Disordered network structure and function in dystonia: pathological connectivity vs. adaptive responses.

Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder.

Adaptive and pathological connectivity responses in Parkinson's disease brain networks.

Functional imaging has been used extensively to identify and validate disease-specific networks as biomarkers in neurodegenerative disorders. It is not known, however, whether the connectivity patterns in these networks differ with disease progression compared to the beneficial adaptations that may also occur over time. To distinguish the 2 responses, we focused on assortativity, the tendency for network connections to link nodes with similar properties. High assortativity is associated with unstable, inefficient flow through the network. Low assortativity, by contrast, involves more diverse connections that are also more robust and efficient. We found that in Parkinson's disease (PD), network assortativity increased over time. Assoratitivty was high in clinically aggressive genetic variants but was low for genes associated with slow progression. Dopaminergic treatment increased assortativity despite improving motor symptoms, but subthalamic gene therapy, which remodels PD networks, reduced this measure compared to sham surgery. Stereotyped changes in connectivity patterns underlie disease progression and treatment responses in PD networks.

Experimentally generated randomness certified by the impossibility of superluminal signals.

From dice to modern electronic circuits, there have been many attempts to build better devices to generate random numbers. Randomness is fundamental to security and cryptographic systems and to safeguarding privacy. A key challenge with random-number generators is that it is hard to ensure that their outputs are unpredictable1-3. For a random-number generator based on a physical process, such as a noisy classical system or an elementary quantum measurement, a detailed model that describes the underlying physics is necessary to assert unpredictability. Imperfections in the model compromise the integrity of the device. However, it is possible to exploit the phenomenon of quantum non-locality with a loophole-free Bell test to build a random-number generator that can produce output that is unpredictable to any adversary that is limited only by general physical principles, such as special relativity1-11. With recent technological developments, it is now possible to carry out such a loophole-free Bell test12-14,22. Here we present certified randomness obtained from a photonic Bell experiment and extract 1,024 random bits that are uniformly distributed to within 10-12. These random bits could not have been predicted according to any physical theory that prohibits faster-than-light (superluminal) signalling and that allows independent measurement choices. To certify and quantify the randomness, we describe a protocol that is optimized for devices that are characterized by a low per-trial violation of Bell inequalities. Future random-number generators based on loophole-free Bell tests may have a role in increasing the security and trust of our cryptographic systems and infrastructure.