Aerobic Exercise Mitigates the Severity of Motor Symptoms in Parkinson’s Disease

Post by Shireen Parimoo

What's the science?

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises from the loss of dopamine neurons in the substantia nigra, resulting in motor symptoms like bradykinesia (slow movement), impaired posture, and resting tremors. Patients are typically treated with medications that increase dopamine levels in the brain or mimic the effects of dopamine, such as Levodopa or dopamine agonists, respectively. Although these medications help to reduce motor symptoms, they are often not as effective in the long-term. Previous studies linked exercise to an improvement in motor symptoms among PD patients; for example, a recent treadmill study showed attenuation of motor symptoms after aerobic exercise in unmedicated PD patients. However, few studies have investigated the long-term effects of aerobic exercise in PD patients, particularly in those who regularly take medication to treat symptoms. This week in The Lancet Neurology, van der Kolk and colleagues examined the impact of aerobic exercise on the severity of motor symptoms over a six-month period in patients with Parkinson’s disease.

How did they do it?

One hundred and thirty patients with mild PD participated in a double-blind, randomized controlled trial. Patients were randomly assigned to an aerobic exercise treatment group or an active control stretching group for six months. In the treatment group, participants exercised on a stationary cycle for 30-45 minutes at least three times a week, whereas the control group performed stretching and flexibility exercises for 30 minutes three days a week. Participants completed these exercises at home using a tablet-based application, and the stationary cycle included virtual reality software with videos to make the exercises more engaging. The groups were randomized based on sex and medication status, and the trial was double-blind. The authors assessed the following measures at the beginning of the study (baseline) and after six months: (i) severity of motor symptoms using the motor section of the Movement Disorders Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), (ii) other motor symptoms such as frequency of falls and finger-tapping performance, (iii) non-motor symptoms like sleep and depression, and (iv) cardiovascular fitness. Importantly, to rule out acute effects of medication on these outcomes, these symptoms were assessed during the off-state when at least 12 hours had passed since patients had taken their medication. On the MDS-UPDRS, a higher score is associated with more severe symptoms, thus, a bigger difference in scores after treatment suggests a worsening of symptoms. To determine if aerobic exercise improved the severity of motor symptoms, the authors compared the change in MDS-UPDRS scores after six months between the two groups.

What did they find?

There were no differences in baseline measures across the treatment and control groups. After six months, the score for motor symptoms on the MDS-UPDRS increased by 1.3 points in the treatment group but by 5.6 points in the control group. In other words, the motor symptoms became more severe in the control group after six months than in the treatment group. This difference of 4.2 points between the two groups is clinically relevant (>3.5 points), and provides support for the effectiveness of aerobic exercise in mitigating motor symptoms in PD. Cardiovascular fitness also increased in the treatment group but decreased in the control group. Interestingly, the severity of motor symptoms evaluated during the on-state (within 12 hours of taking medication) as well as other motor symptoms like the frequency of falls and finger-tapping performance did not differ across the two groups after the trial. Moreover, patients who exercised did not differ from those in the control group in non-motor symptoms. Thus, the specific effect of exercise during patients’ off-state indicates it can be a promising complementary treatment approach to medication in alleviating the severity of motor symptoms in PD.

What's the impact?

This study is the first to demonstrate that consistent aerobic exercise can attenuate the progression of motor symptoms in patients with PD. These findings have important implications for the treatment approaches available to PD patients and open the door for future research to investigate the longer-term impact of exercise on both motor and non-motor symptoms.

Van der Kolk et al. Effectiveness of home-based and remotely supervised aerobic exercise in Parkinson’s disease: a double-bind randomised controlled trial. The Lancet Neurology (2019). Access the original scientific publication here.

Communication Between Brain Regions During Working Memory

Post by Lincoln Tracy

What's the science?

Working memory refers to the temporary storage and manipulation of information. There is a wide-ranging network throughout our brain involving frontal and parietal regions that are responsible for working memory tasks. However, it is not known how the parietal brain regions can communicate with distant prefrontal brain regions (involved in cognitive control) in situations where a high level of cognitive function is required. Evidence from animal studies suggests that theta oscillations from the hippocampus—a pattern where neurons fire between five and 12 times per second—may play a role in working memory. This week in Nature Communications, Berger and colleagues explored the role of theta oscillations in the coordination of neuronal activity in remote brain areas in humans.

How did they do it?

The authors recruited 71 healthy volunteers (41 women) across four experiments to participate in a visual delayed match to sample task while wearing an electroencephalography (EEG) cap to record activity across different brain regions. For each trial of the task the volunteers were presented with a pattern of either one or four squares on a 6 x 6 grid on a computer screen for half a second. If the pattern was green the volunteers had to remember the pattern exactly as it was (retention). However, if the pattern was red, they had to remember a mirror image of the pattern (manipulation). After a two-second interval, the volunteers were presented with a second pattern and were required to indicate if the new pattern was the same as the previous one. First, the authors investigated how the accuracy of the task and frontal-midline theta activity varied according to trial complexity. The authors then investigated how the phase of the frontal-midline theta activity was related to fast rhythmic brain activity (an indicator of increased neuronal activity and information processing) in remote cortical areas. Finally, the authors used transcranial magnetic stimulation (TMS) during the interval between the presentation of the two patterns to examine the impact of disrupting fast rhythmic brain activity.

What did they find?

First, the authors found that the volunteers were more accurate when they only had to retain a less complicated pattern (i.e., a one-square pattern) compared to mentally manipulating a more complex pattern (i.e. the four-square pattern). Theta activity in frontal-midline brain region increased during trials involving the more complex pattern, regardless of whether participants had to remember or manipulate it. Second, they found that stronger gamma amplitude modulation by the frontal-midline theta phase occurred only in the right temporo-parietal brain region. They also found that the relationship between the frontal-midline theta phase and the gamma amplitude modulation in the right temporo-parietal region varied according to trial complexity. That is, as the trial became more complex, coupling with the gamma amplitude occurred during the trough of the theta cycle, as opposed to the peak of the theta cycle in the earliest condition. Finally, they found that the timing of the TMS pulse and the phase of the frontal midline brain region theta activity changed task performance. That is, TMS applied over the right temporo-parietal region just prior to the trough of the frontal-midline brain region theta activity resulted in poorer task performance. This finding was confirmed and replicated in the final two experiments.

What's the impact?

These findings suggest that the varying phases of the frontal-midline theta activity create windows in which wide-ranging neuronal activity can be synchronized during cognitively demanding tasks. In particular, these findings show that high-frequency EEG activity in the right temporo-parietal region is nested into frontal-midline theta activity and that the alignment of this nesting depends on the amount of cognitive focus when completing a working memory task. These findings highlight the importance of the coordination between brain oscillatory phases and neuronal firing on a wide scale. It is possible that the neural mechanisms identified in this study could serve as a general principle of how the brain coordinates parallel processes and dynamically allocates resources towards cognitively demanding tasks. Further research is required to determine if the proposed neural mechanism also exists for other frequencies and brain structures. 

Berger et al. Dynamic regulation of interregional cortical communication by slow brain oscillations during working memory. Nature Communications (2019). Access the original scientific publication here. 

Cancer Cells Form Pseudo-Synapses with Neurons To Promote Brain Metastasis

Post by Stephanie Williams 

What's the science?

Cancer cells in solid breast tumors commonly seed cells in the brain and acquire the ability to metastasize (grow in an organ distant from the original tumor). Breast-to-brain metastasis is well characterized, but it is not known why this particular form of metastasis is common. Previous research has identified a signaling pathway that may be involved - a type of glutamate receptor called N-methyl-D-aspartate (NMDA), that is activated by the excitatory neurotransmitter glutamate. Glutamatergic signaling via NMDA receptors is known to support neuroendocrine and ductal pancreatic cancer tumor growth. It has not yet been investigated whether similar glutamatergic signaling is responsible for breast-to-brain metastatic growth. This week in Nature, Zeng and colleagues identify a mechanism that explains how breast cancer cells can position themselves in existing synapses (spaces between neurons in the brain) to facilitate metastatic growth in the brain. 

How did they do it?

The authors performed a series of experiments in human and mouse cell lines to assess the role of glutamate-mediated signaling in human breast to brain metastasis. 1) First, they examined the expression of different glutamate receptor subunit genes across human cancer types, and ultimately focused on breast cancer. To understand the relationship between breast-to-brain metastasis and the NMDA receptor, the authors investigated whether a particular subunit of the receptor, a protein called ‘GluN2B’, was phosphorylated at particular sites in brain metastasis tissue versus in primary breast tissue (no metastasis). Phosphorylation at particular sites can allow the NMDA receptor to reach the surface of cells, where it can participate in signaling with glutamate. The authors compared the ratio of phosphorylated to total GluN2B protein in primary breast cancer tissue with that from breast-to-brain metastatic cell tissue. The results of these analyses led the authors to focus on the GluN2B subunit of the NMDA receptor for further analyses. 2) They confirmed NMDA GluN2B-mediated signaling was functional in the breast-to-brain metastatic cells by applying L-glutamate (known to activate the receptor) and analyzing whether phosphorylation of the GluN2B subunit had occurred. They also imaged the breast-to-brain metastatic cells while applying either NMDA or glutamate exogenously and looking for responses typical of active cells (elevated intracellular calcium & single-channel currents), to confirm the signaling was mediated by NMDA. 3) To understand where the activating molecule, L-glutamate (that activated the NMDA receptor subunit), was originating, the authors performed analyses in different cell lines: they stained sections of both tissue around the lesions containing the metastatic cells and normal tissue to investigate whether the cells were absorbing glutamate from glutamatergic synapses. They used stimulated emission depleted super-resolution microscopy to image the synapses. The authors also used electron microscopy to further examine the structure of the interactions between the cells and existing synapses. 4) Finally, the authors identified the stage at which the GluN2B-mediated signaling contributed to brain metastasis. To confirm that NMDA receptor signaling was important for the proliferation of the cells, the authors disrupted signaling at different stages of tumor development in cells in which NMDA receptor signaling could be disrupted (DOX-inducible knockdown).

What did they find?

The authors found that GluN2B-mediated signaling in cancer cells in the brain is activated by interactions between metastatic cells and neurons in the brain. From their analyses of different receptor subunit genes in humans, the authors found that tumors cells in humans exhibited higher NMDA receptor expression scores versus other glutamate receptors, and that gene expression encoding GluN2B was high in a type of breast cancer with a poor prognosis. When the authors compared several human breast cancer cell lines in mice, they found that GluN2 was upregulated in the breast-to-brain metastatic line. When mice were inoculated with cells from this line at different locations in the body, brain metastases were highly stained for phosphorylated GluN2B compared to the breast and lung. 

Super-resolution microscopy revealed that metastatic cell puncta (processes; stained with luciferase) were in close proximity to presynaptic neurons (stained with vGlut2) and NMDA receptors (stained with pGluN2B). The authors also observed that the metastatic tissue exhibited increased expression of a key postsynaptic signal-transducing protein as well as other markers including neuroligin, which facilitates adhesion and psuedo-synapse formation between cells. These findings suggest that metastatic human breast cancer cells access glutamate the same way that neuronal cells do (by forming synapses with neurons), and that upregulated NMDA receptors may play a role in the brain-metastatic proficiency of the breast-to-brain metastatic cells. The electron microscopy images of the metastatic tissue revealed “finger-like processes” that extended from the breast-to-brain metastatic cells toward excitatory synapses. The authors note that extended process from the breast-to-brain metastatic cells did not disrupt the pre-post neuronal synapse, but was similar to the position usually occupied by astrocytes. The results from the 3D electron microscopy suggest that breast-to-brain metastatic cells are positioned in the pseudo-tripartite synapse (i.e. cells were associated with both pre and postsynaptic membrane) and access the glutamate secreted by presynaptic neurons. When the authors disrupted NMDA receptor signaling, they found that the proliferation of the metastatic cells was disrupted, and that restoring NMDA signaling increased the proliferation of the breast-to-brain metastatic cells again. These findings suggest that GluN2B-NMDA receptor signaling was not essential for metastatic seeding, but rather promoted colonization and tumor growth in the brain.  

What's the impact?

The study identified a signaling pathway that mechanistically explains metastatic tumor growth in the brain. The findings show that cancerous cells position themselves next to glutamatergic synapses in the brain, allowing them to access glutamate which ultimately promotes metastasis via NMDA receptor signaling. This finding will enable future research to identify specific vulnerabilities in the NMDA-related metastatic pathway that could be targeted to block brain metastasis without harming nearby neurons.

Zeng et al. Synaptic Proximity Enables NMDAR Signaling To Promote Brain Metastasis. Nature (2019). Access the original scientific publication here.