Faculty Bibliography

Chronic exposure to drugs of abuse perturbs the endogenous opioid system, which plays a critical role in the development and maintenance of addictive disorders. Opioid genetics may therefore play an important modulatory role in the expression of substance use disorders, but these genes have not been extensively characterized, especially in humans. In the current imaging genetics study, we investigated a single nucleotide polymorphism (SNP) of the protein-coding proenkephalin gene (PENK: rs2609997, recently shown to be associated with cannabis dependence) in 55 individuals with cocaine use disorder and 37 healthy controls. Analyses tested for PENK associations with fMRI response to error (during a classical color-word Stroop task) and gray matter volume (voxel-based morphometry) as a function of Diagnosis (cocaine, control). Results revealed whole-brain Diagnosis×PENK interactions on the neural response to errors (fMRI error>correct contrast) in the right putamen, left rostral anterior cingulate cortex/medial orbitofrontal cortex, and right inferior frontal gyrus; there was also a significant Diagnosis×PENK interaction on right inferior frontal gyrus gray matter volume. These interactions were driven by differences between individuals with cocaine use disorders and controls that were accentuated in individuals carrying the higher-risk PENK C-allele. Taken together, the PENK polymorphism-and potentially opioid neurotransmission more generally-modulates functioning and structural integrity of brain regions previously implicated in error-related processing. PENK could potentially render a subgroup of individuals with cocaine use disorder (i.e., C-allele carriers) more sensitive to mistakes or other related challenges; in future studies, these results could contribute to the development of individualized genetics-informed treatments.

We have recently extended conventional single-pulsed-field-gradient (s-PFG) diffusional kurtosis imaging (DKI) to double-pulsed-field-gradient (d-PFG) diffusion MRI sequences, with a method known as double-pulsed DKI (DP-DKI). By virtue of a six-dimensional (6D) formulation for q-space, many of the results and insights of s-PFG DKI are generalized to those of DP-DKI. Owing to the fact that DP-DKI isolates the second order contributions to the d-PFG signal (i.e. second order in b-value), the 6D diffusional kurtosis encodes information beyond what is available from s-PFG sequences. Previously, we have demonstrated DP-DKI for in vivo mouse brain at 7 T, and it is the objective of this study to demonstrate the feasibility of DP-DKI at 3 T for the in vivo assessment of human brain microstructure. In addition, an example is given of how to utilize the additional information obtained from DP-DKI for the purpose of biophysical modeling. The relationship between a specific microscopic anisotropy metric estimated from DP-DKI and other recently proposed measures is also discussed.

Adaptive minimum variance beamformers are widely used analysis tools in MEG and EEG. When the target brain activity presents in the form of spatially localized responses, the procedure usually involves two steps. First, positions and orientations of the sources of interest are determined. Second, the filter weights are calculated and source time courses reconstructed. This last step is the object of the current study. Despite different approaches utilized at the source localization stage, basic expressions for the weights have the same form, dictated by the minimum variance condition. These classic expressions involve covariance matrix of the measured field, which includes contributions from both the sources of interest and the noise background. We show analytically that the same weights can alternatively be obtained, if the full field covariance is replaced with that of the noise, provided the beamformer points to the true sources precisely. In practice, however, a certain mismatch is always inevitable. We show that such mismatch results in partial suppression of the true sources if the traditional weights are used. To avoid this effect, the "alternative" weights based on properly estimated noise covariance should be applied at the second, source time course reconstruction step. We demonstrate mathematically and using simulated and real data that in many situations the alternative weights provide significantly better time course reconstruction quality than the traditional ones. In particular, they a) improve source-level SNR and yield more accurately reconstructed waveforms; b) provide more accurate estimates of inter-source correlations; c) reduce the adverse influence of the source correlations on the performance of single-source beamformers, which are used most often. Importantly, the alternative weights come at no additional computational cost, as the structure of the expressions remains the same.

Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders. In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells. Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders.

During low arousal states such as drowsiness and sleep, cortical neurons exhibit rhythmic slow wave activity associated with periods of neuronal silence. Slow waves are locally regulated, and local slow wave dynamics are important for memory, cognition, and behaviour. While several brainstem structures for controlling global sleep states have now been well characterized, a mechanism underlying fast and local modulation of cortical slow waves has not been identified. Here, using optogenetics and whole cortex electrophysiology, we show that local tonic activation of thalamic reticular nucleus (TRN) rapidly induces slow wave activity in a spatially restricted region of cortex. These slow waves resemble those seen in sleep, as cortical units undergo periods of silence phase-locked to the slow wave. Furthermore, animals exhibit behavioural changes consistent with a decrease in arousal state during TRN stimulation. We conclude that TRN can induce rapid modulation of local cortical state.

Physical exercise produces many beneficial responses in the brain, which affect cognitive function, blood flow, neurogenesis and resistance to injury. However, the exact mechanisms whereby exercise produces an induction in the brain are not well understood. A significant consequence is the induction of growth factors, such as Brain-derived Neurotrophic Factor (BDNF). Cognitive decline that occurs with aging, as well as progression of neurodegenerative diseases, are strongly correlated with decreases in BDNF. In this article, we discuss the properties of neurotrophins and the mechanisms that can account for the ability of exercise to promote brain plasticity through BDNF.

One hundred years after his Nobel Prize, Richard Willstatter's achievements and the fascinating role he played in 20th century chemistry are discussed in this Essay. Several of his discoveries, such as the anthocyanidins, cyclooctatetraene, the ortho-quinones, and the structure of cocaine, will forever be associated with his name.

Neurons live for decades in a postmitotic state, their genomes susceptible to DNA damage. Here we survey the landscape of somatic single-nucleotide variants (SNVs) in the human brain. We identified thousands of somatic SNVs by single-cell sequencing of 36 neurons from the cerebral cortex of three normal individuals. Unlike germline and cancer SNVs, which are often caused by errors in DNA replication, neuronal mutations appear to reflect damage during active transcription. Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function.