The Three Moirai
 

Summary:

Well, it comes as a shock to find that small changes in the brain can make you feel, or appear to be, quite different. So what's going on? John Bradshaw is Professor of Neuropsychology at Monash University in Melbourne and he looks at some familiar examples caused by alterations in just a handful of brain cells. 

Transcript:
 

Parkinson's and Huntington's Diseases and Tourette's Syndrome

Robyn Williams: Do you know who you are? Is your personality sweet-natured or vile, sitting there behind your eyes, familiar and predictable, like a landmark on the horizon?

Well, it comes as a shock to find that small changes in the brain can make you feel, or appear to be, quite different. So what's going on?

John Bradshaw is Professor of Neuropsychology at Monash University in Melbourne and he looks at some familiar examples caused by alterations in just a handful of brain cells.

John Bradshaw: According to Greek mythology, each person's doom was a thread to be cut short, of medium length, or long, by the three Goddesses of Fate. The three Moirai, Clotho, Lachesis and Atropos, were spinsters in both senses of the word. Even today we encounter disorders which typically strike in youth, like Tourette's syndrome, during the adult or middle years (Huntington's disease) or during aging, such as Parkinson's disease. These three disorders moreover, all involve a structure deep within the brain known as the basal ganglia. We are still learning what the basal ganglia actually do, like basements in buildings, their functions are somewhat obscure and shrouded in controversy.

In any case, brain sciences are increasingly suggesting that structures rarely act in isolation, but function as part of an extended network. That network, in the case of the basal ganglia, includes also the prefrontal cortex, the most highly evolved part of the human brain. Underlying the steep brows of modern human skulls, it is thought to mediate functions, known as executive, to do with attention, strategy, planning and aspects of social behaviour. Not surprisingly then, damage in these regions can have devastating consequences, whose manifestations depend precisely upon the exact nature and locus of the lesions.

If we dare generalise, the basal ganglia may act as a filter to select automatically each next stage in a learned response repertoire, or to select out - inhibit - inappropriate behaviours. Damage, therefore, may result in either excess or unwanted activity, as with Tourette's syndrome and Huntington's disease, or movement impoverishment, an inability to get going, as with Parkinson's disease. The sufferers usually know what is required, but either can't do it, or can't stop themselves from going ahead when they shouldn't. These sins of omission or of commission are found in an exaggerated form - inert apathy, or social or sexual disinhibition - after lesions to discrete prefrontal regions. Phineas Gage, working well over 100 years ago on the American railroad, had a steel bar, in an explosion, enter below the eye and destroy much of his prefrontal tissue. Remarkably, he never lost consciousness, and when he eventually recovered, he was a changed man, feckless and irresponsible instead of his previous character as a pillar of society.

The Shaking Palsy, or paralysis agitans, as it was known in Britain until last century, was almost certainly referred to in the sacred Indian Ayurvedic texts of 3,000 years ago, and 1,000 year later was described by Galen the Graeco-Roman physician; however, James Parkinson in 1817 gave the first, and very modern, detailed account. He describes an -

'Involuntary tremulous motion and lessened muscular power, a propensity to bend the trunk forward and to pass from a walking to a running pace, the senses and intellect being uninjured, the symptoms starting imperceptibly, with very slow progress.'

We now know that there is a gradual and progressive loss of cells in the basal ganglia which employ the chemical messenger, dopamine; the symptoms of Parkinson's disease manifest when the number of remaining cells reaches a critical low point. The loss can be partly compensated for by drugs which replace the missing neurotransmitter, or boost the failing system. Otherwise, the patient becomes slow at initiating or executing movements, particularly the normally automatic sequential actions of daily life. There may also be a characteristic tremor and rigidity. Our own work suggests problems in sustaining ongoing behaviours, and in switching automatically from one element in a response sequence to the next. This may stem from the absence of internal signals normally provided by the basal ganglia to prefrontal regions to release each next response stage. Thus patients become unusually reliant upon external sources of information, and may walk relatively normally on a striped surface whose frequency matches that of normal footfall or stride.

We don't know if Parkinson's disease is due to ordinary aging, or to environmental factors like toxins or viruses, or to a genetic predisposition, or indeed, as is so often the case, to a combination of such factors. Recent detective work in America on young folk who unexpectedly became Parkinsonian after using contaminated 'recreational' drugs provided a lead in how toxins may discretely target the basal ganglia. Indeed because the patients were young and otherwise healthy, they were good candidates for the experimental, and largely successful, transplant of cells from a stillborn foetus into the damaged regions of their brains. They recovered considerable function.

Huntington's disease, however, is most certainly inherited in autosomal dominant fashion; this means that if either parent has the disorder, one has a 50% chance of doing likewise. Because the disorder typically manifests clinically in the middle years, after having had one's family, the gene is likely to be passed on. It was first described by George Huntington in 1872, an American physician who, like his doctor father, had seen many cases in their medical practice. He writes -

'The hereditary chorea is confined to certain and fortunately few families, and has been transmitted to them as an heirloom from generations way back in the dim past. It is spoken of by those in whose veins the seeds of the disease are known to exist with a kind of horror ...

... it hardly ever manifests until adult or middle age, and then comes on gradually but surely, increasing by degrees, often taking years in development, until the hapless suffer is but a quivering wreck of his former self ...

... When either parent has shown manifestations ... one of more offspring almost invariably suffer from the disease, if they live to adult age.

If however, they go thru' life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured they will be free of the disease.'

In every way far more serious than Parkinson's, Huntington's disease or chorea, is moved by movement excess, rather than poverty, by intrusive, unwanted movements or gestures which superficially may resemble the postures of certain types of dance. However we find that there is also an underlying slowness to initiate or execute voluntary movement, such as is seen in Parkinson's disease, and later in the disorder's progress, this aspect may predominate.

It is 13 years now since the gene was localised, and three since it was identified, permitting testing of those genetically at risk. There is an unstable expansion, or stutter, of a particular genetic repeat sequence near the end of the short arm of chromosome 4. Up to 31 repeats may be normal, while over 37 may be associated with manifestations of the disorder, whose age of onset roughly correlates, inversely, with the number of repeats. There is a tendency for the number of repeats to increase down the generations, so that the disorder may appear earlier, a phenomenon known as anticipation. Recently a number of other movement disorders have been found to behave in this way. One effect of the Huntington's gene is perhaps to produce toxic quantities of another chemical messenger in the brain, glutamate, and to cause progressive cell loss in parts of the basal ganglia and elsewhere. Indeed excess quantities of the messenger or neurotransmitter, dopamine, which is deficient in Parkinson's disease, may possibly be neurotoxic. While the Parkinsonian patient may have problems in doing what comes naturally, the patient with Huntington's disease may not be able to inhibit unwanted action patterns.

Much of the work in unravelling the genetics of Huntington's disease was performed by a remarkable collaborative research team working with the inhabitants of the Lake Maracaibo region in Venezuela. Last century a sailor with Huntington's disease entered this remote region, and his descendants are now so numerous that sometimes the disorder manifests on both sides of the family. Even some children may be affected, and in their case the disorder is far more severe.

Like Huntington's disease, Tourette's syndrome may be inherited, and also involves unwanted movements - tics - gestures, vocalisations or expressions. Because of the involvement of yet another part of the basal ganglia, with connections to prefrontal limbic regions known to mediate emotional behaviours, the Tourette's patient, often a child when the disorder first manifests, may be unable to restrain socially unacceptable behaviours. However inconvenient or inappropriate these behaviours, the disorder is not lethal; it can often be controlled by medication to modify chemical messengers, dopamine and serotonin, thought to be in imbalance, between the basal ganglia and the prefrontal cortex.

For millenia there have been descriptions of people 'possessed', like this 15th century account:

'A sober priest without any eccentricity ... and no sign of madness or any immoderate action, was said to be possessed by the devil, who, when he passed any church, and genuflected in honour of the glorious virgin, made him thrust out his tongue. When asked whether he could not restrain himself, he replied, "I cannot help myself at all, for he so uses all my limbs, my tongue and lungs whenever he pleases, causing me to speak or cry out ... I am altogether unable to restrain them".'

The disorder was described in detail by the French psychiatrist Gille de la Tourette in 1885. He later went on to be shot by one of his patients - not the last psychiatrist to suffer that fate - to recover, and eventually die of neurosyphilis. There are sudden, unpredictable, jerky, stereotyped movements which can be briefly suppressed, though at the cost of build-up of tension. A common and very benign analog which maybe 10% of the population inherit, is Restless Legs Syndrome, whereby, typically in the evening or at night, increasing sensations of tension in the calf muscles necessitate regular stretching or leg extension to gain only temporary relief.

More complex obsessions and compulsions may accompany - or appear instead of - the tics and profanity of Tourette's syndrome, perhaps in other family members. Samuel Johnson, the 18th century English lexicographer or writer of dictionaries - 'a harmless drudge' as he defines it - exhibited tics, compulsions and eating disorders; the last is now known to be associated with Tourette's and obsessive-compulsive disorder. His biographer records:

'When at table, he was totally absorbed in the business of the moment ... his looks were rivetted to his plate ... he would not say one word or pay the least attention to others, until he had satisfied his appetite, which was so fierce, and indulged with such intenseness, that while in the act of eating the veins on his forehead swelled and generally a strong perspiration was visible. This could not but be disgusting, and doubtless was not very suitable to the character of a philosopher who should be distinguished by self-command.'

It is also noteworthy that just as Parkinsonian patients, at times over-responsive to external stimuli, may freeze on encountering an open doorway, Johnson showed the opposite, or 'release' behaviour - he had to perform an elaborate series of pirouettes before passing through. Similar doorway rituals reported recently include the need to count to exactly 500. One unfortunate man felt compelled to eat exactly 24 eggs every day, ticking them off as they were consumed. At 85, and with no apparent ill-effects otherwise, he complained that it had ruined his life.

Why might a gene for such unfortunate behaviour persist in the genome, especially when they manifest so early? One clue comes from the frequent observations that otherwise deleterious genes in low doses may convey unexpected advantages in other directions. We have ourselves found that Tourette's patients may be unexpectedly fast or well-controlled in certain motor tasks we have devised; such individuals are often also said to be remarkably fond of - and good at - jazz improvisation and dance. Similarly there may be a gene for schizophrenia - it certainly runs in some families - and there are suggestions of possibly enhanced creativity or flow of ideas in clinically-unaffected close relatives. Likewise relatives of autistics are said to excel in engineering and computing occupations.

What might be the genetic compensation for such a devastating disorder as Huntington's? It of course usually only manifests after the family is complete, so it might come less under selective pressures. However there have been suggestions of increased numbers of offspring from individuals later manifesting the disorder, perhaps due to a mild disinhibition. If so, this supports Richard Dawkins' thesis of the selfish gene, which manipulates it carrier's behaviour to maximise its own chances of transmission. Indeed zoologists are finding many instances of parasites which manipulate their host's behavior to enhance their own dispersal. This may of course be why we sneeze with a cold. Truly, in wartime Britain, the public health motto was 'Coughs and sneezes spread diseases'.

In our own laboratory we have developed a number of novel procedures for measuring attentional and motor processes in these three diseases of the basal ganglia. Additionally, we are recording the electrical and metabolic activity of discrete brain regions during such tasks. In some cases we are doing this before and after surgery for the relief of otherwise intractable symptoms in Parkinson's disease and Tourette's syndrome. We are continually struck by the courage and humanity of our patients in the face of often overwhelming adversity. Indeed, brain dysfunction is often the opportunity for the release of new and even adaptive forms of behaviour.

Robyn Williams: Out of adversity comes a new beginning. John Bradshaw is Professor of Neurobiology at Monash University in Melbourne.

And don't forget our Ockham's Razor book, 'All Us Apes', now in the ABC Shops and elsewhere; and it's good to see that it's in the 'New Scientist' best seller list.