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Sunday, September 24, 2023
Dr. Brown: Shedding light on the brain
Dr. William Brown. File Photo

If you want to figure out how the brain works, there are several options.

One classical method, which served clinical neurologists and neurosurgeons very well in the 19th and 20th centuries, was to correlate clinical symptoms and findings with the location of lesions such as a stroke, tumour, or perhaps a traumatic lesion.

For example, discrete lesions affecting the visual pathway from the optic nerve through to the primary visual cortex correlate surprisingly well with deficits in the visual fields.

In addition, electrical shock-like symptoms in the arms and legs, triggered by flexing the neck, correlate with lesions located in the mid-high cervical spinal cord.

Or, a small lesion in the dorsal-medial nucleus of the thalamus may interfere with the inability to form and retain new memories.  

Then, along came CT, and later MRI imaging technologies, which revolutionized correlating the location of lesions with the patient’s clinical signs and symptoms.

However sometimes, as with multiple sclerosis (where multiple lesions widely separated from one another in the nervous system are common), it may be impossible to correlate specific lesions seen with MRI with the patient’s clinical symptoms or findings.

One major problem with CT and MRI studies is they often reveal clinically insignificant abnormalities, especially with degenerative diseases affecting the spine.

In the last two to three decades, functional MRI (fMRI) became the darling of clinical psychologists.

It may be used to correlate regions of increased oxygen utilization and cerebral blood flow with selective movements of the thumb, talking, reading or more complex activities such as listening to or playing music, meditation – the list goes on, depending on the inventiveness of psychologists.

But, as tantalizing as these scans may be to watch when the brain “lights up” in response to some stimulus, the temporal and special resolution of fMRI signals may be poor in relation to the underlying neuronal activity in the brain.

The brain processes information quickly in part because the firing times of neurons may be brief. The speed with which nerve fibers transmit impulses can be as high as 50 to 70 metres per second (that’s 180 to 252 kilometres per hour) between, for example, large nerve cells in the motor cortex and their target motor neurons in the spinal cord. 

What’s needed is a tool that offers much better temporal and spatial resolution – equivalent to the brain’s natural firing patterns and the speeds with which nerve impulses are transmitted.

That’s precisely what opto-genetics offers. This field has taken off because it provides the necessary resolution and can be used to analyze the electrical activity of nerve cells in real time, while the brain goes about its normal business.

Here’s the sequence:

  • Employ a viral vector, which is designed to carry specific genes into functionally specific neurons in the brain, which then create specific light sensitive proteins within the neurons.
  • Those proteins may be designed to emit light signals that can be detected by a nearby device when the targeted neurons naturally fire.
  • Or, the light sensitive proteins may be designed to respond to light signals generated by a nearby probe, by firing (excitation), or in the case of active nerve cells, not firing (inhibition).
  • In both instances, opto-genetics brings unparalleled  specificity to functional, anatomical and genetic studies of how the brain goes about its daily tasks.

In a nutshell, that’s a lot of biological engineering, and what all the fuss has been about for the last three decades.

It was also the reason the Lasker prize in basic medicine was awarded to Karl Deisseroth, Peter Hegemann and Gero Miesenböck. 

Roughly half of all Lasker prize winners in basic medicine go on to win a Nobel Prize within a few years and, in this case, should do so given the magnitude of the achievement.

What these winners and others showed was that it was possible to stimulate and inhibit functionally and genetically-specific neurons to find out what those cells contribute to defined tasks, without injuring the nerve cells.

That’s a big deal compared to what physiologists employing needle or very fine-tipped glass electrodes were able to do not so long ago.

We learned a lot with those technically demanding techniques, some of my own studies included, but the specificity that optogenetics offers now is a “game changer,” to use an overused but, in this case, deserved expression. 

What’s the payoff for diseases? Macular degeneration is the most common cause of serious blindness in later life and is related to degeneration of the light sensitive cells in the retina, which contact the initial neurons in a chain that leads to the visual cortex.

Without those light-sensitive cells, especially in the central field of vision (macula), reading may become impossible, no matter the font size. 

What if we could insert stem cells carrying light sensitive opsins (light sensitive proteins) into the retina to reconnect with those first nerve cells?

So far, animal studies have been encouraging, but it’s not easy.

Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.  

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