BRAIN ACTIVATION AND CONNECTIVITY IN NON-DISABLED MULTIPLE SCLEROSIS PATIENTS

Multiple sclerosis (MS) is the most common demyelinating disease affecting the central nervous system. There is no cure for MS and current therapies have limited efficacy. While the majority of individuals with MS develop significant clinical disability, a subset experiences a disease course with minimal impairment even in the presence of significant apparent tissue damage on magnetic resonance imaging (MRI). The current studies combined functional MRI and diffusion tensor imaging (DTI) to elucidate brain mechanisms associated with lack of clinical disability in patients with MS. Recent evidence has implicated cortical reorganization as a mechanism to limit the clinical manifestation of the disease. Functional MRI was used to test the hypothesis that non-disabled MS patients (Expanded Disability Status Scale ≤ 1.5) show increased recruitment of cognitive control regions (dorsolateral prefrontal and anterior cingulate cortex) while performing sensory, motor and cognitive tasks. Compared to matched healthy controls, patients increased activation of cognitive control brain regions when performing non-dominant hand movements and the 2-back working memory task. Using dynamic causal modeling, we tested whether increased cognitive control recruitment is associated with alterations in connectivity in the working memory functional network. Patients exhibited similar network connectivity to that of control subjects when performing working memory tasks. We subsequently investigated the integrity of major white matter tracts to assess structural connectivity and its relation to activation and functional integration of the cognitive control system. Patients showed substantial alterations in callosal, inferior and posterior white matter tracts and less pronounced involvement of the corticospinal tracts and superior longitudinal fasciculi (SLF). Decreased structural integrity within the right SLF in patients was associated with decreased performance, and decreased activation and connectivity of the cognitive control system when performing working memory tasks. These studies suggest that patient with MS without clinical disability increase cognitive control system recruitment across functional domains and rely on preserved functional and structural connectivity of brain regions associated with this network. Moreover, the current studies show the usefulness of combining brain activation data from functional MRI and structural connectivity data from DTI to improve our understanding of brain adaptation mechanisms to neurological disease.

To boldly go: individual differences in boldness influence migratory tendency

Partial migration, whereby only a fraction of the population migrates, is thought to be the most common type of migration in the animal kingdom, and can have important ecological and evolutionary consequences. Despite this, the factors that influence which individuals migrate and which remain resident are poorly understood. Recent work has shown that consistent individual differences in personality traits in animals can be ecologically important, but field studies integrating personality traits with migratory behaviour are extremely rare. In this study, we investigate the influence of individual boldness, an important personality trait, upon the migratory propensity of roach, a freshwater fish, over two consecutive migration seasons. We assay and individually tag 460 roach and show that boldness influences migratory propensity, with bold individuals being more likely to migrate than shy fish. Our data suggest that an extremely widespread personality trait in animals can have significant ecological consequences via influencing individual-level migratory behaviour.

Sizing up your enemy: individual predation vulnerability predicts migratory probability

Partial migration, in which a fraction of a population migrate and the rest remain resident, occurs in an extensive range of species and can have powerful ecological consequences. The question of what drives differences in individual migratory tendency is a contentious one. It has been shown that the timing of partial migration is based upon a trade-off between seasonal fluctuations in predation risk and growth potential. Phenotypic variation in either individual predation risk or growth potential should thus mediate the strength of the trade-off and ultimately predict patterns of partial migration at the individual level (i.e. which individuals migrate and which remain resident). We provide cross-population empirical support for the importance of one component of this model—individual predation risk—in predicting partial migration in wild populations of bream Abramis brama, a freshwater fish. Smaller, high-risk individuals migrate with a higher probability than larger, low-risk individuals, and we suggest that predation risk maintains size-dependent partial migration in this system.

Effects of Lipophilic Extract of Viscum album L. and Oleanolic Acid on Migratory Activity of NIH/3T3 Fibroblasts and on HaCat Keratinocytes

Viscum album L. lipophilic extract (VALE) contains pharmacologically active pentacyclic triterpenes that are known to exhibit immunomodulatory, antitumor, and wound healing activity. Preliminary clinical observations indicate that VALE was able to influence cutaneous wound healing in vivo. The objective of this study was to investigate wound closure related properties of VALE in vitro. As measured in a wound healing assay, VALE and its predominant triterpene oleanolic acid (OA) significantly and dose dependently promoted the migration of NIH/3T3 fibroblasts in vitro, thereby leading to an enhanced wound closure. Compared to the negative control, maximal stimulation by 26.1% and 26.2%, respectively, was attained with 10 μg/mL VALE and 1 μg/mL OA. Stimulation of proliferation in NIH/3T3 fibroblasts by VALE and OA could be excluded. At higher concentrations both substances affected proliferation and viability of NIH/3T3 fibroblasts and HaCat keratinocytes. In the toxic range of concentrations of VALE and OA, migration of NIH/3T3 fibroblasts was suppressed. The extent of the stimulatory effect on cell migration of VALE quite closely corresponded to the effect expected by the concentrations of OA contained in the crude extract VALE. These data support the casual observation that Viscum album L. lipophilic extract might modulate wound healing related processes in vivo.

The Effects of Smolt Stocking Strategies on Migratory Path Selection of Adult Atlantic Salmon in the Penobscot River, Maine

Understanding the homing behavior of Atlantic salmon Salmo salar is vital to the restoration program employed on the Penobscot River, Maine. To produce significant adult returns, managers currently stock hatchery-raised smolts in specific river sections, providing smolts the opportunity to imprint on chemical signals and enabling their return to productive spawning and rearing habitat as adults. In this study, we used observational evidence from passive integrated transponder telemetry to determine whether adults returning from smolt stockings behaved in a way that suggested strong homing to smolt stocking locations. Adults returning from smolt stocking locations located in or at the mouth of the Piscataquis River were more likely to be detected as entering the Piscataquis River than were adults returning from the upper Penobscot River smolt stocking locations. In general, returning adult Atlantic salmon that had been stocked near or in tributaries as smolts chose a path more quickly than those that had been stocked in more downstream or main-stem locations. These results suggest that Atlantic salmon smolts should be stocked at specific sites with superior habitat for spawning kind juvenile survival to capitalize on the strong homing tendency in adults. This technique call also be utilized to allow for natural selection and the development of localized stocks.

Migratory Urge and Gill Na(+),K(+)-ATPase Activity of Hatchery-Reared Atlantic Salmon Smolts from the Dennys and Penobscot River Stocks, Maine

Hatchery-reared Atlantic salmon Salmo salar smolts produced from captive-reared Dennys River and sea-run Penobscot River broodstock are released into their source rivers in Maine. The adult return rate of Dennys smolts is comparatively low, and disparity in smolt quality between stocks resulting from genetic or broodstock rearing effects is plausible. Smolt behavior and physiology were assessed during sequential 14-d trials conducted in seminatural annular tanks with circular flow. "Migratory urge'' (downstream movement) was monitored remotely using passive integrated transponder tags, and gill Na(+),K(+)-ATPase activity was measured at the beginning and end of the trials to provide an index of smolt development. The migratory urge of both stocks was low in early April, increased 20-fold through late May, and declined by the end of June. The frequency and seasonal distribution of downstream movement were independent of stock. In March and April, initial gill Na(+),K(+)-ATPase activities of Penobscot River smolts were lower than those of Dennys River smolts. For these trials, however, Penobscot River smolts increased enzyme activity after exposure to the tank, whereas Dennys River smolts did not, resulting in similar activities between stocks at the end of all trials. There was no clear relationship between migratory urge and gill Na(+),K(+)-ATPase activity. Gill Na(+),K(+)-ATPase activity of both stocks increased in advance of migratory urge and then declined while migratory urge was increasing. Maximum movement was observed from 2 h after sunset through 1 h after sunrise but varied seasonally. Dennys River smolts were slightly more nocturnal than Penobscot River smolts. These data suggest that Dennys and Penobscot River stocks are not markedly different in either physiological or behavioral expression of smolting.

Disturbed cortico–amygdalar functional connectivity as pathophysiological correlate of working memory deficits in bipolar affective disorder

Patients suffering from bipolar affective disorder show deficits in working memory functions. In a previous functional magnetic resonance imaging study, we observed an abnormal hyperactivity of the amygdala in bipolar patients during articulatory rehearsal in verbal working memory. In the present study, we investigated the dynamic neurofunctional interactions between the right amygdala and the brain systems that underlie verbal working memory in both bipolar patients and healthy controls. In total, 18 euthymic bipolar patients and 18 healthy controls performed a modified version of the Sternberg item-recognition (working memory) task. We used the psychophysiological interaction approach in order to assess functional connectivity between the right amygdala and the brain regions involved in verbal working memory. In healthy subjects, we found significant negative functional interactions between the right amygdala and multiple cortical brain areas involved in verbal working memory. In comparison with the healthy control subjects, bipolar patients exhibited significantly reduced functional interactions of the right amygdala particularly with the right-hemispheric, i.e., ipsilateral, cortical regions supporting verbal working memory. Together with our previous finding of amygdala hyperactivity in bipolar patients during verbal rehearsal, the present results suggest that a disturbed right-hemispheric “cognitive–emotional” interaction between the amygdala and cortical brain regions underlying working memory may be responsible for amygdala hyperactivation and affects verbal working memory (deficits) in bipolar patients.

Functional connectivity in BOLD and CBF data: similarity and reliability of resting brain networks

Resting-state functional connectivity (FC) fMRI (rs-fcMRI) offers an appealing approach to mapping the brain's intrinsic functional organization. Blood oxygen level dependent (BOLD) and arterial spin labeling (ASL) are the two main rs-fcMRI approaches to assess alterations in brain networks associated with individual differences, behavior and psychopathology. While the BOLD signal is stronger with a higher temporal resolution, ASL provides quantitative, direct measures of the physiology and metabolism of specific networks. This study systematically investigated the similarity and reliability of resting brain networks (RBNs) in BOLD and ASL. A 2×2×2 factorial design was employed where each subject underwent repeated BOLD and ASL rs-fcMRI scans on two occasions on two MRI scanners respectively. Both independent and joint FC analyses revealed common RBNs in ASL and BOLD rs-fcMRI with a moderate to high level of spatial overlap, verified by Dice Similarity Coefficients. Test-retest analyses indicated more reliable spatial network patterns in BOLD (average modal Intraclass Correlation Coefficients: 0.905±0.033 between-sessions; 0.885±0.052 between-scanners) than ASL (0.545±0.048; 0.575±0.059). Nevertheless, ASL provided highly reproducible (0.955±0.021; 0.970±0.011) network-specific CBF measurements. Moreover, we observed positive correlations between regional CBF and FC in core areas of all RBNs indicating a relationship between network connectivity and its baseline metabolism. Taken together, the combination of ASL and BOLD rs-fcMRI provides a powerful tool for characterizing the spatiotemporal and quantitative properties of RBNs. These findings pave the way for future BOLD and ASL rs-fcMRI studies in clinical populations that are carried out across time and scanners.

Dynamic directed interictal connectivity in left and right temporal lobe epilepsy.

OBJECTIVE There is increasing evidence that epileptic activity involves widespread brain networks rather than single sources and that these networks contribute to interictal brain dysfunction. We investigated the fast-varying behavior of epileptic networks during interictal spikes in right and left temporal lobe epilepsy (RTLE and LTLE) at a whole-brain scale using directed connectivity. METHODS In 16 patients, 8 with LTLE and 8 with RTLE, we estimated the electrical source activity in 82 cortical regions of interest (ROIs) using high-density electroencephalography (EEG), individual head models, and a distributed linear inverse solution. A multivariate, time-varying, and frequency-resolved Granger-causal modeling (weighted Partial Directed Coherence) was applied to the source signal of all ROIs. A nonparametric statistical test assessed differences between spike and baseline epochs. Connectivity results between RTLE and LTLE were compared between RTLE and LTLE and with neuropsychological impairments. RESULTS Ipsilateral anterior temporal structures were identified as key drivers for both groups, concordant with the epileptogenic zone estimated invasively. We observed an increase in outflow from the key driver already before the spike. There were also important temporal and extratemporal ipsilateral drivers in both conditions, and contralateral only in RTLE. A different network pattern between LTLE and RTLE was found: in RTLE there was a much more prominent ipsilateral to contralateral pattern than in LTLE. Half of the RTLE patients but none of the LTLE patients had neuropsychological deficits consistent with contralateral temporal lobe dysfunction, suggesting a relationship between connectivity changes and cognitive deficits. SIGNIFICANCE The different patterns of time-varying connectivity in LTLE and RTLE suggest that they are not symmetrical entities, in line with our neuropsychological results. The highest outflow region was concordant with invasive validation of the epileptogenic zone. This enhanced characterization of dynamic connectivity patterns could better explain cognitive deficits and help the management of epilepsy surgery candidates.