The study of the neural basis of cognition, or cognitive neuroscience, has evolved rapidly in the last 10 years. In large part this has resulted from the parallel advances in imag ing technology and raw computing power. Indeed, the exponential growth and concomitant movement of extraordinarily powerful computers to the desktop has made routine the analysis of large, complex data sets. Cognitive neuroscience is an enterprise that depends heavily on the use of modern imaging technologies such as positron emission tomography and functional magnetic resonance imaging (fMRI), and because of this reliance on technology, the ability to look noninvasively at the functionings of the human brain has only become possible very recently.
The fundamental goal of the cognitive neuroscientist is to understand the neural basis of the human mind. Historically, the mind had been thought to be separate from the body. Rene Descartes, the eighteenth-century French philosopher-mathematician, was perhaps the most vociferous advocate of mind-body dualism. The question of where the human mind, perhaps even the soul, resides has plagued humanity for at least as long as written records exist. Until recently, there was no reason to suspect that the mind might have components that were tied to the body. After all, this notion might be discordant with the belief of the immortality of the soul—if the body dies, then so does the mind. Descartes circumvented the problem by separating the mind from the body, and therefore the brain.
Mind-body dualism did not last long. Neurologists of the nineteenth century began to notice that patients with specific brain injuries, either from stroke or trauma, displayed consistent behavioral deficits. Pierre Paul Broca, a French neurologist, systematically described the effect of lesions in the left frontal cortex on language. Insightfully, he was the first to state that language was localized to the left cerebral hemisphere. This opened the door for an explosion of cognitive localization in the brain. In its extreme form, phrenology, every function of the human mind could be localized to some bump or valley in the brain (and skull). The use of brain lesions to deduce brain function subsequently became the predominant method for exploring the mind/ brain for the next 100 years.
The lesion method truly was the first cognitive neuroscience technique. Its growth paralleled the recognition of other types of deficiency syndromes in medicine. The lesion method relied solely on the power of observation and a ready supply of patients with various types of brain injury. The history of the field is full of references to famous patients whose unfortunate circumstances led to some insight about the functioning of some particular brain region. Phineas Gage, perhaps the first famous patient, was a nineteenth-century railroad worker who had an iron rod accidentally driven upwards from just below his left eye out through the top of his skull. Remarkably, he lived for another decade, and his subsequent change in personality from a reliable and steady worker to a profane, erratic, and irascible man was aptly characterized by his physician at the time: "Gage was no longer Gage."
The father of modern psychology, William James, was attuned to these advancements in understanding the brain in the late nineteenth century. Further evidence linking brain function to cognitive processing continued to amass. The observation that regional changes in cerebral blood flow were tied to mental function can be traced to the fortuitous discovery in a patient with an arteriovenous malformation in his frontal lobe. This patient (and his physician) noticed an increase in audible blood pulsation when performing mental calculation. This observation, that local changes in cerebral blood flow are linked to neural activity, underlies all of modern functional imaging techniques.
The parallel development of new imaging technologies with increased computational power in the late twentieth century resulted in the development of two new methods to study human brain function. Positron emission tomography (PET) developed as an outgrowth of autoradiography. Unlike its predecessor, PET could be performed without the requirement of sacrificing the animal. PET takes advantage of the fact that when a positron (a positively charged electron) encounters an electron, the two particles annihilate each other, and two high-energy gamma rays are emitted in exactly opposite directions. When a series of gamma-ray detectors are arranged in a ring, the origin of the particle can be computed. Positron emitters can be synthesized into common molecules, like water or 2-deoxyglucose, and when injected into a subject they can be used to map cerebral blood flow or metabolism respectively. Similarly, fMRI relies on the coupling of neural activity to local cerebral blood flow. Current thinking suggests that transient increases in neural activity result in a hyperremic blood flow response. Oxygenated hemoglobin and deoxygenated hemoglobin have different magnetic properties, and because the increase in blood flow results in a transient increase in the oxy-deoxy ratio, this can be detected with MRI. By rapidly acquiring MRIs while a subject is performing a cognitive task in the scanner, one can correlate the changes in blood flow to what the subject is doing.
Although PET and fMRI typically measure only relative changes in brain activity, through careful experimental design it is possible to isolate the neural circuits associated with specific cognitive processes. The basis for this is called subtractive design. When an experiment is designed with at least two cognitive conditions, one of which is a control state, the brain activity maps obtained during the control state can be subtracted from the brain activity during the condition of interest. In actual practice, a statistical test is usually performed instead of a simple subtraction, but the assumption is that whatever brain regions show different activity between the conditions represent the circuit associated with processing the extra information. It is critical that the control state be chosen appropriately. Otherwise, one might be subtracting cognitive states that are so different from one another that the assumptions of this method are violated. In particular, subtraction assumes that cognitive process behave linearly: that is, that pro cesses can be added and subtracted without interacting with each other. This may be true under some circumstances, but not all.
In general, the subtractive approach to imaging has confirmed what was known from the lesion method, but recent advances in fMRI have allowed the description of more subtle processes. By presenting subjects with very brief stimuli, we can measure the cerebral blood flow response and correlate it with individual events. This goes beyond the subtractive approach, which often requires the subject to maintain a cognitive state for tens of seconds to minutes. Event-related fMRI measures the brain response on a scale less than a second, which is much closer to the time scale at which the brain operates. New computational algorithms are also revealing the complex correlations that occur between different brain regions, which begins to reveal the choreography of brain activity that must be the hallmark of cognition. With the combination of rapid imaging and new algorithms, perhaps the elusive goal of identifying the neural basis of the mind will be achieved.
Gregory S. Berns
Emory University School of Medicine
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