Picking your brains: what’s going on inside your head?

 Neuroscience has made great gains but the best is yet to come. Jenn and Tony Bot

Welcome to On the Brain, a new Conversation series by people whose job it is to know as much as there is to know about the body’s most complex organ. Here, Professor Geoffrey Donnan, a world-renowned stroke researcher and director of the Florey Neuroscience Institute, summarises major highlights in brain diagnoses and ponders the future of treatments for brain disease. Enjoy.
The past 30 years have seen the most remarkable advances in the study of the brain. And the past ten have seen more advances in our understanding than all the other years combined.
These range from the most fundamental changes within cells right through to how the brain interconnects and functions.

X-ray computed tomography.

Enormous strides were made in brain research during the 19th century and consolidated during the latter half of the 20th century. But then, while our knowledge of brain disease plateaued, significant advances were being made in unravelling our understanding of disease processes in accessible organs such as the heart, liver, kidney and blood.
So much so that exciting new treatments were developed for diseases of these organs.
Meanwhile, progress in neuroscience research remained frustratingly slow as the brain remained in its lofty and boney chamber, isolated, often ravaged by disease and largely untreated.
Up until the mid-1970s, the only way to really access the brain was either during surgical operations or, less fortunately, at autopsy. There were some incredibly crude imaging techniques that offered limited and indirect insight into brain structure – and which were, frankly, dangerous.
The most invasive procedure involved injecting air into the ventricles of the brain via the lumbar spinal region. This took advantage of the continuity of the ventricles with the fluid spaces surrounding the spinal cord.
Interestingly, the technique was an extension of a serendipitous finding by clinicians during the First World War. They found that, when penetrating injuries to the brain allowed air entry to the ventricles, plain X-rays would clearly outline the ventricular contours in sharp relief.
In Melbourne, we had the world expert in research into the interpretation on these images, Dr E Graeme Robertson. This did not diminish the discomfort felt by most patients who were subjected to the procedure: most were left with quite a headache.
Fortunately, the imaging revolution was not far away. During a remarkable decade from the mid-1970s to the mid-1980s, X-ray computed tomography (CT) took us all to another level.
For the first time, neurologists could actually see brain pathologies such as intracerebral haemorrhage – when a blood vessel bursts within the brain – with startling clarity.
The technological advance of computing had allowed a stereotaxic computation of multiple X-ray images accrued by rotating gantry (see below) to be displayed as a simple image.

As if this was not enough, almost overnight, in the 1970s, along came another even more sophisticated technique: magnetic resonance imaging (MRI). Here, scientists had taken advantage of the differing response of atomic structures, particularly protons, to perturbations by radio frequency waves within a magnetic field.
In practice, this meant high-powered computing could generate maps of these protons. Even better, brain blood vessel flow and brain function could be studied.
At about the same time, another technique, Positron Emission Tomography (PET), a nuclear imaging technique, was developed which allowed the distribution of chemical reactions within the brain to be mapped. The sky seemed the limit.
Even the location of human emotions could be mapped to specific locations. If there was ever any doubt the brain ruled the body, this was being dispelled almost weekly as we learned how brain function interpreted the senses and drove motor function.
While these extraordinary advances were occurring in imaging the entire brain and its function, similar developments were occurring in imaging individual cells and their function.

An animation of MRI head scans.

In much the same way astronomers were seeing new objects in space and, as a consequence, determining new theories about the universe, scientists were seeing the inner workings of the cell in wonderful and colourful detail to make similar inferences about its mechanism of action.
These days, critical compounds for cell survival such as calcium can now be imaged as it is pumped in and out of cells. By genetically modifying cells to carry light-sensitive rhodopsin, they may be switched on and off from the distance.
Then groups and systems of cells can be studied so the means by which they interact can be better understood. Suddenly the very working of the brain can be observed at a cellular systems level and scientists have insight into how whole brain components have a functional output.
For example, it should be possible to observe how the brain stem systems work in controlling blood pressure and breathing.

The avant-garde

When considering the drivers of the tremendous advances in neuroscience in this fairly brief period of time, imaging is an absolute standout. The other two critical components have been the unravelling of cellular biology generally and the revolution that has occurred in the genetics of disease.
Cellular biology involves the study of cellular structure and function in all its facets – how it acts as a minute factory with inputs, outputs and energy sources.

A PET image of the brain.

The third factor associated with this revolution in neuroscience, the genetics of disease, is equally intriguing. The adventure was really launched with the plan to map the human genome in the late 1980s.
It was thought to be such a massive task that it would take more than 20 years. Because of the remarkable advances in technology, not least the harnessing of unexpected increases in computing technology, the genome was cracked in just 13 years, culminating in 2003.
Here in Melbourne we had our own wins with Professor Sam Berkovic and his team of collaborators discovering the first genes responsible for epilepsy.
By tracing the function of these genes, Berkovic and his team were able to establish that the cause of many of the epilepsies involves a disorder of pumps on the surface of cells which keep the ionic concentrations stable within cells.
A failure of these pumps alters the excitability of the cells and allows them to discharge their impulses to neighbouring cells and promote seizures more broadly in the brain.
The next step is to design new medications which might stabilise these cellular pumps.

Gains

So what therapeutic advances have occurred as result of all this frenetic scientific activity? Numerous therapies are now part of the neurologist’s toolkit, whereas in earlier years his or her role was to diagnose and prognosticate with virtually no therapies to offer.
Now a neurologist must be familiar with:

• four categories of intervention to be of proven benefit immediately after the onset of stroke
• seven forms of intervention to prevent recurrent stroke
• four categories of therapy for multiple sclerosis
• new categories of therapies for movement disorders such as Parkinson’s disease and dementias such as Alzheimer’s disease.

Where will it end? My view is that we’re at the beginning of an even more wonderful period of the flowering of the neurosciences.
If I were a young clinician or scientist wondering which area of research to enter there would be no hesitation – the mysteries of our most complex organ and the seat of the soul await.