From the BRAIN Director: What’s the Payoff?

photo of Dr. John Ngai

Last week marked my second anniversary as BRAIN Director, an amazing opportunity and challenge for which I am deeply grateful. Over the past two years, I’ve strived to maintain perspective about all that we do, and to be guided by others’ views and critiques. People often ask me, “What’s the payoff, and when will we see it?” These questions are important, considering the magnitude of BRAIN investments and the promises we’ve made to better understand neural circuit function and develop new cures.

In this post, I will share my views on where BRAIN programs are starting to pay off, focusing on our recent successes in deconstructing neural circuits and translating some of these groundbreaking discoveries into new therapies for human neurologic and neuropsychiatric disorders.

One fascinating question in the area of learning and memory is how an individual’s internal mental state influences the memory of their external surroundings. Using new recording technologies to simultaneously monitor the activity of hundreds of neurons in the mouse medial entorhinal cortex, BRAIN-funded researchers found that neuronal networks representing location can switch from one pattern of activity to another even as the animal traverses the same path. This “remapping” can occur repeatedly while preserving a stable representation of the sensory environment, like recognizing the same landmarks along the same route to the grocery store whether hungry or sated after a large meal. This work suggests how brain circuits can layer episodes of distinct memories on top of more stable representations of space and raise fascinating questions about how internal states contribute to this remapping process.

We are also gaining insights into the underpinnings of human memory. Previous studies have suggested that memories about our continuous lived experience are segmented into discrete events in different moments in time, but the biological basis for this has remained a mystery. While recording from electrodes implanted in the medial temporal lobes of patients awaiting surgery for drug-resistant epilepsy, BRAIN-funded investigators identified two different types of neurons that organize memories by discrete events. When these individuals were shown movies of various scenes, the “boundary cells” responded when action within a scene or the scene itself changed: for example, when watching different plays during the Superbowl (“soft” boundaries) or a shift from game play to the halftime show (a “hard” boundary). In contrast, the “event cells” responded only to hard boundaries, in this example the shift from ball play to the halftime show. The two different cell types thus seem to be markers in the brain to store and recall distinct episodes. This discovery is not just scientifically interesting; it has direct implications for understanding memory disorders such as Alzheimer’s disease, where patients have trouble segmenting memories.

On the clinical front, recent advances in deep brain stimulation (DBS) for Parkinson’s disease have led to improvements in providing precise and effective control of unwanted motor symptoms, as I reported last year. In an exciting new development, BRAIN-funded investigators identified a personalized neural signature – a pattern of brain activity mapped over the course of 10 days to an anatomically defined brain region – associated with different mood states in an individual with severe treatment-resistant depression. They then designed a customized DBS stimulation based on this signature to relieve the patient’s symptoms. A complementary study from another BRAIN-funded team similarly performed long-term intracranial recordings in a different patient with severe depression to identify activity “biomarkers” for mood. The data were then used to design an adaptive or “closed-loop” DBS approach that sensed and responded to these biomarkers in real time to alleviate the person’s symptoms.

Tailoring treatments to individuals goes beyond a one-size-fits-all approach to psychiatric disorders that don’t always work for everyone. The personalized approach promises to make circuit-targeted treatments like DBS more effective and ultimately more widely applicable for other disorders.

I am also reminded that the most basic discoveries can open new avenues of inquiry with exciting translational potential, sometimes sooner rather than later. One example is provided by the NIH BRAIN Cell Census Network, which is developing new tools to illuminate the diversity of brain cell types at ever increasing levels of resolution and depth. In a recently published study, researchers used spatial transcriptomics to reveal an unanticipated diversity of midbrain dopamine neurons based on the genes they express and where they reside in the human brain. They identified cell types that map to a specific set of neurons known to be vulnerable in Parkinson’s disease, a finding confirmed by analysis of brain tissue from Parkinson’s disease patients.

Importantly, these vulnerable neurons were found to express genes that harbor mutations associated with sporadic forms of Parkinson’s disease, suggesting that certain mutations may be acting in the degenerating cells themselves to cause damage leading to their loss. This discovery provides a clear path toward understanding how the disease develops and progresses. And with a better understanding of mechanism lies hope for a cure.

The handful of advances I’ve highlighted here showcase the payoff of BRAIN in the basic, translational, and clinical domains, with much more on the way. Many other discoveries made with BRAIN support, including those enabled by the new suite of BRAIN 2.0 Transformative Projects, promise help for millions of Americans. At the upcoming 8th Annual BRAIN Initiative Meeting, we will hear more about new findings and directions that are transforming the intersection of technology and neuroscience toward cures for human brain disorders.

With respect and gratitude,

John Ngai, Ph.D.
Director, NIH BRAIN Initiative