose DHA groups had greater decreases in the occipital cortex and cerebellar cortex, respectively. Relative to low-dose DHA, high-dose DHA resulted in greater decreases in activation of bilateral cerebellum. The erythrocyte DHA composition was positively correlated with dorsolateral prefrontal cortex activation and was inversely correlated with reaction time, at baseline and endpoint. CONCLUSION: Dietary DHA intake and associated elevations in erythrocyte DHA composition are associated with alterations in functional activity in cortical attention networks during sustained attention in healthy boys. This trial was registered at clinicaltrials.gov as NCT00662142.

Cortical plasticity following motor skill learning during mental practice in stroke.

BACKGROUND: and purpose. Mental practice (MP), which involves cognitive rehearsal of physical movements, is a noninvasive, inexpensive method of enabling repetitive, task-specific practice (RTP). Recent, randomized controlled data suggest that MP, when combined with an RTP therapy program, increases affected arm use and function significantly more than RTP only. As a next step, this 10-subject case series examined the possibility that cortical plasticity is a mechanism underlying the treatment effect of MP when combined with RTP. METHOD: Ten chronic stroke patients (mean = 36.7 months) exhibiting stable, moderate motor deficits received 30-minute therapy sessions for their affected arms, occurring 3 days/week for 10 weeks, and emphasizing valued activities of daily living (ADLs). Directly after therapy, subjects received 30-minute MP sessions, which required MP of the ADLs performed during therapy. Behavioral outcomes were blindly evaluated using the Action Research Arm Test (ARAT) and the Fugl-Meyer Assessment (FM). Functional magnetic resonance imaging (fMRI) was administered before and after intervention to assess cortical changes. RESULTS: Before intervention, subjects exhibited stable motor deficits. After intervention, subjects exhibited ARAT and FM score increases (+5.3 and +4.2, respectively) and clinically significant gains in ADLs. Postintervention fMRI revealed significant increases in activation to wrist flexion and extension of the affected hand in the premotor area and primary motor cortex ipsilateral and contralateral to the affected hand, as well as in superior parietal cortex ipsilateral to the affected hand. Decreased activation was noted in parietal cortex of the hemisphere ipsilateral to the affected hand. These changes correlated with anatomical regions in which behavioral changes were observed in the ARAT and FM. CONCLUSIONS: MP is an easy to use, cost-effective strategy that was again shown to improve affected arm outcomes after stroke. This is the first study to demonstrate alteration in the cortical map in response to MP training.

An event-related FMRI investigation of implicit semantic priming.

The neural basis underlying implicit semantic priming was investigated using event-related fMRI. Prime-target pairs were presented auditorily for lexical decision (LD) on the target stimulus, which was either semantically related or unrelated to the prime, or was a nonword. A tone task was also administered as a control. Behaviorally, all participants demonstrated semantic priming in the LD task. fMRI results showed that for all three conditions of the LD task, activation was seen in the superior temporal gyrus (STG), the middle temporal gyrus (MTG), and the inferior parietal lobe, with greater activation in the unrelated and nonword conditions than in the related condition. Direct comparisons of the related and unrelated conditions revealed foci in the left STG, left precentral gyrus, left and right MTGs, and right caudate, exhibiting significantly lower activation levels in the related condition. The reduced activity in the temporal lobe suggests that the perception of the prime word activates a lexical-semantic network that shares common elements with the target word, and, thus, the target can be recognized with enhanced neural efficiency. The frontal lobe reductions most likely reflect the increased efficiency in monitoring the activation of lexical representations in the temporal lobe, making a decision, and planning the appropriate motor response.