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Cedars-Sinai

The Sound of Musing

Two investigators use direct-brain recording to listen in on the brain’s deepest internal dialogues. What they learn could illuminate the biology of memory.

sound-of-musing1Yes, she remembers seeing the picture of the coffee cup. The car, too. And the dog, the face, and the fried egg. But the apple? From her hospital bed, the patient searches her memory. Did she see the apple in an earlier set of photographs?

The questions she is answering and the pictures she is viewing on a screen are not part of her medical care — but the thin wires slipped through a small hole in her skull and the electrodes positioned deep inside her brain are.

Every time she sees a new image and whenever she tries to recall those she has already seen — every time her brain works on a task — specialized brain cells “fire.” A researcher then captures the activity of individual neurons inside the brain, recording what happens at the instant when electrical impulse turns into thought or a memory forms.

Adam Mamelak, MD, and Ueli Rutishauser, PhD, cannot read your mind. Nor is mind reading at the top of their to-do list. Not exactly. But they would like to come close in order to understand the biology of memory or, as Dr. Mamelak says, “how a brain becomes a mind — how a collection of neurons constitutes a memory and a consciousness.”

The only way to do that, according to Dr. Rutishauser, director of Human Neurophysiology Research at Cedars-Sinai, is to witness the activity of single cells in the brain’s thought-processing and memory-creating centers while a person receives information, interprets it, and commits it to memory.

The ultimate objective is to treat or cure disorders of thought, diseases of the brain, and disruptions of memory-making processes. Understanding the origins of these ailments is the first piece of the overall puzzle. One brain structure of great interest to researchers — an almond-shaped set of nuclei called the amygdala — is known to play a primary role in the processing of memory, decisionmaking, and emotional reactions like fear and anxiety. It is thought to be involved in a wide spectrum of problems, including autism, phobias, anxiety disorders, and other complex conditions.

Ground-level direct brain recording — in which the activity of single brain cells is recorded and analyzed — is currently a hot research area. The Department of Defense recently invested $40 million to fund research that might lead to treatments for traumatic brain injury (TBI). TBI can occur when the head is struck, jolted, or pierced — during a fall, a car accident, or in sports that involve repeated collisions, such as football. In military contexts, bullets, fragments, blasts, falls, motor vehicle crashes, and assaults are the leading causes of TBI. In recent years, doctors and researchers have begun to note that even relatively mild TBI can have serious long-term consequences, and that all injuries should be addressed immediately.

Despite being one of the fastest-growing areas of neuroscience, direct-recording studies in humans are performed only in a few research centers worldwide. Cedars-Sinai is among them. Such studies require equal parts clinical expertise and scientific knowledge, and an environment that fosters close partnerships between basic scientists and physicians. What’s been learned so far has come mostly courtesy of a population of patients battling one of the most complex, difficult, and lifedisrupting disorders of the brain: epilepsy.

When medications fail to control seizures, special devices called depth electrodes can be implanted in the area of the brain suspected to be the source of the seizures. At Cedars-Sinai, patients are referred to a specialized unit headed by Jeffrey Chung, MD, director of the Epilepsy Program and the Neurophysiology Laboratory. Dr. Mamelak, director of Functional Neurosurgery, performs the procedure.

Dr. Rutishauser records exactly what happens the precise moment when thoughts take shape, memories are made, or past events are called back to mind.

With the electrodes providing continuous readings to a monitoring system, the patient and treatment team wait for a seizure to happen. It could occur within the hour. Or it might happen three weeks down the line. When it does strike, signals relayed from the electrodes will pinpoint precisely where the faulty, seizure-producing electrical impulses were centered. Often, removing or altering that section of the brain can finally make the seizures stop.

Many epileptic seizures originate in the brain’s temporal lobe — often in or near the amygdala and the hippocampus, which happen to be the same structures where thoughts and emotions are processed and memories are formed and stored.

“We know you can’t make new memories when these structures are removed, which tells us they play a key role in the making or processing of memories. But what we don’t know is how they make new memories, and that’s the big question we are asking,” says Dr. Rutishauser, who, with patient consent and state-of-the-art technology, sets out to decipher the answers.

Like the heart, the brain is powered by electricity that can be detected at several levels and displayed on a screen. A routine electroencephalogram (EEG) with sensors placed on the scalp gives doctors an overview of brain activity. An intracranial electrode grid positioned on the surface of the brain provides even more detail. But depth electrodes pick up electrical activity directly at the source. Dr. Rutishauser records on his system exactly what happens at the precise moment when thoughts take shape, memories are made, or past Neuroevents are called back to mind.

He flashes a series of pictures on a screen in a patient’s room. The images and their duration on the screen vary, depending on the goal of the experiment. But everything the patient sees — the coffee cup, the dog, the apple — snaps brain cells into action, and the computer stores the responses, which will be analyzed in Dr. Rutishauser’s laboratory.

“Our current belief is that the basic unit of computation in the brain is the single neuron,” he says. “Most studies of brain function are done with noninvasive methodologies, and while useful, they are limited. It’s like looking at city lights from space. You can make some assumptions and generalizations, but to really understand what’s going on, you have to be on the ground.”

A neuron is a complex, electrically active brain cell that is polarized, meaning some parts of the cell receive electrical input and some parts produce output. The input portion, the dendrite, has many synapses — points of contact where the neuron receives signals from other neurons.

Recording and “seeing” neurons in action, says Dr. Rutishauser, is only one part of an evolving quest for knowledge that seeks to understand the big picture of neurological disorders.

The neuron integrates all the input it gets at a given time from all the synapses, and, if that input is sufficiently strong, it becomes active and fires an electric pulse, or “action potential.” The action potential travels down the cell’s nerve fiber — the axon — which makes contact with many synapses on other neurons. So every time this particular neuron activates and fires an action potential, all the synapses that the neuron’s axon is in contact with will receive that signal.

What Drs. Rutishauser and Mamelak are measuring is the output of the neuron. When the neuron activates and fires an action potential, the researchers can “see” and record that output. In most neurons, the entire process takes place in about a thousandth of a second.

Recording and “seeing” neurons in action, says Dr. Rutishauser, is only one part of an evolving quest for knowledge that seeks to understand the big picture of neurological disorders. One study led to important findings about autism spectrum disorder, a group of complex developmental disorders affecting social interaction, communication, and behavior.

“From a series of studies, we now know the amygdala contains specialized neurons that respond when people look at and mentally process faces. We also know that the neurons of patients with autism respond differently than others,” says Dr. Mamelak. “We have a lot to learn about why, but this gives us a foundation for further investigation.”

Understanding the electrical signature of memory storage and retrieval at the single neuron level may also help scientists investigate what happens when the normal process of memory goes awry, as in dementia, Alzheimer’s, and, sometimes, Parkinson’s disease.

“At its core, memory is the interaction between ‘categorization’ and ‘novelty,’” says Dr. Rutishauser. “You see a creature and categorize it by saying, ‘Is this an animal? Is it a kind of bird?’ And then you ask yourself, ‘Have I seen this bird before?’ If the answer is ‘no,’ that’s novelty, and novelty also can act on different levels. ‘Is that a kind of bird from a species I have seen before?’ Novelty always takes precedence. That’s the way the memory system is set up.”

Say you walk into your kitchen and discover on the counter a rotting fruit you’ve never seen before. The fruit and the odor are what grab your attention to form a lasting memory. The toaster? The sponge? The dish towel? Were they there? Probably, but they were not new and different and interesting, so you do not remember them.

Understanding the electrical signature of memory storage and retrieval at the neuron level may help reveal what happens when the process of memory goes away.

For Dr. Rutishauser, the most interesting aspect of memory is the human ability to learn something “in a single shot” and play it back. That’s what initially grabbed his attention and steered him to study the brain.

“Brains, both human and animal, have many memory systems that work together,” he says. “One system, ‘declarative memory,’ is almost unique to humans. It is the ability to learn something very quickly and ‘declare,’ or describe, what it is. The surprising aspect of this is how quickly we learn the information.”

When the patient saw the picture of the apple or the fried egg, she was using her declarative memory system: Something was learned in the span of an instant and later recalled. Dr. Rutishauser’s computer captured the activity of the individual neurons that made it happen.

Dr. Rutishauser says humans have hundreds of declarative memory experiences each day. “We don’t yet understand how this kind of learning works, but it’s instrumental. Our best bet is to look at single neurons in the brain.”

Growing up in the small Swiss town of Wolfhalden, young Ueli Rutishauser discovered early on that he had a natural knack for computers and programming. In college, where he majored in computer science, a neuroscientist urged him to apply his gift to the study of the brain. Following this advice, he headed to the California Institute of Technology to earn a PhD in neuroscience. There, pioneering researchers were developing methods for studying the human brain at the single-cell level, a possibility he found immensely fascinating. He later adapted these techniques for the study of memory.

But only about a dozen centers around the world have successfully surmounted the complex technical demands inherent in direct-brain recording research in humans.

“Entering the field of brain function research is not an easy thing,” says Dr. Mamelak. “You need to invest in equipment, and you need a certain degree of experience. You have to build your own software and have hardware designed. It also takes time, because you may have few patients who are appropriate for your studies.”

sound-of-musing2 In addition to neuron activity studies, the team also investigates how different types of brain waves affect thought processes and memory. Dr. Mamelak says his collaboration with Dr. Rutishauser is an ideal match for his clinical experience and provides a fertile ground to pursue his own research interests.

“Neurosurgeons often ‘facilitate’ research, maybe removing a tumor and sending a sample of tissue from the operating room to the research lab. But we don’t often have a chance to be involved in the process,” Dr. Mamelak says. “In this situation, I can help design the experiments because I have a clinical understanding of which ones can realistically be done. I’m also involved in placing the electrodes in the brain, and I participate in the data acquisition and analysis stage, too.”

As a “functional” neurosurgeon, Dr. Mamelak performs procedures that improve the way the brain works. For a patient with epilepsy, he may remove or modify a defective section of brain tissue after pinpointing the site using depth electrodes as diagnostic tools. For patients with Parkinson’s disease, essential tremor, or dystonia, he works with Michele Tagliati, MD, director of the Movement Disorders Program, to permanently implant deep brain stimulation devices as therapeutic tools. “Many large hospitals implant deep brain stimulation electrodes, but very few use the electrode placement process for research,” says Dr. Rutishauser.

Each electrode placed deep inside a patient’s brain points to a new piece of a very complex puzzle and raises new questions. If we understand the interaction between brain cells and their networks — and discover how things are correctly and incorrectly learned — how can this knowledge be translated into a variety of practical applications for patients? Can basic mechanisms in the brain be enhanced to improve learning? Can we devise new drugs and treatments to slow down or stop the damage of degenerative brain disorders such as dementia, Alzheimer’s, and Parkinson’s? By determining precisely how nerve cells should work in the emotion-processing centers of the brain, can we help people suffering from emotional and behavioral disorders change their social skills, alter troublesome emotional responses, and possibly address some aspects of autism?

The big picture will eventually fill in as the pieces come together, little by little.

The apple. Does the patient remember seeing the picture of the apple?

A neuron fires.

Yes, she does.

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