Spotlight on the cerebellum

Activity of neurons in the frontal cortex of rodents was recorded during a timing task. At the start of the trial, controls showed a burst of activity in the frontal cortex (red; image above left). Animals with timing impairments similar to patients with schizophrenia have less frontal activity (blue; middle image) that is rescued with cerebellar stimulation (red; image above right). Reprinted by permission from Macmillan Publishers Ltd: Molecular Psychiatry, copyright 2017.

Back-of-brain region key to frontal dysfunction tied to schizophrenia

By Jennifer Brown

“A beautiful, lobular structure,” is how Krystal Parker, PhD, describes the cerebellum—a brain region located at the base of the skull just above the spinal column. The cerebellum is most commonly associated with movement control, but work from Parker’s lab at the University of Iowa and others is gradually revealing a much more complex role in cognition that positions the cerebellum as a potential target for treating diseases that affect thinking, attention, and planning—diseases like schizophrenia.

In a study published in the May 2017 issue of the journal Molecular Psychiatry, Parker and colleagues show that stimulating the cerebellum in rats with schizophrenia-like thinking problems normalizes brain activity in the frontal cortex and corrects the rats’ ability to estimate the passage of time—a cognitive deficit that is characteristic in people with schizophrenia.

“Cerebellar interactions with the frontal cortex in cognitive processes have never been shown before in animal models,” says Parker, UI assistant professor of psychiatry and a member of the new Iowa Neuroscience Institute. “In addition to showing that the signal travels from the cerebellum to the frontal cortex, the study also showed that normal timing behavior was rescued when the signal was restored.”

The UI study adds to the accumulating evidence, including recent human studies from Harvard University, which suggests cerebellar stimulation might help improve cognitive problems in patients with schizophrenia.

This idea of the cerebellum’s importance has been “brewing for a long time,” Parker notes, and was an influential undercurrent in her own career development.

Iowa Neuroscience Institute researchers Nancy Andreasen, Kumar Narayanan, and Krystal Parker have made significant progress in understanding the cerebellum’s role in behavioral dysfunction.

About 20 years ago, Nancy Andreasen (70MD), PhD, a nationally recognized expert on schizophrenia and brain imaging and a UI faculty member for more than 40 years, was among the first to suggest that the poor mental coordination seen in schizophrenia might be due to disruption of extended brain circuits involving the cerebellum and the frontal cortex.

Just a few years after the publication of Andreasen’s seminal paper, Parker’s fascination with the cerebellum was ignited by a charismatic young graduate student teaching one of her undergraduate courses at Iowa State University. Parker completed a bachelor’s degree in psychology at ISU and continued her research on the cerebellum through a doctoral degree with ISU professor Vlastislav Bracha. As she studied the role of the cerebellum in eyeblink conditioning—a classic model of cerebellar learning—Parker’s ideas about a more expansive role for the cerebellum continued to develop. Soon came an opportunity to train with Andreasen.

Andreasen, who holds the Andrew H. Woods Chair of Psychiatry, and her team had created a unique eyeblink dataset from schizophrenia patients along with PET imaging data that allowed Parker to study frontal cortex and cerebellar abnormalities in schizophrenia.

Besides Andreasen’s pioneering application of neuroimaging techniques in major mental illnesses like schizophrenia, what impressed Parker was Andreasen’s complete empathy for her patients.

“She could build trust very quickly. Patients felt listened to and cared for and would open up to her,” Parker recalls.

That expertise taught Parker the enormous value of patient interactions to understand the complex effects of schizophrenia. For Parker, it also crystallized that her passion lay in defining the underlying biological causes of patients’ cognitive and behavioral symptoms.

“If we can take what we see in patients back to the lab and devise experiments that allow us to understand the neurocircuitry involved in mood and cognition—and how that network is disrupted by diseases like schizophrenia—maybe we can find ways to overcome those deficits and develop treatments that actually provide relief from the symptoms that are so debilitating for patients,” she says.

Parker embarked on a second postdoctoral fellowship with Nandakumar Narayanan, MD, PhD, assistant professor of neurology at the UI Carver College of Medicine and a Parkinson’s disease specialist. Narayanan was new to the UI and was building a research program using new techniques like optogenics to probe brain circuits involved in cognition.

A different kind of mentor, Narayanan was much closer in age and not so far ahead of Parker in his career path. She describes him as “very present” in the lab, providing hands-on training and mentoring her through the maze of early scientific career obstacles and opportunities.

“Kumar was motivated and motivating,” says Parker, who joined the UI faculty in 2015. “He really taught me what it takes to be successful both in practical terms and in attitude.”

She is excited that as her cerebellar research starts to take off, it seems to be picking up steam across a much broader swath of the scientific community.

“More and more people are coming on board to the idea that this brain region may have an important role in regulating mood and cognition in people, and disruptions to its function are important in several serious neuropsychiatric diseases—schizophrenia, bipolar disorder, Parkinson’s disease, and possibly autism, too,” she says.

Schizophrenia is a serious and debilitating psychiatric illness that disrupts a person’s ability to think and to understand the world around them. About 1 percent of the population is affected by schizophrenia. There is no cure, and few therapies reliably improve the condition’s cognitive problems.

Knowing it’s essential for cognitive function, Parker and her colleagues, including Narayanan and Andreasen, recorded brain activity from the frontal cortex of nine patients with schizophrenia and nine healthy controls while they performed a timing task of estimating the passage of 12 seconds.

“We think timing is a window into cognitive function,” Parker explains. “It allows us to probe executive processes like working memory, attention, planning—all those things are abnormal in schizophrenia.”

Compared to healthy individuals, patients with schizophrenia performed poorly on the timing task. They also lacked a low-frequency burst of brain activity (the delta brain wave) that occurs right at the start of the trial in healthy subjects.

To probe the brain circuitry involved in this signal, and to assess the role of the cerebellum, the team turned to an animal model. In schizophrenia, dopamine signaling in the frontal cortex is abnormal. By blocking dopamine signaling in the frontal cortex of rats, the team was able to reproduce the schizophrenia-like timing problems in the animals.

Recordings of neural activity in the frontal cortex of the rats showed that, like humans with schizophrenia, these rats also lacked the low-frequency burst of brain activity (delta wave) during the timing task. The study also showed that, in control rats, the same delta wave activity occurred in the rat’s cerebellum during the timing task and, interestingly, the cerebellar activity preceded the activity in the frontal cortex.

“We think that delta wave burst of activity acts like a ‘go’ signal that triggers individual neurons to start ramping their activity to encode the passage of time,” Parker explains. “That happens in both the frontal cortex and the cerebellum, but there is synchrony between the two, and the cerebellum is actually leading the frontal cortex and providing the signal to the frontal cortex.”

Finally, the researchers used optogenetics to stimulate the rats’ cerebellar region at the precise delta wave frequency of 2 hertz. This cerebellar stimulation restored normal delta wave activity in the rats’ frontal cortex and normalized the rats’ performance on the timing test.

The findings explain how cerebellar stimulation might have a therapeutic benefit in schizophrenia. Parker adds that the research may also inspire novel cerebellar-targeted pharmacological treatments for schizophrenia.

Non-invasive brain stimulation is currently approved as a treatment for depression. However, cerebellar stimulation is still an experimental approach and is not approved by the Food and Drug Administration as a therapy. Early experimental studies from Harvard in patients with schizophrenia suggest that cerebellar stimulation is safe and appears to improve some of the patients’ cognitive abnormalities. Parker is currently pursuing human testing of non-invasive cerebellar stimulation at the UI in collaboration with Aaron Boes (09MD/PhD), director of the Iowa Brain Stimulation Program. They are working to understand how cerebellar stimulation influences cognitive function and frontal cortex activity in patients with schizophrenia.

Neuroscience programs awarded $4.6 million

The Iowa Neuroscience Institute, created in 2016 with a transformational $45 million grant to the University of Iowa from the Roy J. Carver Charitable Trust, has awarded its first round of funding—a total of $4.6 million over five years for the following projects:

Neuromodulation Research Program of Excellence. By investigating neuromodulation, a technique that alters neuronal activity with pulses of electricity, researchers hope to identify how frequency-specific stimulation to different brain regions can influence symptoms associated with conditions like Parkinson’s disease and schizophrenia.

The Bipolar Disorder Research Program of Excellence. Brain imaging, genetics and epigenetics, circuit-level mechanistic studies, and neuromodulation will be used to probe brain circuits that regulate mood state and are disrupted in bipolar disorder.

The Composition and Trafficking of Neuronal Ion Channels Research Program of Excellence. Exploring the molecular and genetic maintenance of electrical signaling, with a focus on sodium channel complexes, could inform new treatment of diseases such as inherited and acquired pain disorders, epilepsy, amyotrophic lateral sclerosis, and muscular dystrophy.

Science Behind Curing Heritable Blindness Research Program of Excellence. Researchers will study the genetics and disease mechanisms underlying inherited blindness and seek to translate discoveries into therapies including gene therapy, pharmaceuticals, and genome editing.

The Mitochondrial Dynamics and Calcium Cycling in Neuronal Injury, Excitability and Plasticity Research Program of Excellence. State-of-the-art imaging techniques and behavioral analysis in novel transgenic mouse models will provide information that could be useful in developing therapies for neurodegenerative disease and epilepsy.

Neuropsychiatry Research Junior Research Programs of Excellence will study two areas: prenatal environmental factors—including maternal stress, environmental exposures, and genes—that can affect early brain development; and cognitive and motor control in health and disease, particularly how age- and disease-related impairments to these functions can be alleviated.