Faculty Bibliography

Accumulating evidence suggests brain network dysfunction in attention-deficit/hyperactivity disorder (ADHD). Whether large-scale brain network connectivity patterns reflect clinical heterogeneity in ADHD remains to be fully understood. This study aimed to characterize the differential within- and between-network functional connectivity (FC) changes in children with ADHD combined (ADHD-C) or inattentive (ADHD-I) subtypes and their associations with ADHD symptoms. We studied the task-free functional magnetic resonance imaging (fMRI) data of 58 boys with ADHD and 28 demographically matched healthy controls. We measured within- and between-network connectivity of both low-level (sensorimotor) and high-level (cognitive) large-scale intrinsic connectivity networks and network modularity. We found that children with ADHD-C but not those with ADHD-I exhibited hyper-connectivity within the anterior default mode network (DMN) compared with controls. Additionally, children with ADHD-C had higher inter-network FC between the left executive control (ECN) and the salience (SN) networks, between subcortical and visual networks, and between the DMN and left auditory networks than controls, while children with ADHD-I did not show differences compared with controls. Similarly, children with ADHD-C but not ADHD-I showed lower network modularity compared with controls. Importantly, these observed abnormal inter-network connectivity and network modularity metrics were associated with Child Behavioral Checklist (CBCL) attention-deficit/hyperactivity problems and internalizing problems in children with ADHD. This study revealed relatively greater loss of brain functional network segregation in childhood ADHD combined subtype compared to the inattentive subtype, suggesting differential large-scale functional brain network topology phenotype underlying childhood ADHD heterogeneity.

Development of therapies for Alzheimer's disease has only resulted in a few approved drugs that provide some temporary symptomatic relief in certain patients. None of these compounds in clinical use halts or slows the progression of the disease. To date, several drugs targeting the amyloid-β peptide, and some against the tau protein, have failed in clinical trials. While there are various reasons for these failures, considering the following points may aid in improving the outcome of future trials. First, the tau protein should ideally be targeted intracellularly because most of tau pathology is within cells, neurons in particular. Second, an overriding emphasis in recent years has been on implementing drug-screening models that focus on prevention of seeding/spread of aggregates. Much less attention has been paid to identify compounds that inhibit neurotoxicity of these aggregates, which may not necessarily relate to their seeding/spread propensity. Ideally, all these markers should be readouts in the same assay or model. Third, diversity in conformers/strains of aggregates complicates drug development of small molecule aggregation inhibitors but is likely to be less of an issue for antibody-based treatments. Lastly, other more general targets associated with neurodegeneration should continue to be pursued but are in many ways more difficult to address than clearing amyloid-β and tau, the defining hallmarks of AD.

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Photoswitchable blockers of potassium channels can be used to optically control neuronal excitability and hold great promise for vision restoration. Here, we report a series of improved photoswitchable blockers that are furnished with a new pharmacophore based on the local anesthetic bupivacaine. These azobupivacaines (ABs) enable optical control over the delayed rectifier channel K_v2.1. and target the two-pore domain potassium channel TREK-1. For the first time, we have identified a compound that blocks conductance in the dark and potentiates it upon illumination. Using light as a trigger, ABs efficiently and reversibly silence action potential firing of hippocampal neurons in acute mouse brain slices.

Observational learning occurs when an animal capitalizes on the experience of another to change its own behavior in a given context. This form of learning is an efficient strategy for adapting to changes in environmental conditions, but little is known about the underlying neural mechanisms. There is an abundance of literature supporting observational learning in humans and other primates, and more recent studies have begun documenting observational learning in other species such as birds and rodents. The neural mechanisms for observational learning depend on the species' brain organization and on the specific behavior being acquired. However, as a general rule, it appears that social information impinges on neural circuits for direct learning, mimicking or enhancing neuronal activity patterns that function during pavlovian, spatial or instrumental learning. Understanding the biological mechanisms for social learning could boost translational studies into behavioral interventions for a wide range of learning disorders.

Uncovering spatial representations from large-scale ensemble spike activity in specific brain circuits provides valuable feedback in closed-loop experiments. We develop a graphics processing unit (GPU)-powered population-decoding system for ultrafast reconstruction of spatial positions from rodents' unsorted spatiotemporal spiking patterns, during run behavior or sleep. In comparison with an optimized quad-core central processing unit (CPU) implementation, our approach achieves an ∼20- to 50-fold increase in speed in eight tested rat hippocampal, cortical, and thalamic ensemble recordings, with real-time decoding speed (approximately fraction of a millisecond per spike) and scalability up to thousands of channels. By accommodating parallel shuffling in real time (computation time <15 ms), our approach enables assessment of the statistical significance of online-decoded "memory replay" candidates during quiet wakefulness or sleep. This open-source software toolkit supports the decoding of spatial correlates or content-triggered experimental manipulation in closed-loop neuroscience experiments.

Measuring how the brain encodes and processes an animal's own motion presents major technical challenges. New approaches demonstrate the viability and merit of measuring vestibular responses throughout the entire brain.

Patients with Hereditary Sensory & Autonomic Neuropathy type III exhibit marked ataxia, including gait disturbances. We recently showed that functional muscle spindle afferents in the leg, recorded via intraneural microelectrodes inserted into the peroneal nerve, are absent in HSAN III, although large-diameter cutaneous afferents are intact. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. We tested the hypothesis that manual motor performance is also compromised in HSAN III, attributed to the predicted absence of muscle spindles in the intrinsic muscles of the hand. Manual performance in the Purdue pegboard task was assessed in 12 individuals with HSAN III and 11 age-matched healthy controls. The mean (SD) pegboard score (number of pins inserted in 30 s) was 8.11.9 and 8.61.8 for the left and right hand respectively, significantly lower than the scores for the controls (15.01.3 and 16.01.1; p<0.0001). Performance was not improved after applying kinesiology tape over the joints of the hand. In five patients we inserted a tungsten microelectrode into the ulnar nerve at the wrist. No spontaneous or stretch-evoked muscle afferent activity could be identified in any of the 11 fascicles supplying intrinsic muscles of the hand, whereas rich tactile afferent activity could be recorded from four cutaneous fascicles. We conclude that functional muscle spindles are absent in the hand, and most likely absent in the long finger flexors and extensors, and that this largely accounts for the poor manual motor performance in HSAN III.