Seeking the Neurobiology of Psychiatric Disorders

by Carl Sherman

November 10, 2011

Mental illness is brain disease: recent decades have seen growing recognition that the suffering inflicted by  depression, schizophrenia, and the like can ultimately be related to disturbances in brain function.

The neurobiology of psychiatric disorders has become an intensely active and promising research arena that brings together brain imaging, genetics, and molecular and cellular biology. The   23rd NYC Annual Mental Health Research symposium, sponsored by the Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia and Depression), offered a provocative sampling of where this research has been and where it is going.  

“Key insights have accumulated over the last 30 years of psychiatry, but we’ve hit a wall in many areas,” said Daniel S. Pine, chief of the section on development and affective neuroscience in the Mood and Anxiety Disorders Program at the National Institute of Mental Health. “To get over that wall, we need a radical shift.”

To suggest the direction of that shift, Pine described one of those insights:  the connection between childhood anxiety and adult emotional disorders. Two-thirds of adults with anxiety disorders, bipolar disorder, PTSD, or major depression suffer from anxiety as children. But only one-fourth of anxious children go on to have such problems. Most get better. 

“How are these kids different? Nothing we look at clinically will answer this question: that’s where neuroscience comes in,” said Pine.

Children overcome their fears, he suggested, through the process of memory extinction, now understood to be less a matter of forgetting than of new learning that reverses previous conditioning. Research of recent years, Pine said, has shown what parts of the brain (chiefly the ventromedial prefrontal cortex) are activated when extinction occurs, in children as well as adults.

He described work in his laboratory that found this area to be underactive in children with anxiety disorders. “This tells us something about the difference between kids with transient and persistent anxiety… we would expect the child’s ability to engage this brain region would more powerfully predict his or her ability to overcome their fear than any clinical measure.”

Further investigations will test that hypothesis, and may also lead to neuroscience-informed treatments “to augment the child’s ability to learn the difference between what’s dangerous and what’s safe,” Pine said.  

Carol A. Tamminga, chair of psychiatry at University of Texas Southwestern Medical Center, is  examining disturbances in brain activity that may generate the hallucinations and delusions of schizophrenia.

“My work has explored schizophrenia as a learning and memory disorder,” said Tamminga, who also is a member of the Dana Alliance for Brain Initiatives. She  described her  research into the internal circuitry of the hippocampus, a brain region central to these faculties.

Some studies have suggested that in schizophrenia, brain activity involving the neurotransmitter glutamate drops in one part of the hippocampus, the dentate gyrus. Tamminga hypothesizes that reduced transmission from the dentate gyrus makes the CA3 region, to which it is closely connected, more sensitive.

 CA3 is key to how we link diverse perceptions and fill in details to form complex memories: You recall what a person said, how he looked, and the setting, and blend it with past experiences into a coherent picture. If this part of the hippocampus is overactive and makes connections too readily, it might form memories that combine real and imagined details—which would be impossible to distinguish from what actually happened. And thus, Tamminga hypothesizes, are psychotic symptoms born.

Her recent research has found signs of abnormal CA3 activity in people with schizophrenia:  increased blood flow there but not elsewhere, and a raised concentration of chemicals, like brain-derived neurotrophic factor (BDNF), associated with the formation of new synaptic connections.

“This new way of looking at schizophrenia has treatment implications,” Tamminga says. “Direct current stimulation could be used to stimulate one region of the hippocampus and inhibit activity of another, or selective hippocampus-active drugs might be developed.”

A closer look

Other presenters reported research dissecting the cellular and molecular events that may underlie disease processes.

A number of gene variants have been found to be more common in people with schizophrenia. Amanda Law, of the National Institute of Mental Health, described efforts to link proteins associated with these genes to disturbances in neurodevelopment and adult brain function. 

Her work has focused on the growth factor neuroregulin and its receptor, ErbB4, “a signaling pathway that plays key roles in cell migration, myelination, and survival—it helps determine how the brain forms and is wired together,” Law said.

She described experiments to characterize the effects of genetic variations in neuroregulin and ErbB4—a chain of molecular events that runs downstream from the cell surface to processes inside the neuron.   

Ultimately, she hopes to identify elements of this pathway that could provide “favorable therapeutic targets, which might be altered by clinical pharmacology,” Law said.

Inter-neuron communication has been the focus of research by Bruce E. Herring, of University of California, San Francisco.

Reduced grey matter in the cortex has been among the most consistently observed features of schizophrenia. There are no fewer neurons than normal in these areas, Herring noted; “what’s reduced are synaptic connections between them.”  

On a micro-anatomical level, there are fewer dendritic spines—protuberances on the projections from the neuron body that connect to other neurons—in schizophrenic grey matter. Herring has looked closely at a protein, kalirin, that is concentrated inside these spines.

“If you eliminate kalirin, the number of spines is dramatically reduced,” he said. Interestingly, a number of genes and proteins implicated in schizophrenia, neuroregulin and ErbB4 among them, appear to influence the activity of kalirin, suggesting kalirin in may play a role the pathophysiology of the disease.

Herring hypothesized that without kalirin, electrical currents between neurons, a measure of their ability to communicate, would drop drastically. So he genetically manipulated mice to eliminate the protein—and found precisely that effect. What was more, adding kalirin artificially to the neuron restored the electrical activity.  

“You might think of kalirin as a tuning knob for the strength of communication between neurons,”   Herring said. “By facilitating kalirin function pharmacologically or with gene therapy, we might reverse some of the underlying pathology of schizophrenia.”

Romina Mizrahi, of the University of Toronto, reported research that could help identify people on the verge of schizophrenia and find ways to protect them. Her work involved “ultra-high risk” individuals, those who have close relatives with the disease and who already show social problems, or show the first glimmers of symptoms like auditory hallucinations.

Using PET scans, she compared the brain responses of people with schizophrenia, ultra-high risk, and low-risk individuals during a stress-inducing task (stress has been linked to a vulnerability to schizophrenia). She found much more dopamine than normal released in the brains of those with the disease, and an intermediate amount in the high-risk group.

“This allows us for the first time to understand how an environmental factor affects the biology of schizophrenia,” Mizrahi said. The next step will be seeking ways to modulate stress-linked dopamine release in hopes of easing, delaying, or preventing symptoms.

Mizrahi now is using a recently developed tracer chemical that binds to a compound associated with inflammation, again comparing PET scans of healthy people with those who have or are at risk of the disease. Her hypothesis: neuroinflammation plays a key role in schizophrenia, even before symptoms emerge.

Will a link between stress and neuroinflammation provide another treatment target? Only time—and more research—will tell.

The   23rd NYC Annual Mental Health Research symposium was held Oct. 26 at Bohemian National Hall in New York City. Find out more from the Brain & Behavior Research Foundation.