New Connections

How we understand brain function has changed how we understand disease

Posted Dec 29, 2020 | Reviewed by Kaja Perina

Why do we get jealous, scared, or anxious? How is it we’re able to entertain competing ideas, project our potential actions into the future, and decide on a course of action? What happens within the brain that manifests in the afflictions of depression, Parkinson’s disease, or Alzheimer’s? The curious minds of philosophers and scientists have sought answers to these questions for centuries.

In fourth century B.C., mental faculties and the brain were divorced. Thought, reason, and other abilities of the mind were instead associated with the heart. The brain was a secondary organ—a cooling agent and a space where the spirit could flow freely. By one A.D., basic structures of the brain were identified. And by two, mental activity was properly assigned to the brain. Physicians of the Middle Ages focused on the cavities, called ventricles, believing each housed a different mental activity. The Renaissance came with more frequent dissections and detailed diagrams. And sixteenth and early seventeenth century anatomists contributed terms such as cerebrum, cerebellum, and medullar. Little was known about the relationship between brain structures and function.

In 18th century Vienna, physician Franz Joseph Gall developed theories of brain anatomy and function that have influenced the way we think about the brain to this day. A skilled anatomist, Gall saw the brain as an amalgamation of specialized parts, each serving a specific mental or emotional function. In Gall’s conception of the brain, each faculty—affection, vanity, musical ability—could be explained by the size and development of its respective brain region. Gall’s theories eventually developed into phrenology—the study of the bumps and indentations of the skull, which Gall believed reflected the structure, and therefore, function and character of the brain beneath.

The practice of phrenology was eventually discredited. But the idea that function could be localized in specialized brain regions persisted. Pierre Paul Broca—the French physician, anatomist, and anthropologist—observed two patients: Louis Victor Leborgne and Lelong. At thirty years old, Leborgne was unable to produce any words or phrases besides repetitively uttering “tan.” Lelong was able to say five words (“yes”, “no”, “three”, “always”, and “lelo”). Lesions in the lateral frontal lobe were identified in both men posthumously and the area of the cortex, now known as Broca’s area, was identified as being specialized for speech. The German anatomist Korbinian Brodmann segregated the cortex into functional areas based on the histological structure and organization of the cells. Sir David Ferrier electrically stimulated the brains of animals to develop a comprehensive map of the motor cortex. Technologies like fMRI (functional magnetic resonance imaging) that allow researchers to observe brain regions “light up” while solving problems, recognizing faces, reacting to groups of words, or thinking about money, sex, or God have fueled this Swiss Army Knife view of the brain in more recent years.

Since Gall and phrenology, some neuroscientists have always contested the modular view of the brain. Prominent opposers from the annals of neuroscience include figures such as Marie Jean Pierre Flourens, Camillo Golgi, and Karl Lashley. Perhaps the greatest contributions to a distributed model of brain function come from the Spanish neuroscientist Justo Gonzalo and researchers like Anthony McIntosh. Gonzalo studied different cortical lesions in patients and observed functional gradients within the sensory system that could not be explained by traditional localization theories. Scientists such as McIntosh use neuroimaging to mathematically observe interactions (or covariance) between regions of the brain during a task. Increased blood flow in the auditory cortex while hearing a sound, for example, is correlated with activity in visual areas of the brain. Synchronous activity in different brain regions suggests the respective regions are both contributing to performing the function. In this view, the brain is organized into functional networks, with different parts performing portions of the task.

Our understanding of how the brain works dictates how we think of disease and guides the questions researchers ask when trying to understand how diseases and brain maladies work. If we think mental faculties and functions are segregated into defined regions, we look for regions to associate with a function or faculty. If sadness belongs to one part of the brain, the feelings that lead to depression can be associated with a brain region and targeted for treatment. Likewise, if a distinct brain region is responsible for memory or motor function, Alzheimer’s and Parkinson’s disease can be understood and treated by identifying and targeting the region of the brain responsible.

Today, a hybrid view between functional specialization and distributed processing prevails. Brain regions likely participate in many different aspects of mental activity and cognition; some being more specialized for some tasks relative to others. And, neuroplasticity as a result of injury or experience can alter the brain landscape, changing the degree of specialization or what an area may be capable of or responsible for.

The degree to which brain regions work together and specialize in aspects of a computation can be visualized using network theory. Olaf Sporns, a professor of Psychological and Brain Sciences at Indiana University explains the utility of network theory in brain science: “…these approaches provide fundamental insights into the means by which simple elements organize into dynamic patterns, thus greatly adding to the insights that can be gained by considering the individual elements in isolation.”

Network theory is applied to data acquired from fMRI (a measure of water molecules and an insight into brain activity). The MRI data is then segmented into brain regions, called nodes, and the magnitude of flow from node to node is calculated. Connections between nodes are “edges.” The more connections a brain region has, the larger the node. And the stronger the connection between brain regions, the thicker the line between nodes. Being able to mathematically visualize connections between brain regions has influenced how we understand and approach research into brain disease and mental afflictions. Research is increasingly steering towards the connections.

Brain regions are connected to one another by tracts of white matter—bundles of nerve fibers individually encased in a fatty substance called myelin. Myelin supports the function of the axon (allowing electrical impulses to travel long distances) and increases the speed information can pass between brain regions. Many maladies of the brain previously thought to involve specific aspects of neural function or brain regions are now being linked to altered connections.

Two pathological hallmarks of Alzheimer’s disease are amyloid plaques and neurofibrillary tangles: signs of degradation and death of nerve cells that leads to difficulties with memory, language problems, disorientation, and mood swings that progressively worsen over time. New research looking at oligodendrocytes and myelin—the primary constituents of white matter—suggests abnormalities in these cells and structures that likely contributes to pathology. And Alzheimer’s is not alone. Parkinson’s disease, thought to be driven by the death of dopaminergic neurons in the substantia nigra; major depressive disorder, linked to monoaminergic systems, immunological dysfunction, and the HPA axis (hypothalamus-pituitary axis); and generalized anxiety disorder, panic disorder, obsessive compulsive disorder, post traumatic stress disorder, social anxiety disorder—all with pathological mechanisms linked to one brain area or another—are now being recognized as having white matter abnormalities (links to studies are attached to the disorder names above).

For the brain to function optimally, timing is everything. Information in the form of electrical impulses race between areas of the brain, arriving and departing from several locations simultaneously. Arrive to late or too soon and the network is thrown into disarray and the brain function cannot be performed. The speed, and therefore the timing, of electrical impulses along white matter tracts is dictated by myelin (the fatty wrapping around nerve fibers) and cells called oligodendrocytes (the producers of myelin). An extra or longer wrap of myelin and the impulse is sped up. Shorter or lesser wraps and the impulse is slowed.

Degradation of connections between brain regions may preclude abnormalities in specific areas, which leads to neural degradation. Or, the degradation of white matter may arise as a symptom of poor neuron health, initiating a negative feedback loop of deterioration where each compliments the other. The initiating event may even differ among brain conditions. Only more research can answer these questions.

What’s clear is that network theory has expanded our understanding of how the brain works and allowed more questions to be asked. Questions that enhance our understanding of disease and will ultimately lead to better and more effective treatments.