Evidence for Altered Basal Ganglia-Brainstem Connections in Cervical Dystonia

Background: There has been increasing interest in the interaction of the basal ganglia with the cerebellum and the brainstem in motor control and movement disorders. In addition, it has been suggested that these subcortical connections with the basal ganglia may help to coordinate a network of regions involved in mediating posture and stabilization. While studies in animal models support a role for this circuitry in the pathophysiology of the movement disorder dystonia, thus far, there is only indirect evidence for this in humans with dystonia. Methodology/Principal Findings: In the current study we investigated probabilistic diffusion tractography in DYT1-negative patients with cervical dystonia and matched healthy control subjects, with the goal of showing that patients exhibit altered microstructure in the connectivity between the pallidum and brainstem. The brainstem regions investigated included nuclei that are known to exhibit strong connections with the cerebellum. We observed large clusters of tractography differences in patients relative to healthy controls, between the pallidum and the brainstem. Tractography was decreased in the left hemisphere and increased in the right hemisphere in patients, suggesting a potential basis for the left/right white matter asymmetry we previously observed in focal dystonia patients. Conclusions/Significance: These findings support the hypothesis that connections between the basal ganglia and brainstem play a role in the pathophysiology of dystonia

White Matter Changes in Cervical Dystonia Relate to Clinical Effectiveness of Botulinum Toxin Treatment

In a previous report showing white matter microstructural hemispheric asymmetries medial to the pallidum in focal dystonias, we showed preliminary evidence that this abnormality was reduced 4 weeks after botulinum toxin (BTX) injections. In the current study we report the completed treatment study in a full-size cohort of CD patients (n = 14). In addition to showing a shift toward normalization of the hemispheric asymmetry, we evaluated clinical relevance of these findings by relating white matter changes to degree of symptom improvement. We also evaluated whether the magnitude of the white matter asymmetry before treatment was related to severity, laterality, duration of dystonia, and/or number of previous BTX injections. Our results confirm the findings of our preliminary report: we observed significant fractional anisotropy (FA) changes medial to the pallidum 4 weeks after BTX in CD participants that were not observed in controls scanned at the same interval. There was a significant relationship between magnitude of hemispheric asymmetry and dystonia symptom improvement, as measured by percent reduction in dystonia scale scores. There was also a trend toward a relationship between magnitude of pre-injection white matter asymmetry and symptom severity, but not symptom laterality, disorder duration, or number of previous BTX injections. Post-hoc analyses suggested the FA changes at least partially reflected changes in pathophysiology, but a dissociation between patient perception of benefit from injections and FA changes suggested the changes did not reflect changes to the primary “driver” of the dystonia. In contrast, there were no changes or group differences in DTI diffusivity measures, suggesting the hemispheric asymmetry in CD does not reflect irreversible white matter tissue loss. These findings support the hypothesis that central nervous system white matter changes are involved in the mechanism by which BTX exerts clinical benefit

Brain structure can mediate or moderate the relationship of behavior to brain function and transcriptome. A preliminary study

Abnormalities in motor-control behavior, which have been with concussion and head acceleration events (HAE), can be quantified using virtual reality (VR) technologies. Motor-control behavior has been consistently mapped to the brain's somatomotor network (SM) using both structural (sMRI) and functional MRI (fMRI). However, no studies habe integrated HAE, motor-control behavior, sMRI and fMRI measures. Here, brain networks important for motor-control were hypothesized to show changes in tractography-based diffusion weighted imaging [difference in fractional anisotropy (dFA)] and resting-state fMRI (rs-fMRI) measures in collegiate American football players across the season, and that these measures would relate to VR-based motor-control. We firther tested if nine inflammation-related miRNAs were associated with behavior-structure-function variables. Using permutation-based mediation and moderation methods, we found that across-season dFA from the SM structural connectome (SM-dFA) mediated the relationship between across-season VR-based Sensory-motor Reactivity (dSR) and rs-fMRI SM fingerprint similarity (p = 0.007 and Teff = 47%). The interaction between dSR and SM-dFA also predicted (pF = 0.036, pbeta3 = 0.058) across-season levels of dmiRNA-30d through permutation-based moderation analysis. These results suggest (1) that motor-control is in a feedback relationship with brain structure and function, (2) behavior-structure-function can be connected to HAE, and (3) behavior-structure might predict molecular biology measures.Comment: 62 pages, 4 figures, 2 table

The Affective Impact of Financial Skewness on Neural Activity and Choice

Few finance theories consider the influence of “skewness” (or large and asymmetric but unlikely outcomes) on financial choice. We investigated the impact of skewed gambles on subjects' neural activity, self-reported affective responses, and subsequent preferences using functional magnetic resonance imaging (FMRI). Neurally, skewed gambles elicited more anterior insula activation than symmetric gambles equated for expected value and variance, and positively skewed gambles also specifically elicited more nucleus accumbens (NAcc) activation than negatively skewed gambles. Affectively, positively skewed gambles elicited more positive arousal and negatively skewed gambles elicited more negative arousal than symmetric gambles equated for expected value and variance. Subjects also preferred positively skewed gambles more, but negatively skewed gambles less than symmetric gambles of equal expected value. Individual differences in both NAcc activity and positive arousal predicted preferences for positively skewed gambles. These findings support an anticipatory affect account in which statistical properties of gambles—including skewness—can influence neural activity, affective responses, and ultimately, choice

The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and remains without effective cure. Increasing evidence is supporting the mitochondrial cascade hypothesis, proposing that loss of mitochondrial fitness and subsequent ROS and ATP imbalance are important contributors to AD pathophysiology. Methods: Here, we tested the effects of SUL-138, a small hibernation-derived molecule that supports mitochondrial bioenergetics via complex I/IV activation, on molecular, physiological, behavioral, and pathological outcomes in APP/PS1 and wildtype mice. Results: SUL-138 treatment rescued long-term potentiation and hippocampal memory impairments and decreased beta-amyloid plaque load in APP/PS1 mice. This was paralleled by a partial rescue of dysregulated protein expression in APP/PS1 mice as assessed by mass spectrometry-based proteomics. In-depth analysis of protein expression revealed a prominent effect of SUL-138 in APP/PS1 mice on mitochondrial protein expression. SUL-138 increased the levels of proteins involved in fatty acid metabolism in both wildtype and APP/PS1 mice. Additionally, in APP/PS1 mice only, SUL-138 increased the levels of proteins involved in glycolysis and amino acid metabolism pathways, indicating that SUL-138 rescues mitochondrial impairments that are typically observed in AD. Conclusion: Our study demonstrates a SUL-138-induced shift in metabolic input towards the electron transport chain in synaptic mitochondria, coinciding with increased synaptic plasticity and memory. In conclusion, targeting mitochondrial bioenergetics might provide a promising new way to treat cognitive impairments in AD and reduce disease progression

Redefining neuromarketing as an integrated science of influence

Multiple transformative forces target marketing, many of which derive from new technologies that allow us to sample thinking in real time (i.e., brain imaging), or to look at large aggregations of decisions (i.e., big data). There has been an inclination to refer to the intersection of these technologies with the general topic of marketing as “neuromarketing”. There has not been a serious effort to frame neuromarketing, which is the goal of this paper. Neuromarketing can be compared to neuroeconomics, wherein neuroeconomics is generally focused on how individuals make “choices”, and represent distributions of choices. Neuromarketing, in contrast, focuses on how a distribution of choices can be shifted or “influenced”, which can occur at multiple “scales” of behavior (e.g., individual, group, or market/society). Given influence can affect choice through many cognitive modalities, and not just that of valuation of choice options, a science of influence also implies a need to develop a model of cognitive function integrating attention, memory, and reward/aversion function. The paper concludes with a brief description of three domains of neuromarketing application for studying influence, and their caveats

Application of the MEGNO technique to the dynamics of Jovian irregular satellites

We apply the MEGNO (Mean Exponential Growth of Nearby Orbits) technique to the dynamics of Jovian irregular satellites. We demonstrate the efficiency of applying the MEGNO indicator to generate a mapping of relevant phase-space regions occupied by observed jovian irregular satellites. The construction of MEGNO maps of the Jovian phase-space region within its Hill-sphere is addressed and the obtained results are compared with previous studies regarding the dynamical stability of irregular satellites. Since this is the first time the MEGNO technique is applied to study the dynamics of irregular satellites we provide a review of the MEGNO theory. We consider the elliptic restricted three-body problem in which Jupiter is orbited by a massless test satellite subject to solar gravitational perturbations. The equations of motion of the system are integrated numerically and the MEGNO indicator computed from the systems variational equations. An unprecedented large set of initial conditions are studied to generate the MEGNO maps. The chaotic nature of initial conditions are demonstrated by studying a quasi-periodic orbit and a chaotic orbit. As a result we establish the existence of several high-order mean-motion resonances detected for retrograde orbits along with other interesting dynamical features. The computed MEGNO maps allows to qualitatively differentiate between chaotic and quasi-periodic regions of the irregular satellite phase-space given only a relatively short integration time. By comparing with previous published results we can establish a correlation between chaotic regions and corresponding regions of orbital instability.Comment: 15 pages, 13 figures, 2 tables, submitted to MNRA