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Advances in Behavioral Neuropsychiatry — Neural Networks in Neurodegenerative Disease, Cognitive Development, and OCD


doi: 10.1097/01.NT.0000361420.34679.f8
Best of the Field

A The way the brain is built — its “architecture” and the movement of impulses within the complex neuronal networks — how the system fails to pave the way for neurodegenerative diseases, and a new theory on neuronal communication between specific regions that culminates as the obsessive compulsion syndrome all come together in papers selected as the Best of the Field in the past year by neuropsychiatry experts David Arciniegas, MD, and Daniel I. Kaufer, MD.

Dr. Arciniegas is director of the Neurobehavioral Disorders Program and associate professor of psychiatry and neurology at the University of Colorado School Denver of Medicine and medical director of the Brain Injury Rehabilitation Unit at HealthONE Spalding Rehabilitation Hospital. Dr. Kaufer is director of the Memory and Cognitive Disorders Program at the University of North Carolina School of Medicine.

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In the April 16 Neuron, investigators at the University of California-San Francisco and Stanford University studied 24 patients in the early stages of Alzheimer disease (AD), 24 with frontotemporal dementia (FTD), 24 with semantic dementia, 13 with progressive nonfluent aphasia, and 17 with corticobasal syndrome. For comparison they included 65 healthy controls.

MRI scans measuring the volume of gray matter volume for each patient showed patterns of neural networks specific to each of the diseases. And when the networks were compared to those of healthy brains, the pattern that emerged suggested that the networks themselves had undergone neurodegeneration.

For example, AD is associated with episodic memory problems and involves medial temporal, posterior cingulate/precuneus, and lateral temporo-parietal atrophy, while frontotemporal dementia involves a network that combines the anterior cingulate, frontoinsular, striatal and frontopolar degeneration.

Each disease showed a “unique deficit signature,” according to the scientists. The study findings proved that there is a normal functional network in healthy brains and that these networks became abnormal in the disease state. The damage was specific for each of the specific disorders, even though dementia is a feature in all of them.

The study shows for the first time that specific networks form during development and may actually confer a selective vulnerability to specific diseases with different features of dementia later in life.

“We showed that diseases don't spread across the brain like a wave, but instead travel along established neural network pathways,” said the lead study author William W. Seeley, MD, associate professor of neurology at the University of California-San Francisco.

He and his colleagues suspect that proteins common to specific brain networks can misfold and accumulate within neurons to trigger specific symptoms arising from an unhealthy network.

This study raises new questions: How and why does neurodegeneration spread through a specific network? The findings also put a kink into theories about some of the conditions, such as AD, which are thought to spread throughout many brain regions beyond the specific neural network. The findings suggest new ways to identify, follow, and perhaps even treat a neurodegenerative disease.

“This research provides the field with an elegant example of how cognitive neuroscience can inform our understanding of normal and abnormal brain functioning,” Dr. Kaufer said. “It sheds light on a plausible mechanism for why different degenerative brain disorders typically affect selected and distinct brain regions.”

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Continuing on the theme of neural networks, a collaborative team of scientists has identified important differences in how neural networks evolve throughout development. They found that neural regions in the young brain are localized — that is, the areas are arranged by anatomical proximity and regions close to one another communicate — whereas in the maturing brain, regional communication becomes distributed across the whole brain.

The finding, published in PLoS Computational Biology, may help scientists better understand how the brain learns and processes cognitive information over the course of a life.

The scientists conducted MRI studies to study real-time spontaneous brain activity in a resting state in 210 people between seven and 31 years old. The scientists used the brain scans to watch how these areas — including the frontoparietal, cingulo-opercular, and cerebellar networks — change in the brains of young people to those in adults. The resting state connectivity scans the activity that supposedly takes place when people are doing nothing. They measure connectivity when brain activity of different regions ebb and flow together. It suggests that these regions are working together.

“We took a group of the youngest subjects, analyzed their results, then dropped data from the youngest and added data from the next-oldest and redid the analysis until we had worked our way through all subjects,” said Damien A. Fair, PhD, a former Washington University graduate student now at Oregon Health and Science University. “The result was a detailed movie of how the organizational transition from a child's brain to an adult's brain takes place. It clearly shows a switch from localized networks based on physical proximity to long-distance networks centered on functionality.”

Steven E. Petersen, PhD, the James McDonnell Professor of Cognitive Neuroscience at Washington University School of Medicine in St. Louis and the senior author of the study, added that the child's brain has a different organization but “it is not inherently disorganized or chaotic.”

The cortical networks in the young brain were close to each other where the networks in adolescents and adults were communicating, or working together, at greater distances.

By age seven, the brain is almost 95 percent of the adult size. But clearly the geography of the brain is vastly different. The investigators saw new networks forming as they studied adolescents so that more remote regions were beginning to talk to one another. In adults, Dr. Fair and his colleagues found “a fully integrated system,” meaning that networks were more flexible in interactions with other networks — that is, they were more of a global rather than local information transportation system.

These novel discoveries suggest that the brain is wired at different points in development to solve similar problems “in divergent ways,” the scientists wrote in the new study.

For example, the laying down of the myelin sheath during development, which coats the axons with protective insulation, ultimately leads to more efficient communication that can extend to more distant regions — akin to laying down track on a railway to extend the route.

Ultimately it means the brain is more efficient at talking globally to other brain regions which may pave the way to more complex thought and behavior possible.

“This work provides a window of opportunity for understanding the normal development of neural architecture serving various cognitive processes, and identifying common features of childhood developmental disorders,” Dr. Kaufer said.

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A third important paper appeared in the fall 2008 Journal of Neuropsychiatry and Clinical Neurosciences, proposing a new theory to explain behaviors of obsessive compulsive disorder (OCD). Previous models of OCD had often focused on either the neuroanatomy or the psychology that might drive the obsessive or compulsive behavior.

But a new paper by Edward D. Huey, MD, director of clinical science at the Litwin-Zucker Center for the Study of Alzheimer's Disease and Memory Disorders at The Feinstein Institute for Medical Research in Manhasset, NY, has pulled together anatomical and neuropsychological studies to develop a theory about how these behaviors might unfold, based on a particular vulnerability.

“Our paper attempts to integrate the neuroanatomy of OCD with the experience of the patient,” said Dr. Huey. “The goal of the new model is to suggest new experiments that may ultimately shed light on this often debilitating disorder.”

The new model of OCD is based on what is known about the brain regions involved in the common disorder from imaging studies (MRI, fMRI and PET) of patients with idiopathic OCD and patients with OCD-like behaviors after injury to the brain or neurodegenerative disorders. Dr. Huey has examined hundreds of patients with these frontotemporal disorders.

The investigators also incorporated neurological evidence that shows that symptoms are diminished in OCD patients who undergo surgery or deep brain stimulation to quiet the hyperactive brain regions thought to provoke the obsessive behavior.

According to Dr. Huey, an expert on diseases that affect the frontal lobes, there are three brain regions that are involved in both sets of patients — those who develop repetitive behaviors after frontal lobe damage and those whose lives are altered by idiopathic OCD. The regions include the orbitofrontal cortex, which is important for the correct execution of a behavior; the anterior cingulate that is important in detecting errors (so the individual knows when the right behavior will follow with a reward); and the basal ganglia, which set a certain threshold for a behavior to generate a reward.

One important difference in the two groups of patients is that those with idiopathic OCD have much anxiety associated with the unstoppable behaviors, according to patient reports, case studies and other research on OCD patients. The behaviors are usually performed in response to obsessive thoughts while those who develop OCD behaviors following frontal lobe damage usually do not have this anxiety / obsessional component, Dr. Huey said.

Reward states are dynamic and the start of any behavior is accompanied by a motivation/anxiety that continues until the job is completed. Dr. Huey theorizes that people with idiopathic OCD have a deficiency in this process. Either they don't get the relief (or reward) at the end of the behavior (and thus the anxiety continues) or their brains fail to detect having completed a behavior, Dr. Huey explained

By comparison, those with frontotemporal damage have the compulsive behavior without the anxiety. “They are not motivated by anxiety to complete a behavioral task,” Dr. Huey said. “They are losing the ability to know when it is appropriate to carry out a specific behavior. It is as if the storage bin is missing some information on when something requires doing and when it doesn't.”

Dr. Huey and his colleagues hope that breaking down the anatomy and the psychological experience of OCD will lead to the development of new ideas for research. He added that the theory is important because it enables him to make testable predictions of human behaviors based on injuries/lesions in the brain of areas involved in OCD. Also, if the theory is confirmed, it could inform pathways for the development of novel treatments.

“This article offers an outstanding example of the scholarship of integration between neurology and psychiatry. It synthesizes the psychiatric, neuroimaging, and neurosurgical literature (from patients who develop OCD-like behavior following specific brain damage) to propose a neurobiologically-based model of obsessive-compulsive disorder,” Dr. Arciniegas said.

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• Huey ED, Zahn R, Krueger F, et al. A psychological and neuroanatomical model of obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci 2008;20:390–408.
    • Seeley WW, Crawford RK, Zhou J, et al. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009;62:42–52.
      • Fair DA, Cohen AL, Power JD, et al. Functional brain networks develop from a “local to distributed organization. PloS Comput Bol 2009; 5: Epub ahead of print May 1, 2009.
        ©2009 American Academy of Neurology