Stimulating the brain with ultrasound could help counter the delusions people experience in schizophrenia, a small trial finds.

The trial involved transcranial ultrasound stimulation, in which a device placed on a patient's head delivers ultrasound waves through the skull and into the brain. Its goal is to change the activity in a targeted brain region.

Delusions are false beliefs that are very difficult to shake; for example, a person might believe they are being stalked when they aren't or think that a major disaster is about to occur without any evidence to suggest so. In the trial, researchers found that a 10-minute session of the ultrasound treatment reduced the severity of delusions for at least a week in patients with schizophrenia or a related disorder.

This targeted ultrasound treatment delivered directly to the brain could avoid some of the full-body effects of antipsychotic medications, such as weight gain and high blood pressure. That said, the new results, published Tuesday (Oct. 20) in the journal npj Acoustics, are a first step and will need further verification in larger trials.

"It's too early to know for certain what the therapeutic benefits will be, but it's very exciting," study co-author Dr. Donald Goff, a professor of psychiatry at the New York University Grossman School of Medicine, told Live Science.

Targeting deep brain structures

The pilot study included 10 patients with either schizophrenia or schizoaffective disorder. In both conditions, patients experience psychotic symptoms, including delusions and hallucinations. Schizoaffective disorder also includes mood symptoms, such as mania.

The researchers interviewed each participant to characterize the content of their delusions, and also documented their cognitive state and experiences with auditory hallucinations — perceptions of sounds that aren't actually occurring. The participants then received both an ultrasound treatment and a placebo treatment, spaced one week apart.

Other noninvasive therapies — such as transcranial magnetic stimulation, which uses magnetic fields — can also stimulate the brain. But the ultrasound technique differs from these therapies because ultrasound waves can penetrate deeper into the brain with greater specificity, study co-author Shy Shoham, a neural engineer at NYU Grossman, told Live Science. He compared the way a transducer directs ultrasound waves toward a given brain region with the way a lens focuses light.

In this case, the researchers focused this lens on a brain network called the cortico-striatal-pallido-thalamic circuit, which includes structures underneath the brain's outer cortex. The relationship between this circuit and schizophrenia symptoms is still somewhat unclear, partly because its deeper components are hard to study in adequate resolution with MRI, said co-author Dr. Wei Qi, a clinical assistant professor of psychiatry at NYU Grossman. However, some past studies have suggested that this network plays a part in schizophrenia.

Much of what scientists know about the network comes from research in movement disorders, such as Parkinson's disease, in which there is an imbalance between excitation and inhibition in the neurons that control movement. A similar dynamic could help to explain symptoms of schizophrenia, the scientists think.

"Our hypothesis is that, in schizophrenia, there is an imbalance between excitation and inhibition regarding what in the environment is actually important," Qi told Live Science. "The failure to inhibit irrelevant signals could be the basis of psychosis."

"Quite optimistic"

The researchers surveyed the study participants after each treatment, asking about the degree of belief each person had in their delusions and the amount of stress they caused. Compared with the placebo treatment, the ultrasound stimulation was associated with less-severe delusions over the following week. There was no significant change in patients' auditory hallucinations or overall cognition, though.

The ultrasound therapy came with mild side effects, such as fatigue and headache. Some patients had transient increases in delusions, which Qi attributed to normal fluctuations in symptoms that are expected in schizophrenia. These outcomes were just as common after the placebo treatment, so they may not be related to the ultrasound specifically.

The stimulation was aimed specifically at the right side of a brain structure called the globus pallidus internus (GPI). In a previous study, the authors found that greater connectivity between this region and another structure — the dorsal anterior cingulate gyrus — was linked to more-severe psychotic symptoms in schizophrenia. So, they made the GPI their target.

To date, "there haven't been many successful therapeutic attempts at targeting some of these deeper structures," said Dr. Deepak Sarpal, an associate professor of psychiatry at the University of Pittsburgh School of Medicine who was not involved with the study. Ultrasound waves reach brain regions under the cortex in a less-invasive manner than deep brain stimulation, in which a surgeon implants an electrode in a patient's brain, Sarpal noted.

The researchers are not the only group using transcranial ultrasound to influence the cortico-striatal-pallido-thalamic circuit. Earlier this year, another group stimulated portions of the striatum, which is located directly under the cortex, in patients with schizophrenia. They evaluated hallucinations rather than delusions, finding that the treatment reduced symptoms for at least a week after the procedure.

In this line of research, the targeted nature of transcranial ultrasound presents advantages as a research tool as well as a treatment approach.

"If we find that a specific circuit or a node in a circuit seems to be closely linked to symptoms we're trying to treat, then it will be a matter of understanding what pattern of stimulation may allow us to correct that," Goff said. Qi, Goff and colleagues now plan to continue testing their technique on more patients and to experiment with different doses of ultrasound.

"A lot more work needs to be done," Goff said, "but we're really quite optimistic about its promise."

This article is for informational purposes only and is not meant to offer medical advice.

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The patient: A 16-year-old girl in California

The symptoms: The teenager was referred to an emergency department because she was having hallucinations, including seeing a flying green dinosaur and hearing voices telling her to hurt others. She also had a sense that she was being followed.

In the emergency room, she was trembling and sweating and had a racing pulse and shallow, fast breathing. She did not have a fever, although she did have one at the hospital that had referred her.

During her conversations with ER clinicians, the teen reacted to the vision of the dinosaur as though the creature were present in the room. She reported that she had experienced these hallucinations since seventh grade,‬ so for about four years.

While her parents countered that she hadn’t exhibited psychotic symptoms until 48 hours before they arrived in the ER, they noted that her interest in school and extracurriculars had waned over the past month.

What happened next: Because of the patient's abnormal vital signs, the ER doctors suspected that her hallucinations might be secondary to some physical ailment, such as trauma to the brain, they wrote in a case report. However, a CT scan showed no signs of swelling or hemorrhage in her head. The doctors attempted a lumbar puncture (also called a spinal tap) but failed to collect any cerebrospinal fluid that they could test for irregularities.

The doctors judged the girl to be too medically unstable to be referred to the hospital's psychiatric ward, so she was admitted to the general pediatric department. Pediatric neurologists suggested an electroencephalogram (EEG), a test that measures electric signaling in the brain, but this revealed no further clues.

On her second day in the hospital, the girl entered a complete catatonic state. Her specific symptoms were not described in the report, but in general, catatonia disrupts how a person processes and reacts to the world around them. Catatonic patients often stop moving and speaking. Doctors treated the patient with lorazepam, which slows down nervous-system signaling, and her catatonia subsided in days.

Meanwhile, interventional radiologists performed a successful second lumbar puncture, but the girl's cerebrospinal fluid appeared normal in the initial panels they ran.

After the patient had spent eight days in the hospital, psychiatrists recommended that the girl be transferred to their ward. However, this was not possible because she developed problems with feeding herself. Her continued psychotic symptoms were treated with the antipsychotic drug olanzapine.

The diagnosis: While initial tests of the girl's cerebrospinal fluid did not show signs of meningitis or other abnormalities, a later test came back positive for autoantibodies — immune proteins that target healthy tissues instead of foreign invaders. These antibodies targeted neuronal intermediate filament (NIF), a protein that helps give nerve cells structural support.

Based on this finding, the patient was diagnosed with autoimmune encephalitis, a condition in which the body produces antibodies that attack nervous tissue, leading to harmful inflammation that can cause psychiatric symptoms.

Autoimmune encephalitis is often triggered by a tumor; proteins produced by the growth can resemble proteins within nervous tissue, and the immune system develops a harmful response against the latter while attempting to fight the tumor. The doctors performed MRIs and a PET scan to look for tumors, but they did not find any.

The treatment: The girl received intravenous infusions of a steroid to reduce inflammation, as well as immunoglobulin — antibodies from healthy donors that are often used to calm autoimmune reactions. She also got an infusion of rituximab, a drug that kills B lymphocytes, a type of white blood cell that makes antibodies like the ones attacking the girl's neurons.

In addition to these infusions, the girl underwent five sessions of plasmapheresis over the next month. In that procedure, blood is drawn from the body, a machine separates plasma (the liquid portion of blood) from blood cells, and the extracted plasma is substituted with a replacement fluid before that blood is returned to the patient. This treatment can help rid the body of autoantibodies.

The girl was discharged after having spent almost two months in the hospital. She was treated with ongoing prescriptions of olanzapine and lorazepam, as well as prednisone and monthly immunoglobulin treatments. As her symptoms improved over the following year, she stopped taking the psychiatric drugs but continued her immunotherapy.

What makes the case unique: Autoimmune encephalitis is rare. One study conducted in the U.K. suggests it affects only 5 to 8 out of every 100,000 people. Additionally, most data about the condition in pediatric patients comes from cases caused by autoantibodies that target NMDA receptors, which detect a key chemical messenger in the brain, rather than NIF.

The case report did not name a specific trigger for the girl's condition, but the authors noted that anti-NIF autoimmune encephalitis has been documented in adults following infections, including certain tick-borne bacterial infections, HIV and COVID-19. Cases associated with these infections are rarer than those linked to tumors.

The doctors did not attribute the teen's case to a specific infection, but her family did report that she'd had a cough three weeks before going to the emergency room. The family had visited the Philippines, and the girl and multiple relatives came down with the same illness.

For more intriguing medical cases, check out our Diagnostic Dilemma archives.

This article is for informational purposes only and is not meant to offer medical advice.

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