One of the greatest scientific challenges for 21st century medicine is to illuminate the relationship between the brain and what we call “mind.” Psychiatrists want to know how we get from neurons and synapses to mental suffering. How do learning, development, and cognitive flexibility arise? What accounts for the uniqueness of every human self? What goes wrong in psychiatric disease? Within the psychiatric community, brain science has generally been regarded as being still too elementary to explain such complex phenomena.
In this article I describe how analysis of the brain’s intrinsic functional connectivity has become an important approach for expanding our understanding of the astounding complexity of the human brain. Utilizing this new paradigm, it is possible to explore questions that earlier seemed virtually unfathomable; many of these are relevant, even pivotal, to psychiatry.
In news parlance, functional connectivity is a “rapidly developing scientific story.” And for psychiatrists, it is a story worth following.
What is functional connectivity?
Functional “imaging” measures physiological factors that are considered to be a gauge of neuronal functioning (such as changes in regional oxygen utilization); the accumulated data are then transformed into “human readable” images. Functional “connectivity” utilizes functional imaging data and analyzes the statistical associations between measurements of neurophysiological activity in 2 or more spatially remote areas of the brain. Functional connectivity studies are a mathematical, non-theoretical look at activity over the whole brain, in an attempt to discern in which areas the activity is either correlated or anti-correlated. For example, do areas A and X display increased metabolic activity when area D exhibits decreased metabolic activity?
Traditional functional connectivity methods do not tell us about the direction of connectivity—which region is influencing which. Functional connectivity also does not tell us whether 2 regions are simultaneously being influenced by a third. Nor does functional connectivity say anything about the way in which various brain areas might be structurally connected. Functional connectivity takes a purely statistical look at larger patterns of neurophysiologic activity that emerge from the brain’s hundreds of billions of neurons, reciprocally interacting over both short and long distances at microsecond speed.
Early functional connectivity research was designed to study the brain while an individual was performing a task or interacting with the environment—termed “psychophysiological interactions.” More recent work has shifted to a focus on the brain’s intrinsic neural activity while the subject is at “rest” or engaged in undirected thought.
The historical context
It was not until the early 1800s that modern scientific notions about the brain began to take precedence.2 Franz Joseph Gall promoted the idea that various mental capacities were localized to different brain regions; he also believed that the strength of these qualities could be measured by looking at protrusions in the skull overlying these areas. This notion was at the heart of phrenology, extremely popular in the 19th century.
Gall assumed that the brain was symmetrically organized. His categorization of what constituted fundamental, functional capacities of the brain drew on cultural values of his day, including vanity, guile, kindness, and pride. Although scientific advances have discredited many of these claims, Gall’s fundamental insight about localization was profound.
Localization was a powerful new idea at the time; it exhibited the 2 fundamental attributes of a paradigm as first defined by the science historian Thomas S. Kuhn as “. . . sufficiently unprecedented to attract an enduring group of adherents away from competing modes of scientific activity. Simultaneously, it was sufficiently open-ended to leave all sorts of problems for the redefined group of practitioners to resolve.”3
The localization paradigm opened new questions for legitimate scientific inquiry; neurological investigators became the Lewis and Clark of neuro-anatomic territories. More than 200 years of explorations in neurology have been spent mapping the localization of various functional elements within the brain and simultaneously parsing brain activity into its most fundamental capabilities.
For example, until the mid-1950s, memory was considered to be a widely distributed, unitary function of the brain. Then, studies of patient H. M. elucidated a central role for the hippocampus in memory formation. In addition, episodic and procedural memory processes were differentiated.
While the concept of localization drove much of the work of scientific exploration during this time, there also were global, overarching theories of brain function. The eminent British neurologist John Hughlings Jackson posited that the more evolutionarily developed regions of the brain exerted control over primitive brain areas; he articulated how disturbances in this organization were evident in disease states. Indeed, many scientists who are well known for their work on localization (Wernicke, Penfield) also were aware that the brain was extraordinarily complex and that the parts had to work together, like an astoundingly accomplished orchestra.
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