Summary: Using transcranial magnetic stimulation, researchers have successfully restored network function between the prefrontal cortex and cerebellum, helping to improve symptoms in those with treatment resistant schizophrenia.
Schizophrenia is a chronic and disabling mental illness that affects more than three million Americans. Anti-psychotic medication can control schizophrenia’s psychotic symptoms, including the hallucinations and delusions that are well-known hallmarks of the disease. However, there are no effective treatments for the disease’s ‘negative symptoms’ – so-called because they involve a loss of normal function. The negative symptoms of schizophrenia include an inability to feel pleasure, a lack of motivation and difficulty with non-verbal communication. These symptoms can seriously impact patients’ employment prospects, housing, relationships and overall quality of life.
In a first-of-its-kind study, researchers at Beth Israel Deaconess Medical Center (BIDMC) used imaging data to determine the underlying anatomical cause of schizophrenia’s negative symptoms and then applied non-invasive brain stimulation to ameliorate them. The scientists found, as they reported today in the American Journal of Psychiatry, that these symptoms arise from a breakdown in a network between the brain’s prefrontal cortex and the cerebellum. Moreover, the team demonstrated that a novel type of non-invasive brain stimulation restored this crucial network’s function, which in turn improved schizophrenia’s most debilitating and treatment resistant symptoms in patients with the disease.
“There’s an enormous body of research asking how people with schizophrenia are different from people without it, but there is scant literature using imaging in people with schizophrenia to pin down the biological differences between those who are very symptomatic and those who are less so,” said lead author Roscoe Brady Jr., MD, PhD, assistant professor of psychiatry at BIDMC. “If we can pin down what’s different, maybe we can intervene.”
In stage one of this two-pronged study, Brady and colleagues examined functional magnetic resonance imaging (fMRI) scans of 44 patients with schizophrenia. Their analysis revealed that a breakdown in the neural connectivity between the prefrontal cortex and cerebellum was linked to more severe negative symptoms. (The network in question was not associated with hallucinations or delusions.)
“We wanted to find out if we could restore that brain circuit through non-invasive brain stimulation, and if we could, would people get better?” said corresponding author Mark Halko, PhD, assistant professor of neurology at BIDMC’s Berenson-Allen Center for Non-Invasive Brain Stimulation. “The answer is they absolutely do get better. It’s a very provocative finding.”
Halko, an expert in non-invasive brain stimulation, focuses on using the technology – which modifies brain activity using powerful magnetic fields – to relieve symptoms of anxiety, depression and other mental illnesses. In 2012, Halko was principal investigator on a clinical trial testing whether non-invasive brain stimulation could improve symptoms in patients with schizophrenia. But without a known circuit to explain treatment response, the study raised more questions than it answered. Then a mutual colleague introduced Brady and Halko. “When we started looking at our data sets together, we came to the conclusion that if Dr. Brady’s work could identify the networks that are responsible for these symptoms of the illness, then the brain modulation we’ve been doing could change that exact network,” Halko said. To test that idea, the researchers recruited patients diagnosed with schizophrenia, quantified and scored their negative symptom severity and conducted baseline brain imaging. Next, Halko and colleagues administered either active non-invasive brain stimulation or a sham (placebo) treatment as a control. Participants received two brain stimulation sessions per day, four hours apart, for five consecutive days.
Follow-up brain scans and clinical evaluation revealed that patients with schizophrenia who experience increased connectivity between the brain’s prefrontal cortex and cerebellum after brain stimulation also experienced a reduction in symptom severity.
“For some people with schizophrenia, the non-invasive brain stimulation had a powerful impact; for others, it wasn’t as powerful,” said Brady. “In all cases, re-connecting the network explained how much improvement the patient experienced. For the first time, we know what brain circuit to go after.”
n addition to Brady and Halko, co-investigators included Ivy Lee, Larry J. Seidman, PhD, Matcheri S. Keshavan, MD, and Alvaro Pascual-Leone, MD, PhD, of Beth Israel Deaconess Medical Center; Dost Öngür, MD, PhD, of McLean Hospital; Irene Gonsalvez, MD, of St. Elizabeth’s Medical Center; Jeremy D. Schmahmann, MD, of Massachusetts General Hospital; Shaun M. Eack, PhD, of University of Pittsburgh.
Funding: This work was supported in part by awards from the National Institutes of Health, including the National Institute of Mental Health, the National Center for Research Resources, and the National Center for the Advancement of Translational Science (NIMH K23 MH100623; R01 MH111868; R01 MH092440; K24 MH104449; UL1 RR025758). Additional partial support was provided by Sidney R. Baer Jr. Foundation; MINDlink Foundation; Harvard Catalyst; and The Harvard Clinical and Translational Science Center.
The team discloses that Dost Öngür served on the scientific advisory board for Neurocrine, Inc, in 2016; Pascual-Leone serves on the scientific boards for Nexstim, Neuronix, Starlab Neuroscience, Neuroelectrics and Neosync and is listed as an inventor of several issued and pending patents on the real-time integration of transcranial magnetic stimulation with EEC and MRI; Schmahmann serves on the scientific advisory board for Cadent, consults with Biogen, Biohaven and Pfizer, and holds the license with the General Hospital Corporation to the Brief Ataxia Rating Scale and the Cerebellar Cognitive Affective / Schmahmann Syndrome Scale.
Source: Jacqueline Mitchell – BIDMC
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Abstract for “Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophreniay” by Roscoe O. Brady Jr., M.D., Ph.D., Irene Gonsalvez , M.D., Ivy Lee , B.S., Dost Öngür , M.D., Ph.D., Larry J. Seidman , Ph.D., Jeremy D. Schmahmann , M.D., Shaun M. Eack , Ph.D., Matcheri S. Keshavan , M.D., Alvaro Pascual-Leone , M.D., Ph.D., and Mark A. Halko, Ph.D. in American Journal of Psychiatry. Published January 30 2019.
Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia
The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine whether behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms.
In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline.
A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change.
These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.