From the inside out: Making sense of schizophrenia

The senses — which serve as our brain’s window to the outside world — may play a key role in schizophrenia.

Researchers believe the sensory systems in the brain of those living with schizophrenia may become overloaded with visual and auditory signals, and scramble them in a manner that results in the hallucinations that are a hallmark of the disease.

Clinicians and researchers at the Medical Center have a long and distinguished history of innovation and research in the field of schizophrenia. For more than three decades, psychiatrists at URMC Strong Ties Community Support Program have worked directly with individuals and families to better understand and treat this complex disorder that impacts an estimated 2.6 million Americans. Marvin Herz, M.D., and J. Steven Lamberti, M.D., have led the program to become a primary site for studies examining novel psychopharmacological and psychosocial treatment strategies. The Wynne Center for Family Research conducts high-quality clinical research and disseminates those findings to inform clinicians and the public. It was founded by Lyman Wynne, M.D., Ph.D., in 1997 and continues to produce groundbreaking family research under Thomas O’Connor, Ph.D. 3 4

Last year, a team of researchers in the Del Monte Institute for Neuroscience, including Greg DeAngelis, Ph.D., the George Eastman Professor of Brain and Cognitive Sciences, and Ralf Haefner, Ph.D., an assistant professor of Brain and Cognitive Sciences, were awarded a $12.2 million grant from the National Institutes of Health’s (NIH) Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. The grant will be used to better understand the neurons in the brain involved in causal inference — the key to learning, reasoning, and decision-making — and how this is used by the brain to distinguish self-motion from object-motion. These findings could have major implications for our understanding of schizophrenia.

Just before the pandemic hit, a team of researchers joined the psychiatrists in the Del Monte Institute for Neuroscience, bringing with them research innovation that aims to change how we understand and treat schizophrenia. Each researcher is looking to the brain for answers from different perspectives.

THROUGH THE EYES

Steven Silverstein, Ph.D., George L. Engel Professor of Psychosocial Medicine, professor in the departments of Psychiatry, Neuroscience, and Ophthalmology, and a member of the Center for Visual Science, has spent more than three decades studying visual perceptual deficits in schizophrenia. Recently, his focus has shifted to the lowest level of the visual system — the retina. “The idea is that it serves, in a way, as a window to the brain. Loss of retinal volume or thinning of neural layers in the retina, reduced strength of firing of retinal cells, and reductions in the microvasculature, are some of the early indicators of neurological or serious psychiatric illness, and, in some cases, are also predictors of illness progression. The retina can be thought of as an extension of the brain — the two structures grow out of the same tissue during embryonic development.” Silverstein said. “That can be examined as a biomarker of changes in brain structure, function, and/or perfusion, but in a faster and much less-invasive manner than when examining the brain.”

Two techniques allow Silverstein to investigate known retinal function and structural changes in schizophrenia: electroretinography (ERG), which detects electrical activity in retinal cells rather than brain cells; and optical coherence tomography (OCT), which uses light reflected from the back of the eye to generate detailed images of the retina. Evidence of weakening of the firing in retinal neural cells or delays in firing have been observed in people with schizophrenia and in unaffected family members. Different ERG tests — such as using different levels of light intensity or speed of flash presentation — have the potential to help understand changes at the neural level that precede the emergence of psychotic symptoms, and to aid in differential diagnosis. In a recently published study, Silverstein found that patients with major depressive disorder did not demonstrate any of the ERG impairments shown by schizophrenia patients, and an ongoing study will determine if ERG can discriminate schizophrenia from bipolar disorder. In a recently published OCT study, Silverstein found that patients recovering from a first psychotic episode did not show any evidence of thinning of retinal layers, whereas people who had had multiple episodes demonstrated clear evidence of retinal thinning in both eyes. Even more recent evidence using optical coherence tomography angiography (OCT-A), which generates details of blood flow and 3D maps of retinal and choroidal vascular systems, suggests that loss of small blood vessels in the retina may be found as early as the first episode.

“There is still so much we do not know about schizophrenia,” said Silverstein. “What causes weak and slow signals to come in from the eye? Are some overcompensations by the brain for poor quality sensory information causing symptoms? For example, does increasing the intensity of signals but also noise lead to the stimulus overload and confusion reported by many patients? Do the brain’s predictions about what is ‘out there’ when sensory evidence is of poor-quality lead to hallucinations? What is the best way to treat sensory impairments in people with, or at risk for, schizophrenia and what effects do these treatments have on symptoms and overall functioning? By using the retina as a model of overall central nervous system structure, function, and vasculature, our hope is that our research can eventually help with early diagnosis, clinical monitoring and prediction, and treatment development.”

INTO THE EARS

Judy L. Thompson, Ph.D., assistant professor in Psychiatry, has spent a number of years collaborating with Silverstein to study visual processing impairments and related behavioral interventions in psychosis. But her current research is shifting more toward positive symptoms of schizophrenia — such as delusions and hallucinations. Although these positive symptoms often respond to antipsychotic medication, they persist in about a third of the people affected despite treatment with standard medical interventions.

“One of my aims is to do work that advances our understanding of underlying mechanisms to inform the development of novel interventions,” Thompson said, “and to address questions about how alterations in auditory and speech processing may relate to auditory hallucinations.”

Thompson is collaborating with Neuroscience and Biomedical Engineering researcher Edmund Lalor, Ph.D., and using his expertise in electroencephalography (EEG) to characterize hierarchical speech processing. Recent models suggest there are disturbances in the brain processing incoming sensory information, and predicting information based off of what the brain already knows and expects. Finding a way to measure this and understanding what is happening at the mechanistic level, Thompson aims to identify novel treatment targets to inform the development of new treatment approaches.

“As part of my research over the years, I’ve done lots of clinical interviews with people who have schizophrenia and also their family members,” Thompson said. “Hearing about the experiences of an individual with schizophrenia and the factors that seem to potentially contribute to that — it’s just a really important reminder of why we’re doing all this.”

WATCHING THE BRAIN

For Brian Keane, Ph.D., assistant professor in Psychiatry, Neuroscience, and the Center for Visual Science, visual perception is special. It dominates our subjective experience from the time we open our eyes in the morning to the time we go to sleep. It recruits more than one-quarter of the human cortex, more so than any other sense. And, more surprisingly, it can shed light onto the underlying pathophysiology and objective markers of psychotic illness. Keane’s research is transdisciplinary to its core, seeking to identify the mechanisms that make normal visual perception possible and that function differently during psychotic illness. He avails himself of tools in computational functional neuroimaging — which can provide fine-grained, second-by-second images of whole-brain activity — and behavioral psychophysics, which can precisely characterize the outward consequences of abnormal vision.

In the non-clinical arena, Keane’s lab is showing that the brain’s ability to integrate spatial information into completed shapes depends on a sparse but densely interconnected set of cortical regions that are strewn across five different brain networks. His clinical work has been showing that relatively subtle alterations to everyday visual experience are strongly associated with a variety of clinical variables such as age of illness onset, delusional ideation, auditory hallucinations, and depressed symptoms. Keane believes that assaying these visual disturbances, combined with other visual system assessment methods, could help identify individuals who are most at risk for a psychotic disorder.

“There is a ton of potential for understanding psychiatric disorders through investigating the neural basis of vision, the behavioral basis of vision, and the retinal basis of vision, particularly at the University of Rochester and the Medical Center — where research in the visual arena is well represented,” Keane said.

Keane is collaborating with a number of researchers including Silverstein to develop a new set of tools that combines behavioral measures, fMRInd retinal measures to provide markers for whether a person has or will develop a certain disorder.

Quickly moving from the bench to the clinic is a priority for researchers investigating this complex disorder. The research of John Foxe, Ph.D., director of the Del Monte Institute for Neuroscience, has shown the filtering of incoming visual information, and also of simple touch inputs, is severely compromised in individuals with the condition. The lab of Steve Goldman, M.D., Ph.D., director of Center for Translational Neuromedicine, is studying how support cells in the brain may contribute to schizophrenia. And assistant professor of Psychiatry David Dodell-Feder, Ph.D., recently published a study finding positive results for using real-time fMRI neurofeedback for treatment of psychiatric illness by targeting specific neural circuits known to contribute to psychopathology. These researchers are part of the large, multidisciplinary team in Rochester working to find answers and bring clinical applications to make a true difference for those suffering from this devastating disorder.