‘Ghost’ Test May Help Put Parkinson’s Hallucinations to Rest

Altered sensorimotor processing in the frontotemporal network appears to be responsible for hallucinations experienced by patients with Parkinson’s disease (PD), according to a novel study that uses a robotic method to provoke “presence hallucinations.”

Presence hallucinations occur in about half of patients with PD and are associated with poor cognitive outcomes and death.

Dr Fosco Bernasconi

“Despite the great clinical relevance of hallucinations in PD, the absence of objective measures, empirical techniques, and methods to measure and induce hallucinations has always made their investigation and diagnosis particularly challenging,” study investigator Fosco Bernasconi, PhD, Laboratory of Cognitive Neuroscience, Ecole Polytechnique Fédérale de Lausanne (EPFL), Geneva, Switzerland, told Medscape Medical News.

“Our robotic procedure provides the opportunity to investigate specific hallucinations in real time and in a fully controlled environment and conditions. We believe that our robotic procedure and method will be of great help for the diagnosis and prognosis of hallucinations and more severe forms of PD characterized by cognitive decline,” said Bernasconi.

The study was published online April 28 in Science Translational Medicine.

Robotic “Ghost” Test

In an earlier study, the researchers found that they could induce presence hallucinations in healthy individuals using a robotic procedure involving specific movements and somatosensory signals.

In the current study, they used the robotic procedure to induce presence hallucinations in 26 patients with PD. During the procedure, patients make repeated poking gestures, and a robotic arm imitates the poking gestures on the patient’s back.

When the human and robotic poking movements are synchronized, the brain successfully computes the spatial dissonance, and patients report nothing out of the ordinary. However, when the movements are out of synchrony, both healthy adults and patients with PD report presence hallucinations.

Patients with preexisting presence hallucinations are more sensitive to robotic stimulations than are their peers who have not previously had hallucinations, the researchers observed.

The success of the robotic “ghost” test helped researchers pinpoint the neural network responsible for presence hallucinations.

This “presence hallucination network,” as they call it, includes three regions in the frontotemporal cortex of the brain ― the inferior frontal gyrus, the ventral premotor cortex, and the posterior middle temporal gyrus.

The presence hallucination network was selectively disrupted in patients with PD and was predictive of the occurrence of symptomatic presence hallucinations and associated cognitive decline.

“Adapting the robotic device and procedure to the scanner allowed us to identify a brain network that is relevant for presence hallucinations in patients with Parkinson’s disease and that could potentially serve as a biomarker for more severe forms of the disease associated with hallucinations and cognitive deficits,” Eva Blondiaux, PhD student at EPFL and co–first author of the study, said in a news release.

Bernasconi hopes this technology will lead to new treatments for hallucinations in the near future.

“Such therapies could be based on a future version of the robotic method and device. Such work is ongoing. Early prediction of heightened hallucination sensitivity could also help physicians avoid certain treatments and may in the future also allow early interventions of other therapies,” he said.

The researchers are currently conducting a large clinical trial to confirm and extend their findings.

They also plan to use the robotic technology while performing MRI for patients with PD to capture in real time the neural activity associated with hallucinations as they occur, Bernasconi said.

“In parallel, we are adapting and improving our robotic technology and currently work on developing a fully wearable system,” he said.

“Noteworthy” Research

Reached for comment, James Beck, PhD, senior vice president and chief science officer with the Parkinson’s Foundation, said, “Being able to generate these hallucinations in a controlled fashion will help facilitate the development of medicines to potentially control these types of presence hallucinations and maybe hallucinations in general.”

The research also provides a basis for understanding the neural pathway for hallucinations, said Beck.

“Understanding that the neural connections are different in a person with Parkinson’s hallucinations, we can work around that to find medications, which, in this case, strengthen connections that are weakened, or just even address the symptom head on, in order to solve this problem,” he told Medscape Medical News.

“I see this being utilized for research and for clinical trials. I don’t see it, right now in its current form, as something that you’re going to see in routine use,” said Beck.

Also weighing in, Andrew D. Siderowf, MD, professor of neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, said the study is “noteworthy because the investigators used a novel experimental approach to provoke PH [presence hallucinations].

“The robotic paradigm is flexible and allows for testing of hypotheses of the relationship between sensory stimulation and PH and can be used in conjunction with structural brain imaging,” Siderowf told Medscape Medical News.

“This study points to a way to elicit PH in patients who may be susceptible but have not yet developed spontaneous hallucinations, either PH or VH [visual hallucinations]. This could be useful prognostic information, since hallucinations are both a negative outcome on their own and often co-occur with cognitive impairment/dementia,” Siderowf added.

He said this approach may also provide an efficient way to test drugs that could be used to treat hallucinations in exploratory-phase clinical trials.

“Drugs that work in this model could be carried forward in development to larger and more clinically oriented trials ― ie, effective blocking of induced hallucinations may predict blocking spontaneous hallucinations,” Siderowf said.

Also weighing in on this research, Prabitha Urwyler, PhD, University of Bern, Bern, Switzerland, said, “The approach of using robotics to investigate hallucinations in PD is new. However, they investigate only presence hallucinations, while the phenomenology of hallucinations in PD is complex.”

Urwyler also noted, “PD is a progressive disease that is different from person to person, and there are influences of medication on the PD hallucination too which can play a role. This paper may drive the research field into more quantitative measures.”

Funding for the study was provided by two donors and by grants from several noncommercial entities. Bernasconi has disclosed no relevant financial relaitonships. Three authors are inventors on patients related to this work, and two are cofounders and shareholders of Metaphysiks Engineering SA, a company that develops immersive technologies, including applications of the robotic induction of presence hallucinations. One author is a member of the board and shareholder of Mindmaze SA. Beck, Siderowf, and Urwyler have disclosed no relevant financial relationships.

Sci Transl Med. Published online April 28, 2021. Abstract

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