Under the Microscope: When the brain goes down the drain

"From a whisper in the forest to the felling of a tree, 'tis all movement": a great pioneer physiologist of the first half of this century, Charles Sherrington, thus put his finger on a vital aspect of brain function - movement. We tend to think of the brain as concerned with inner, private "mental" functions, such as hopes, fears, dreams and memories. But whereas our inner life can, of course, bowl along whilst we are not moving a muscle, any communication of those thoughts or ideas, will eventually depend on moving a part of the body in some way.

It was once remarked that, "Thinking is movement confined to the brain." Sadly, for sufferers of Parkinson's disease, the ability to translate the mental into the physical, the thought into the deed, becomes increasingly hard.

James Parkinson first documented the signs of the disease that was to bear his name in 1817, in his masterly "Essay on the Shaking Palsy". He wrote of three main features: rigidity of the muscles, tremor, and difficulty in moving. These symptoms are still used to describe Parkinson's disease today. Since that time however, the improvements in public health and living habits, leading to the increased life expectancy we all crave, have thrown the condition more sharply into focus. For Parkinson's disease is a disorder of the elderly: like Alzheimer's disease, it is a "neuro- degenerative" disorder in which certain regions of the brain very slowly dwindle away, often over a time scale of years.

I personally have always found neurodegeneration a hard concept to grasp. Normally in biological systems, and the brain is no exception, the thermostat principle of homeostasis operates. Diverse compensatory mechanisms will swing into action once the normal workings of a group of brain cells is thrown out of kilter. For example, we all know that in a stroke, patients can make dramatic recoveries as, in the weeks following the death of certain brain cells, other neurones are gradually able to compensate: a once flaccid arm can often grasp again, memories may return, and confusion recede. In neurodegenerative conditions however, this principle clearly does not apply. Why not?

One idea is that the specific neurons that are lost in Parkinson's disease have some special features, such that the very attempts at compensation might be actually adding to the cause of the problem. The more cells that died off, the greater the "compensation", the greater the death, and so on in a vicious circle reflected in the all too familiar years of increasing debilitation.

Current therapy works wonders for alleviating the disorders of movement: but it would not help break this relentless cycle of self-destruction. By replacing the chemical (dopamine) normally released by the neurons in question, neither L-DOPA therapy, nor the far more novel therapy of brain transplants, would actually arrest the continuing death of the vulnerable neurons themselves.

An alternative approach might eventually lie in identifying, and then tackling, the pernicious factors that could be generated during compensation. For example neurones need calcium to enter them in order to adapt, but excessive calcium can be toxic. Similarly, it is normal for the brain to generate "free radicals", molecular Rambos, normally held in check by a host of natural chemical defence mechanisms, but deadly in large amounts, or if defences weaken. What is becoming clear is that all number of factors, such as excessive calcium mobilisation or the unfettered generation of free radicals, not only play decisive roles during normal operations, but in addition, they can also be very much at large during processes of compensation. To add to the headache of any neuroscientist trying to unravel what is going on, these factors can actually influence each other, so that the area of brain primarily affected in Parkinson's disease (the "substantia nigra") resembles not so much a bustling molecular metropolis, as a neurochemical ecosystem.

The wealth of chemicals in the substantia nigra has earned it the sobriquet, in at least one textbook, of "treasure trove for the pharmacologist". As a result of such diversity, there is probably no single villainous substance, and thus probably no magic bullet cure for Parkinson's disease. But by the same token, an enormously wide range of potential therapeutic targets is starting to open up. Although an improved drug therapy might still be in the future, our increasing familiarity with these key neurons, and the intriguing ways in which they function and malfunction, offers hope.

! Susan Greenfield is a neuroscientist at the University of Oxford and Gresham Professor of Physic, London