Brief Report: Pallidothalamic Tractotomy by Focused Ultrasound for Parkinson’s Disease

“Patience and fortitude conquer all things.” Ralph Waldo Emerson

“I know of no higher fortitude than stubborness in the face of overwhelming odds.” Louis Nizer

Overview: Recently, I reviewed a clinical trial involving ablation of the globus pallidus by focused ultrasound to treat Parkinson’s (click here to read this blog post). Some time ago, I was asked my opinion about using Focused Ultrasound Ablation (FUSA) on the pallidothalamic tract (PTT). Herein is an overview of FUSA-PTT.

“It is by surmounting difficulties, not by sinking under them that we discover our fortitude.” Hannah Webster Foster

Rationale: The FDA (in the USA) has approved the use of FUSA for treating tremor-dominant forms of Parkinson’s that have a therapeutic point of poorly responding to current therapy. A group of Neurologists genuinely believe that focused ultrasound can be used to achieve symptomatic relief of motor symptoms by ablating elements of the basal ganglia.

There is a long history of ablative neurosurgery on various basal ganglia regions. The basal ganglia can be considered the brain’s central processing unit for receiving, organizing, and implementing motor functions. The idea may sound somewhat brutal by ablating brain tissue, but chronic therapy-resistant Parkinson’s provides only a few options. Deep brain stimulation (DBS) surgery and FUSA are considered viable options.

The symptoms that can be relieved by FUSA are summarized in the following drawing by using focused ultrasound to ablate part of the basal ganglia:

A Simple Analogy: While it may only be early March, the past two weeks have seen temperatures average in the upper 70s-low 80s (^oF), and the central air conditioner (A/C) has been needed (mainly for reducing the humidity in the house). Until yesterday, it stopped altogether. At eleven years old, we hoped it last a few more years. The A/C repair person assessed the problem. Two solenoids in the outside cooling unit receive signals from the furnace and thermostat in the house. They were over-active, and bypassing them from the system restored cool air into the home. My simple A/C analogy has these hyperactive solenoids in the cooling unit represented by the thalamus, globus palllidus, subthalamic nucleus, or pallidothalamic tract. The A/C technician removing the hyperactive solenoids is like the neurosurgeon ablating brain tissue using focused ultrasound.

A feeble analogy, especially since my entire understanding of electrical circuits was in a college Physics Laboratory course. Hopefully, the metaphor of faulty solenoids being bypassed from the system to restore A/C airflow is vaguely similar to FUSA to ablate brain tissue to restore more normal-like motor function in Parkinson’s. Like in my A/C story above, bypassing the solenoids refreshes cool air, but the defect remains in the system. Likewise, ablating brain tissue by FUSA does not get to the cause of Parkinson’s. Instead, it reroutes disruptive signals to hopefully alleviate and restore a defective motor pathway.

A Conduit Named Pallidothalamic Tract (PTT): The PTT connects the globus pallidus internus and the ventrolateral portion of the thalamus. Ablation of the PTT is thought to be anti-Parkinson’s, especially relevant in chronic therapy-resistant Parkinson’s. The pioneers of the PTT reside in Switzerland. Aufenberg et al. (2005) and Magara et al. (2014) showed that focused ultrasound ablation of the PTT significantly improved tremors, dyskinesia, and akinesia. Furthermore, these patients had reduced levodopa equivalent daily dose (LEDD). More recently, Gallay et al. (2020) reported the results of fifty-one chronic-therapy-resistant Parkinson’s patients by FUSA of the PTT. The patients had an 88% mean tremor relief and 82% mean global symptom relief on the operated side, and 69% mean global improvement in the whole body.

Aufenberg, Christoph, Johannes Sarnthein, Anne Morel, Valentin Rousson, Marc Gallay, and Daniel Jeanmonod. “A revival of Spiegel’s campotomy: long term results of the stereotactic pallidothalamic tractotomy against the parkinsonian thalamocortical dysrhythmia.” Thalamus & Related Systems 3, no. 2 (2005): 121-132.

Magara, Anouk, Robert Bühler, David Moser, Milek Kowalski, Payam Pourtehrani, and Daniel Jeanmonod. “First experience with MR-guided focused ultrasound in the treatment of Parkinson’s disease.” Journal of therapeutic ultrasound 2, no. 1 (2014): 1-8.

Gallay, Marc N., David Moser, Franziska Rossi, Anouk E. Magara, Maja Strasser, Robert Bühler, Milek Kowalski et al. “MRgFUS pallidothalamic tractotomy for chronic therapy-resistant Parkinson’s disease in 51 consecutive patients: single center experience.” Frontiers in surgery (2020): 76.

One or Two? In the USA, focused ultrasound is approved to treat only one side of the brain; thus, the impact of surgery will affect only one side of the body. However, clinical trials are underway to treat patients on both sides of the brain (bilaterally). Several clinical trials are underway in the USA, Japan, and Europe to study the feasibility and safety of focused ultrasound to treat different symptoms of Parkinson’s. Some of these clinical trials will assess the FUSA of the PTT by comparing unilateral to bilateral pallidothalamic tractotomy.

In 2021, Gallay et al. reported a study with ten patients of bilateral FUSA of the PTT. They followed these patients for a year after receiving the second PTT. This is an interesting paper with an honest assessment of what worked and what did not work in these patients. I encourage you to read it thoroughly if you are interested in exploring FUSA-PTT for the treatment of chronic therapy-resistant Parkinson’s.

They start by stating that to justify brain surgery, in the framework of a lesioning procedure, this intervention should provide globally better results than drug therapy. Keep this point in mind. One year after bilateral PTT, the patients reported a high global symptom relief for both sides of the body. However, they found that axial symptoms were the most difficult to control. Axial symptoms are summarized in the drawing below (click here to read more from the source).

This study found that scoring for axial items, gait, and postural instability remained unchanged after 1-year bilateral FUSA of the PTT. Furthermore, scoring revealed a 58% worsening of speech [hypophonia (reduced speech intensity), tachyphemia (rapid speech, often having erratic rhythm and grammar and mixed with irrelevant words), and reduced speech initiation].

Please remember that this procedure does not alter disease progression; thus, one speculative conclusion is the possibility of disease progression unimpeded by the FUSA-PTT process. I like the following statement, and I want to quote the paper: “Gait is the key to independence and voice to communication, two essential psychosocial components of human life. The strength of the neurodegeneration concept imposed on PD patients and threatening their bodily and mental functions cannot be underrated. It can explain the modest improvements of emotionality and quality of life described by our patients in spite of very significant and multiple symptom reductions.” They concluded that a more extensive series of patient evaluations are needed to advance their hypothesis about FUSA of the PTT.

Gallay, Marc N., David Moser, Anouk E. Magara, Fabio Haufler, and Daniel Jeanmonod. “Bilateral MR-guided focused ultrasound pallidothalamic tractotomy for Parkinson’s disease with 1-year follow-up.” Frontiers in neurology (2021): 20.

The Next Step and Concluding Comments: As a biological chemist and person-with-Parkinson’s, I greatly ponder our situation and think about others further along in their disease progression.

It scares me to think I may need DBS or FUSA at some point in time when my medications have failed me. These last two blog posts make me pause and consider the future.

My calcitrant mind tells me to double my daily workout and start doing much more aerobic exercise (I remember those lab mouse studies where the rodents ‘ran off’ their chemically-induced Parkinson’s on a running wheel).

Alternatively, my even-keel mode tells me that over time, these surgical techniques (DBS vs. FUSA) will come full circle, and we will have a better choice of options for treating chronic therapy-resistant Parkinson’s.

My science-minded part has not given up on the brilliant group of folks studying the pathophysiology and signaling pathways that could one day lead to better therapeutic drugs to treat Parkinson’s.

And my enthusiastic mind still wants to remain positive and reinforce the current options and, hopefully, the new options coming soon.

In closing, I will continue to read and educate myself (and us) about the various options available as we approach chronic therapy-resistant Parkinson’s. Please remain active, hopeful, optimistic, persistent, and informed regardless of our current or future situation. As always, you are still you.

“The king-becoming graces,
As justice, verity, temp’rance, stableness,
Bounty, perseverance, mercy, lowliness,
Devotion, patience, courage, fortitude,
I have no relish of them, but abound
In the division of each several crime,
Acting in many ways.” William Shakespeare

Cover Photo Image by Joe from Pixabay