The Spark of Life: Electricity in the Human Body (34 page)

Perhaps the most infamous of drugs that interact with serotonin receptors, however, is LSD. Its extraordinary effects on perception are poetically described in the Beatles’ song ‘Lucy in the Sky with Diamonds’. But not all trips are so pleasant. In the TV series
Dr Who
, the Time Lord is ‘regenerated’ every few years, enabling him to be played by a different actor. Papers in the BBC archive explain to producers that the experience of regeneration is horrifying – it is, they say, ‘as if he has had the LSD drug and instead of experiencing the kicks, he has the hell and dank horror which can be its effect’.

LSD is a psychedelic drug related to a natural compound, ergotamine, found in the purple-brown fruiting bodies of the ergot fungus,
Claviceps purpurea
. It grows wild on rye and in mediaeval times contaminated rye bread caused dramatic outbreaks of ergot poisoning. Whole communities were sometimes affected. In 1930 the active ingredient of ergot was isolated and named lysergic acid, and subsequently the Swiss chemist Albert Hoffman produced a derivative that he named lysergic acid diethylamide – or LSD-25 for short. Although he did nothing with it for the next five years, he never forgot that experimental animals became restless when given the drug and, in 1943, having decided to reinvestigate the drug, he synthesized some more. Despite taking considerable precautions (for he knew ergot was toxic), during the final step of the synthesis he was overcome by a string of strange sensations including ‘an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors’.

Thinking this astonishing experience must have come from the drug, in the time-honoured tradition of pharmaceutical scientists, Hoffman cautiously ingested a tiny amount in a self-experiment three days later. It had a most dramatic effect. His notebook records, ‘My surroundings had now transformed themselves in more terrifying ways. Everything in the room spun around, and the familiar objects and pieces of furniture assumed grotesque, threatening forms. They were in continuous motion, animated, as if driven by an inner restlessness. The lady next door, whom I scarcely recognized, brought me milk – in the course of the evening I drank more than two liters. She was no longer Mrs. R., but rather a malevolent, insidious witch with a colored mask.’ Hoffman clearly had a bad trip, for he also remarks, ‘A demon had invaded me, had taken possession of my body, mind, and soul.’ He feared he was going to die, leaving his wife and three children bereft and his promising research work unfinished. Slowly, however, these horrors faded to be replaced by phantasmagorical visions of ‘circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux’, sounds that transformed themselves into optical images, and a sensation of renewed life.

LSD is one of the most powerful hallucinogens known. It has extraordinary effects on auditory and visual perception, producing a sparkling world in which colour, brightness and sounds are intensified, objects morph into strange shapes, and walls may ‘breathe’. But altered percept and hallucinatory visions are not its only effects. It also produces changes in time perception, the emotions and self-awareness. Some users claim it even leads to higher states of consciousness (whatever those might be), spiritual awareness, even enlightenment. More prosaically, what all these experiences boil down to is changes in the electrical activity of the brain. LSD and other hallucinogens produce their ‘magic’ effects by binding very tightly to a specific subset of serotonin receptors at brain synapses, known as 5HT-2A receptors. Why LSD causes such intense hallucinations and serotonin does not, given that they both bind to the same receptors, is far from clear, but one clue may be that they seem to trigger different signalling pathways in their target cells.

The Art of Memory

Our understanding of the physiological basis of emotions other than pleasure and despair – of anger, embarrassment, envy, grief, disgust, guilt and astonishment, to name but a few – is less clearly established. What is well recognized, however, is that our emotional reaction to a given situation is strongly influenced by our previous experience. Memory plays a key role in how we feel, and it is in the amygdala, two almond-shaped brain regions that lie on either side of the head, that memories are interwoven with emotions. Here, too, reward and fear memories are stored and recovered.

Memory – how to enhance it, and how memories are laid down, stored and retrieved – has perplexed and fascinated people for centuries. In the days before cheap paper, or computers, it was of particular importance. The Ancient Greeks and Romans were especially skilled in the art of memory, for lawyers and politicians were expected to speak for hours without notes. Consequently, methods of remembering were widely discussed. Quintilian tells of how the poet Simonides delivered the victory ode for his host, a champion boxer, at a magnificent banquet in Thessaly. As was traditional, his panegyric included a passage that lauded the twin gods Castor and Pollux. Annoyed at having to share the credit, and despite the price having been agreed beforehand, Simonides’ host withheld part of the fee, telling him he should claim the balance from Castor and Pollux. A little later, Simonides was summoned from the room by a message that two young men wished to see him urgently. Scarcely had he left the building before it collapsed and all inside were crushed to death beneath the rubble. The callers who had saved Simonides’s life had vanished, but were assumed to be Castor and Pollux. The message of this story was not, as one might imagine, the moral importance of paying one’s bills, but rather of what Simonides did next. So badly mutilated were the bodies of the dead that it was impossible to recognize any of them. However, Simonides was able to remember the precise positions in which all the diners had been sitting, thus enabling their bodies to be restored to their respective families. He had invented the ‘art of memory’.

Referring to the story, Quintilian recommends that when learning a long text you should break it up into shorter pieces. Then you should visualize a familiar place – your home, for example – and put different bits of the text in different rooms. To recall the text again, you just walk through the imaginary house, room by room, recollecting the text as you go. The place method, and continual repetition, are still the best ways to remember something and are often used by memory savants today.

Remembrance of Things Past

Exactly how and where memories are stored in the brain is still unclear. The fact that stimulation of certain bits of the brain can evoke vivid memories of things past – a familiar scent, a snatch of a song, even the complete recall of an event with all its sensations intact – suggests that at least some memories are stored in certain specific brain locations. People who suffer from visual agnosia may lose the ability to recognize particular objects, despite their senses and memory being intact. As Oliver Sacks relates in his book
The Man Who Mistook His Wife for a Hat
, they can describe what a glove looks like, but may be quite unable to recognize that it is, in fact, a glove, or know what it is used for. They may also fail to recognize one person, but not another, or confuse their wife with their hat. All this suggests that there may be discrete regions of the brain that are used for processing and storing specific types of information.

There is also a distinction between short-term and long-term memory. You use the former when you remember a number for a few minutes, or plan the outcome of a series of chess moves before you decide which one to use. Short-term (or working) memory seems to involve regions within the cortex, particularly the frontal lobes. Long-term memory enables us to recall events from our childhood. The fact that most people fail to recollect many events before the age of about three suggests that long-term memory storage may not be fully developed until then. How working memories are selected for long-term storage, how, where and in what form they are laid down, and how they are retrieved is currently under intensive investigation.

One brain region of key importance for memory storage is the hippocampus, so called because it is shaped like a seahorse. We have two of them, one on each side of the brain. Their role was discovered serendipitously by studies of Henry Gustav Molaison, better known to scientists as HM. As a young boy, HM suffered from intractable epilepsy. In an attempt to cure his seizures, most of the hippocampus on both sides of his brain was removed when he was twenty-seven. The consequence was disastrous for HM (but a goldmine for science), as he lost the ability to make new memories and his memory of some preceding events was also impaired. He was confined to living in the past. Nevertheless, he was able to perform tasks that need only short-term memory, clearly demonstrating that short-term and long-term memory are distinct. His ability to learn new motor skills was also intact; he became an accomplished table-tennis player, despite being adamant he had never played it before. He was also a gracious, patient and modest individual whom the researchers he worked with considered as one of the family, although he never recognized who they were, even if they returned just a few minutes after leaving the room.

The hippocampus is particularly important for spatial memory – for our ability to recall places. Taxi drivers who have to memorize the streets of London, information colloquially known as the ‘Knowledge’, tend to have larger hippocampi than the rest of us. Brain imaging has revealed that their hippocampi also light up when they are planning a route; simply thinking about how they might travel from Paddington Station to Buckingham Palace activates this bit of the brain. Fascinatingly, when they cease to use the ‘Knowledge’ regularly their hippocampi revert back to the same size as ours. ‘Lose it or use it’ seems to be an aphorism that is as valid for the brain as for your muscles.

It turns out that we construct a spatial map of our environment inside our heads, which can even be detected at the level of single hippocampal neurones. Nerve cells known as ‘place cells’ increase their activity only when an animal is in a specific location in its environment. As a rat runs along a corridor, for example, an individual cell bursts into activity and then ceases to fire as the animal enters and leaves the location corresponding to its ‘place field.’ Multiple neurones, each with a different place field, together provide an ‘electrical map’ of the whole environment. This map is established within minutes of entering a new environment, and if the animal is returned to the same environment a few days later, the same nerve cells fire at exactly the same location. Thus this spatial reference map may be involved in formation of spatial memories.

Although the hippocampus is crucially involved in laying down long-term memories, most memories are not actually stored there. Many other bits of the brain appear to be involved. Imagine you are watching an opera –
The Magic Flute
, for example. Your eyes capture the image of the Queen of the Night robed in a gorgeously coloured gown, and your ears pick up the wonderful aria she sings. These are relayed to the visual and auditory cortex respectively, where they are interpreted, and linked together to create a picture of the scene. The information is then forwarded to the hippocampus, which decides whether to pass it on to your long-term memory. If it does, the information is relayed back to the appropriate cortical areas, where it is laid down as new synapses or existing connections are strengthened. Information is thus circulated around the brain; it is not a matter of it being channelled straight from the eyes to your memory, but of a complex series of information-processing events that take place in multiple different brain regions.

The hippocampus enables associations between sensations and experiences to be hard-wired, enabling you to ‘play back’ a scene from memory. Damage to this bit of the brain affects your ability to store new memories. However, memory formation does not only involve the hippocampus. The amygdala also plays a part in memory consolidation. How interested you are in an event and what emotional associations it has for you will influence your ability to recall it later. This is why most of us will remember events such as the birth of our child or where we were when we heard that the Twin Towers of the World Trade Center had collapsed, but will probably quickly forget what we were doing at lunchtime last Tuesday.

Memories of mechanical skills are stored separately and are not channelled through the hippocampus. Your ability to remember how to ride a bike even though you have not done so for many years is stored in your cerebellum and motor cortex. This is why it is still possible for people to play music despite having lost much of their memory of places and events, and why HM was able to play table tennis.

Memories are Made of This

How memories are laid down appears to involve changes in the physical structure of the brain. Contrary to what was once believed, your brain is not a static structure, but extraordinarily adaptable. New connections between nerve cells are continuously being made and existing ones strengthened or eliminated as you go about your daily life. This process, known as synaptic plasticity, is the physical basis of learning and memory.

The fine filaments – the dendrites – that extend outwards from the nerve cells in your brain are covered in tiny knob-like extensions called spines. Thousands of them decorate a single dendrite. The dendritic spines are the sites of the synapses and it is here that memories are hard-wired, for as we learn new things and lay down new memories, new spines appear and existing ones change shape or disappear. As they grow in size and number so a particular neuronal pathway is reinforced. Such reinforcement often happens when connections between neurones are simultaneously activated, and has given rise to the neuroscientists’ adage ‘Cells that fire together, wire together.’ This happens very rapidly. Experiments in mice have shown that learning to press a button to obtain a food reward is associated with a dramatic increase in new synapses within just an hour of starting training. Strikingly, in these experiments, the new spines endured long after training had ceased, but the total number gradually returned to the pre-training level because older ones were eliminated. Perhaps the brain can only support a finite number of connections, which is why learning new things may reduce our capacity to remember older events. Ion channels lie at the heart of memory for the presence of different kinds of glutamate receptor channels is necessary both to retain existing synapses and to grow new ones. If these channels are absent, or their function is impaired, our ability to remember is reduced.