Brain Network Manipulation

Understanding and developing more effective treatments for neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, has been challenging for neuroscientists and pharmaceutical companies alike. Now, research from the Feinstein Institute’s Center for Neurosciences in New York may have opened up a new avenue of investigation: reorganizing functional brain connectivity through gene therapy that drives the formation of more favorable neural pathways (1).

Using a combination of state-of-the-art imaging and mathematical predictive models, the same group had already identified a Parkinson’s disease related pattern (PDRP) of glucose metabolism, which increases in expression with advanced motor symptoms. Notably, PDRP levels appeared to correlate significantly with clinical severity (2)  By using an AAV viral vector construct to deliver glutamic acid decarboxylase (GAD) to the sub thalamic (STN) nucleus in the brain, the Feinstein team hoped to reduce the activity of PDRP brain networks in their patients.

But the results were far from expected. Professor and Head of the Center, David Eidelberg, explains: “We learnt almost immediately that the treated group had totally abnormal and consistent increases in their PDRP. In fact, PDRP levels in both our treated group and the Parkinson’s patient control group went up in parallel – there was no modulation of PDRP by gene therapy, which ought to have happened.” But, crucially, there was still a clinical improvement in patients receiving gene therapy. The confounding results led to a rethink. “The hunt began!” says Eidelberg. “Was there an induction of a brand new brain network by the gene therapy that managed to achieve some level of clinical response – but independent of PDRP?”

Indeed, the group had discovered the development of an entirely unique neural pathway in Parkinson’s patients treated with gent therapy. “There was a rewiring of these connections in a very unique way to communicate the STN target into the motor cortex – plasticity was occurring downstream,” explains Eidelberg.

The major outcome of the research? Eidelberg believes it’s not so much the impact of the gene therapy on Parkinson’s patient outcomes (which he admits was modest and comparable with current treatments, such as deep brain stimulation), but rather the validation of 20 years of work on brain networks, and how a better understanding of these networks could hold promise in the clinic either diagnostically or therapeutically, down the line. “The brain networks are stable enough that they can be really used as signatures. They are not mistakable; it’s rather unambiguous as to what is going on,” concludes Eidelberg.