Focused Ultrasound for the Treatment of Parkinson’s Disease

Post by Natalia Ladyka-Wojcik

A primer on motor symptoms in Parkinson’s disease

Parkinson’s disease (PD) is a complex neurodegenerative disorder that affects over 10 million people globally, typically in individuals aged 60 years or older. PD affects a central brain area called the basal ganglia, leading to a range of motor, cognitive, and sleep changes. A particularly affected region of the basal ganglia is a crescent-shaped cell mass in the brain stem called the substantia nigra. The neurons in this tiny region produce the neurotransmitter dopamine and play a big role in planning and controlling body movement. In PD, these neurons begin to die off and hallmark motor symptoms of PD such as tremor, rigidity, and slowness of movement tend to emerge when about 80% of dopamine is lost.

Dopamine is critical for stimulating receptors in one of the basal ganglia called the striatum, which works with the substantia nigra to send signals between the spinal cord and the brain. If striatum receptors aren’t sufficiently stimulated, other portions of the basal ganglia may also be over- or under-stimulated: the hallmark tremors associated with PD result from overstimulation whereas rigidity and slowness of movement result from understimulation. Perhaps unsurprisingly, patients with PD report that the severity and frequency of these symptoms significantly decrease their quality of life, highlighting the importance of targeted treatment for these symptoms.

Current challenges in treating Parkinson’s disease symptoms

Traditionally, PD treatments have largely relied on medications, which aim to either preserve dopamine in the brain by preventing its breakdown, increase dopamine release, or mimic dopamine altogether. Although clinical research has made great strides in developing effective medications for PD, these medications tend to work better in the early stages of the disease. Moreover, some of these medications can cause unwanted side effects, including hallucinations, nausea, depression, and even obsessive behavior. Given these considerations, research has turned to exciting new avenues for treating PD by leveraging advanced therapeutic technologies. Here, we’ll survey two major technologies to better understand the future of PD treatment: (1) deep brain stimulation, and (2) focused ultrasound.

Deep brain stimulation for Parkinson’s disease

Deep brain stimulation (DBS) is a surgical therapy that addresses the movement symptoms of PD but can also help improve other non-motor symptoms including changes in sleep. In the U.S., it is approved by the Food and Drug Administration and is especially effective in individuals with severe tremors. In DBS surgery, electrodes are inserted into the basal ganglia and then a pacemaker-like implant is placed either under the collarbone or in the abdomen. This implant delivers electrical neurostimulation to the basal ganglia which the patient controls with a remote. On average, DBS patients with optimal drug therapy require lower medication doses compared to a control group receiving only optimal drug therapy. Importantly, DBS patients also show slowed progression of tremor symptoms. The future of DBS as a therapy for PD holds much promise, with larger randomized control studies to investigate DBS efficacy underway by the Food and Drug Administration.

Focused ultrasound: A cutting-edge therapy for Parkinson’s tremors

When imagining what neurosurgery is like, you might visualize the surgical incisions needed for neurosurgeons to access the brain. However, focused ultrasound therapy is a new noninvasive approach: beams of ultrasonic energy are used to precisely and accurately target deep brain structures with thermal lesions without damaging surrounding healthy tissue. This technique massively reduces risks of infection or brain bleeding compared to traditional surgery and does not require any external implants to be placed in the patient’s body. Neurosurgeons typically use magnetic resonance imaging (MRI) to guide the ultrasound beams to the desired location in the patient’s brain, ensuring that thermal lesions are done accurately. On average, patients show marked improvements in motor symptoms of PD, especially tremor, although some negative side effects have been reported. In the future, some scientists hope that focused ultrasound technology can even be used to disrupt the blood-brain barrier, a selective semi-permeable membrane that defends the brain from external substances and can sometimes prevent medication from successfully reaching the brain. This means that in addition to directly manipulating dysfunctional brain signaling, focused ultrasound may also help PD medications be even more effective.

What’s the bottom line?

Every year 90,000 people are diagnosed with PD in the United States alone, and it is the second-most common neurodegenerative disease after Alzheimer’s dementia. PD is associated with progressive symptoms, especially related to motor skills, which are managed by available medications only to a certain degree of efficacy. New technologies, including DBS and focused ultrasound, provide exciting new avenues for the treatment of PD.

References +

Hacker, M. L., Turchan, M., Heusinkveld, L. E., Currie, A. D., Millan, S. H., Molinari, A. L., Konrad, P. E., Davis, T. L., Phibbs, F. T., Hedera, P., Cannard, K. R., Wang, L., & Charles, D. (2020). Deep brain stimulation in early-stage Parkinson disease. Neurology, 95(4), e393–e401.

Moosa, S., Martínez‐Fernández, R., Elias, W. J., Del Alamo, M., Eisenberg, H. M., & Fishman, P. S. (2019). The role of high‐intensity focused ultrasound as a symptomatic treatment for Parkinson's disease. Movement Disorders, 34(9), 1243-1251.

Rahman, S., Griffin, H. J., Quinn, N. P., & Jahanshahi, M. (2008). Quality of life in Parkinson’s disease: The relative importance of the symptoms. Movement Disorders, 23(10), 1428–1434.

Whitney, C. M. (2007). Medications for Parkinsonʼs Disease. The Neurologist, 13(6), 387–388.

How Transplanting Microglia Could Fight Age-Related Disease

Post by Anastasia Sares

The takeaway

Microglia are an important type of support cell in the brain. While mice brains without microglia can develop normally, they become severely compromised in old age. Restoring microglia can help prevent these age-related diseases in mice, paving the way for similar therapies in humans.

What's the science?

When it comes to neuroscience research, neurons are often the stars of the show. However, the brain has essential supporting actors. Cells like microglia and oligodendrocytes have a variety of roles, like aiding neuronal growth and signaling. Without the aid of these cells, neurons couldn’t do what they do. For example, microglia prune and sometimes devour other cells if they’re not pulling their weight, while oligodendrocytes wrap around the axons of neurons like the plastic around a power cord, insulating them and making the signal travel faster. They are important to the integrity of the white matter in the brain, where information is transported across long distances between different parts of the cortex. However, we still don’t fully understand the importance of these supporting cells. For example, even without the genes needed for functional microglia, some mice seem to grow and develop normally. So, what’s going on here?

This week in Neuron, Munro and colleagues showed that while mice can develop normally without microglia, their brain health takes a sharp turn for the worse in old age. However, these effects can be reversed by transplanting microglia into the brains of mice without them.

How did they do it?

This study focused on genetically modified mice that lacked a specific portion of a gene (Csf1r) that is important for microglia to form. These mice have fairly normal development, with normal levels of most other brain cells and normal performance on behavioral tests. The authors used a technique called RNA sequencing to understand how cells acted differently without microglia present. RNA is a messenger molecule carrying instructions from a cell’s DNA, a crucial step in determining which genes get made into proteins in a given cell. Different cells need different kinds of proteins depending on their function, and the cells' needs can change over time. By seeing what kinds of RNA are around in a cell, researchers can tell if the cell is functioning normally or not.

The authors collected cells from the brains of these mice and tracked RNA expression in young, adult, and elderly mice with and without their microglia to see how this expression changed as the mice were aging. They also performed other tests on the mouse brains, including scanning them with high-resolution magnetic resonance imaging (MRI), so they could detect overall changes in brain structure.

Finally, the researchers tried an intervention: they transplanted microglia into the brains of the mice who couldn’t produce them. They tracked these mice in the same way as the other two groups.

What did they find?

In young mice who were missing their microglia, the RNA profiles of most other brain cells looked normal. One exception was the oligodendrocytes, which had subtle signs of abnormal activity.

As the mice lacking microglia aged, they had increasing neurological health problems. The oligodendrocyte’s RNA profiles became even more abnormal, and other cells started showing signs of stress, producing RNA related to injury, infection, and disease. The decline could also be seen in MRI, with white matter degrading faster over time in the mice without microglia. MRI measures showed that blood flow to the thalamus was particularly affected, and the authors discovered large calcium deposits in the thalamic brain regions of these aged mice. This means that microglia play an important role in maintaining the brain’s white matter and blood flow in old age, especially in the thalamus. Interestingly, when mice without microglia received transplanted ones, they aged normally.

What's the impact?

This study shows that while microglia might not be crucial for brain development (at least in mice), they are important for helping maintain continued functioning in old age. The recovery of mice who received microglia transplants is exciting because similar therapies could be developed for humans with microglial abnormalities, potentially preventing age-related degeneration and increasing longevity and quality of life.

Access the original scientific publication here.

How Are Chronic Pain and Depression Related?

Post by Laura Maile

What is chronic pain?

Pain is a necessary part of life. It helps us learn what is dangerous and how to avoid things that will cause injury to our bodies. In many instances, however, the acute pain that alarms us to a potential threat to our physical safety can outlast both the source of the harm and our physical recovery from the initial injury. When this happens and the pain lasts more than three months, it is called “chronic.” Chronic pain, which is endured by 100 million people in the US alone, is a burden that causes daily suffering, reduces quality of life, often leads to loss of work, and negatively impacts mental health.  

Normally, when an injury or environmental stimulus causes us pain, something has caused physical damage, like burning a finger on a hot stove or surgery to repair a broken arm. In these situations, nociceptors (a type of neuron), receive signals of that damage in the part of the body that is hurt and relay those messages to the spinal cord and then the brain, where those signals are often interpreted as pain. In many instances of chronic pain, there is no apparent ongoing damage in the parts of the body where pain is felt. Pain, therefore, exists in the brain, not in the body. It is now understood that chronic pain can be a symptom of disease, such as cancer-related pain and chronic headache, or it can be a disease in its own right, which is seen in conditions like fibromyalgia.  

How are pain and mood disorders related?

Chronic pain and mood disorders like depression occur frequently in the same patients and tend to exaggerate the symptoms of one another. Studies indicate that if you have major depressive disorder (MDD), you are three times as likely to develop chronic pain. According to the World Health Organization, if you have persistent pain you are four times as likely to have a mood disorder like anxiety or depression. In addition to their frequent co-occurrence, the severity of symptoms also plays a role. In one study of older adults with chronic pain, both the number of body parts affected and the frequency and severity of pain were associated with a higher incidence of depression. In another study where patients were followed for 12 months, a change in the severity of depression symptoms strongly predicted an increase in the severity of reported pain. Chronic pain, understandably, can lead to feelings of loneliness, despair, and anxiety. Symptoms caused by pain, such as loss of sleep, can exacerbate those feelings, many of which overlap with symptoms of depression. It may therefore seem logical that individuals with chronic pain are more likely to develop mood disorders like depression. Why though, are people with depression more likely to develop chronic pain? 

Neurobiology of chronic pain and depression

Both chronic pain and depression have been studied for decades in humans and animal models. Pain researchers have uncovered a set of brain regions involved in pain processing, often called the pain matrix. These include areas of the medial prefrontal cortex (mPFC), anterior cingulate cortex, the somatosensory region of the parietal cortex, insula, amygdala, thalamus, nucleus accumbens, and areas of the midbrain including the periaqueductal gray. Importantly, these regions do not exclusively process pain but are important for various other functions including emotional regulation, motivation, memory, and cognition. Some regions of the pain matrix, like the mPFC, insula, and amygdala, are more significantly involved with the affective emotional component of pain that causes suffering, rather than other elements like location and intensity. These regions are also important in processing emotion and analyzing the contextual and emotional significance of relevant stimuli to help drive behavior.  When patients with acute pain transition to chronic pain, reorganization occurs in the brain that shifts activity patterns, often increasing the activity in the emotion regulation areas. This may help explain why chronic pain often coincides with mood disorders, which are associated with changes in some of the same brain regions. Additional changes in gray matter volume, neural activity, or connectivity occur in overlapping regions of the brain in both depression and chronic pain. For example, both animals and patients with chronic pain show a decrease in both activity and volume of the mPFC. This is similar to observations made in both depressed patients and animal models of depression. 

What’s the treatment for depression and chronic pain?

While drugs like opioids have had success in treating intense pain associated with surgery or traumatic injury, they are insufficient in the treatment of chronic pain and come with dangerous side effects like addiction that have influenced the ongoing opioid epidemic. While a few drugs can offer some help with ongoing symptoms, many chronic pain patients find little to no relief from current drug options. There is therefore an urgent need for more effective treatments for ongoing pain. Treatments for depression and chronic pain often overlap. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) are often prescribed, with positive effects, in the treatment of both depression and pain. Ketamine, a drug known to be effective in treating acute post-operative pain, shows promise in treating major depressive disorder, with documented improvement of symptoms in treatment-resistant patients. Though its positive effects on depression symptoms occur more quickly than traditional SSRIs, ketamine administration must be repeated often, and it comes with negative side effects, including the potential for abuse. It also shows limited efficacy in treating chronic pain. In addition to drugs, there are also alternative treatments such as psychotherapy and cognitive behavioral therapy (CBT) that offer assistance for those struggling with mood disorders and chronic pain. Though not a complete replacement for drugs or other treatments, evidence suggests CBT can improve symptoms of ongoing pain in some patients. Similarly, CBT and other forms of psychotherapy can lead to the improvement of symptoms in patients with MDD or anxiety disorders, though some reports indicate these effects may be overestimated in many publications. 

What does the future look like?

Despite the dual nature of these diseases, the neurological basis for the overlap in chronic pain and mood disorders is still unclear. Research is ongoing at both the basic and clinical levels, to better understand the neural biology of both diseases and how they may impact one another, and to develop better treatments that target both diseases. Recent research into psychedelics is quickly changing our understanding of ways major depression, post-traumatic stress disorder, and chronic pain, may be successfully treated.  Clinical trials are ongoing, but evidence suggests that psychedelics such as lysergic acid diethylamide (LSD) and psilocybin may be effective in treating both intractable mood disorders and chronic pain conditions such as migraine. These drugs also may represent future positive alternatives to drugs associated with abuse like opioids. 

Pain and mood disorders, though distinct, overlap in the brain areas affected. These debilitating disorders are a huge cost to human health and wellbeing, making the continued advancement of both basic and clinical research into the neuroscience of these diseases and novel treatment options essential.

References +

Bair MJ et al. Depression and pain comorbidity: a literature review. 2003. JAMA Internal Medicine.

Treede RD et al. Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). 2019. Pain.

Sheng J et al. The link between depression and chronic pain: neural mechanisms in the brain. 2017. Neural Plasticity.

Lépine JP, Briley M. The epidemiology of pain in depression. 2004. Hum Psychopharmacol.

Denkinger MD et al. Multisite pain, pain frequency and pain severity are associated with depression in older adults: results from the ActiFE Ulm study. 2014. Age and Ageing.

Yavi M et al. Ketamine treatment for depression: a review. 2022. Discov Ment Health. Access the original publication here.

Jonkman K et al. Ketamine for pain. 2017. Faculty Rev.

Kooijman NI et al. Are psychedelics the answer to chronic pain: A review of current literature.

Hajihasani A et al. The Influence of Cognitive Behavioral Therapy on Pain, Quality of Life, and Depression in Patients Receiving Physical Therapy for Chronic Low Back Pain: A Systematic Review.

Cuijpers P et al. How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta-analytic update of the evidence. 2016. World Psychiatry.