Tag: basal ganglia

Structural brain changes in patients with post-COVID fatigue: a prospective observational study

Summary:

Background: Post-COVID syndrome is a severe long-term complication of COVID-19. Although fatigue and cognitive complaints are the most prominent symptoms, it is unclear whether they have structural correlates in the brain. We therefore explored the clinical characteristics of post-COVID fatigue, describe associated structural imaging changes, and determine what influences fatigue severity.

Methods: We prospectively recruited 50 patients from neurological post-COVID outpatient clinics (age 18–69 years, 39f/8m) and matched non-COVID healthy controls between April 15 and December 31, 2021. Assessments included diffusion and volumetric MR imaging, neuropsychiatric, and cognitive testing. At 7.5 months (median, IQR 6.5–9.2) after the acute SARS-CoV-2 infection, moderate or severe fatigue was identified in 47/50 patients with post-COVID syndrome who were included in the analyses. As a clinical control group, we included 47 matched multiple sclerosis patients with fatigue.

Findings: Our diffusion imaging analyses revealed aberrant fractional anisotropy of the thalamus. Diffusion markers correlated with fatigue severity, such as physical fatigue, fatigue-related impairment in everyday life (Bell score) and daytime sleepiness. Moreover, we observed shape deformations and decreased volumes of the left thalamus, putamen, and pallidum. These overlapped with the more extensive subcortical changes in MS and were associated with impaired short-term memory. While fatigue severity was not related to COVID-19 disease courses (6/47 hospitalised, 2/47 with ICU treatment), post-acute sleep quality and depressiveness emerged as associated factors and were accompanied by increased levels of anxiety and daytime sleepiness.

Interpretation: Characteristic structural imaging changes of the thalamus and basal ganglia underlie the persistent fatigue experienced by patients with post-COVID syndrome. Evidence for pathological changes to these subcortical motor and cognitive hubs provides a key to the understanding of post-COVID fatigue and related neuropsychiatric complications.

Source: Josephine Heine, et al. Structural brain changes in patients with post-COVID fatigue: a prospective observational study. The Lancet, VOLUME 58, 101874, APRIL 2023.  Published: February 27, 2023 DOI: https://doi.org/10.1016/j.eclinm.2023.101874 (Full text)

Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) subjects suffer from a variety of cognitive complaints indicating that the central nervous system plays a role in its pathophysiology. Recently, the ratio T1w/T2w has been used to study changes in tissue myelin and/or iron levels in neurodegenerative diseases such as multiple sclerosis and schizophrenia. In this study, we applied the T1w/T2w method to detect changes in tissue microstructure in ME/CFS patients relative to healthy controls.

We mapped the T1w/T2w signal intensity values in the whole brain for forty-five ME/CFS patients who met Fukuda criteria and twenty-seven healthy controls and applied both region- and voxel-based quantification. We also performed interaction-with-group regressions with clinical measures to test for T1w/T2w relationships that are abnormal in ME/CFS at the population level.

Region-based analysis showed significantly elevated T1w/T2w values (increased myelin and/or iron) in ME/CFS in both white matter (WM) and subcortical grey matter. The voxel-based group comparison with sub-millimetre resolution voxels detected very significant clusters with increased T1w/T2w in ME/CFS, mostly in subcortical grey matter, but also in brainstem and projection WM tracts. No areas with decreased T1w/T2w were found in either analysis. ME/CFS T1w/T2w regressions with heart-rate variability, cognitive performance, respiration rate and physical well-being were abnormal in both gray and white matter foci. Our study demonstrates that the T1w/T2w approach is very sensitive and shows increases in myelin and/or iron in WM and basal ganglia in ME/CFS.

Source: Thapaliya K, Marshall-Gradisnik S, Staines D, Barnden L. Mapping of pathological change in chronic fatigue syndrome using the ratio of T1- and T2-weighted MRI scans [published online ahead of print, 2020 Jul 31]. Neuroimage Clin. 2020;28:102366. doi:10.1016/j.nicl.2020.102366 https://pubmed.ncbi.nlm.nih.gov/32777701/

Brain imaging reveals clues about chronic fatigue syndrome

A brain imaging study shows that patients with chronic fatigue syndrome may have reduced responses, compared with healthy controls, in a region of the brain connected with fatigue. The findings suggest that chronic fatigue syndrome is associated with changes in the brain involving brain circuits that regulate motor activity and motivation.

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.

According to the Centers for Disease Control and Prevention, chronic fatigue syndrome is a debilitating and complex disorder characterized by intense fatigue that is not improved by bed rest and that may be worsened by exercise or mental stress.

The results are scheduled for publication in the journal PLOS One.

“We chose the basal ganglia because they are primary targets of inflammation in the brain,” says lead author Andrew Miller, MD. “Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients.”

Miller is William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine. The study was a collaboration among researchers at Emory University School of Medicine, the CDC’s Chronic Viral Diseases Branch, and the University of Modena and Reggio Emilia in Italy. The study was funded by the CDC.

The basal ganglia are structures deep within the brain, thought to be responsible for control of movements and responses to rewards as well as cognitive functions. Several neurological disorders involve dysfunction of the basal ganglia, including Parkinson’s disease and Huntington’s disease, for example.

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

“A number of previous studies have suggested that responses to viruses may underlie some cases of CFS,” Miller says. “Our data supports the idea that the body’s immune response to viruses could be associated with fatigue by affecting the brain through inflammation. We are continuing to study how inflammation affects the basal ganglia and what effects that has on other brain regions and brain function. These future studies could help inform new treatments.”

Treatment implications might include the potential utility of medications to alter the body’s immune response by blocking inflammation, or providing drugs that enhance basal ganglia function, he says.

The researchers compared 18 patients diagnosed with chronic fatigue syndrome with 41 healthy volunteers. The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents. People with major depression or who were taking antidepressants were excluded from the imaging study, although those with anxiety disorders were not.

For the brain imaging portion of the study, participants were told they’d win a dollar if they correctly guessed whether a preselected card was red or black. After they made a guess, the color of the card was revealed, and at that point researchers measured blood flow to the basal ganglia.

The key measurement was: how big is the difference in activity between a win or a loss? Participants’ scores on a survey gauging their levels of fatigue were tied to the difference in basal ganglia activity between winning and losing. Those with the most fatigue had the smallest changes, especially in the right caudate and the right globus pallidus, both parts of the basal ganglia.

Ongoing studies at Emory are further investigating the impact of inflammation on the basal ganglia, including studies using anti-inflammatory treatments to reduce fatigue and loss of motivation in patients with depression and other disorders with inflammation including cancer.

 

Source: Emory Health Sciences. “Brain imaging reveals clues about chronic fatigue syndrome.” ScienceDaily. ScienceDaily, 23 May 2014. https://www.sciencedaily.com/releases/2014/05/140523192427.htm

 

Chronic fatigue syndrome patients had reduced activity in brain’s ‘reward center’

Chronic fatigue syndrome, a medical disorder characterized by extreme and ongoing fatigue with no other diagnosed cause, remains poorly understood despite decades of scientific study. Although researchers estimate that more than 1 million Americans are affected by this condition, the cause for chronic fatigue syndrome, a definitive way to diagnose it, and even its very existence remain in question. In a new study, researchers have found differing brain responses in people with this condition compared to healthy controls, suggesting an association between a biologic functional response and chronic fatigue syndrome.

The findings show that patients with chronic fatigue syndrome have decreased activation of an area of the brain known as the basal ganglia in response to reward. Additionally, the extent of this lowered activation was associated with each patient’s measured level of fatigue. The basal ganglia are at the base of the brain and are associated with a variety of functions, including motor activity and motivation. Diseases affecting basal ganglia are often associated with fatigue. These results shed more light on this mysterious condition, information that researchers hope may eventually lead to better treatments for chronic fatigue syndrome.

The study was conducted by Elizabeth R. Unger, James F. Jones, and Hao Tian of the Centers for Disease Control and Prevention (CDC), Andrew H. Miller and Daniel F. Drake of Emory University School of Medicine, and Giuseppe Pagnoni of the University of Modena and Reggio Emilia. An abstract of their study entitled, “Decreased Basal Ganglia Activation in Chronic Fatigue Syndrome Subjects is Associated with Increased Fatigue,” will be discussed at the meeting Experimental Biology 2012, being held April 21-25 at the San Diego Convention Center. The abstract is sponsored by the American Society for Investigative Pathology (ASIP), one of six scientific societies sponsoring the conference which last year attracted some 14,000 attendees.

More Fatigue, Less Activation

Dr. Unger says that she and her colleagues became curious about the role of the basal ganglia after previous studies by collaborators at Emory University showed that patients treated with interferon alpha, a common treatment for chronic hepatitis C and several other conditions, often experienced extreme fatigue. Further investigation into this phenomenon showed that basal ganglia activity decreased in patients who received this immune therapy. Since the fatigue induced by interferon alpha shares many characteristics with chronic fatigue syndrome, Unger and her colleagues decided to investigate whether the basal ganglia were also affected in this disorder.

The researchers recruited 18 patients with chronic fatigue syndrome, as well as 41 healthy volunteers with no symptoms of CFS. Each study participant underwent functional magnetic resonance imaging, a brain scan technique that measures activity in various parts of the brain by blood flow, while they played a simple card game meant to stimulate feelings of reward. The participants were each told that they’d win a small amount of money if they correctly guessed whether a preselected card was red or black. After making their choice, they were presented with the card while researchers measured blood flow to the basal ganglia during winning and losing hands.

The researchers showed that patients with chronic fatigue syndrome experienced significantly less change in basal ganglia blood flow between winning and losing than the healthy volunteers. When the researchers looked at scores for the Multidimensional Fatigue Inventory, a survey often used to document fatigue for chronic fatigue syndrome and various other conditions, they also found that the extent of a patient’s fatigue was tightly tied with the change in brain activity between winning and losing. Those with the most fatigue had the smallest change.

Results Suggest Role of Inflammation

Unger notes that the findings add to our understanding of biological factors that may play a role in chronic fatigue syndrome. “Many patients with chronic fatigue syndrome encounter a lot of skepticism about their illness,” she says. “They have difficulty getting their friends, colleagues, coworkers, and even some physicians to understand their illness. These results provide another clue into the biology of chronic fatigue syndrome.”

The study also suggests some areas of further research that could help scientists develop treatments for this condition in the future, she adds. Since the basal ganglia use the chemical dopamine as their major neurotransmitter, dopamine metabolism may play an important role in understanding and changing the course of this illness. Similarly, the difference in basal ganglia activation between the patients and healthy volunteers may be caused by inflammation, a factor now recognized as pivotal in a variety of conditions, ranging from heart disease to cancer.

Estimates from the CDC suggest that annual medical costs associated with chronic fatigue syndrome total about $14 billion in the United States. Annual losses to productivity because of lost work time range between $9 and $37 billion, with costs to individual households ranging between $8,000 and $20,000 per year.

 

Source: Federation of American Societies for Experimental Biology (FASEB). (2012, April 24). Chronic fatigue syndrome patients had reduced activity in brain’s ‘reward center’. ScienceDaily. Retrieved March 4, 2017 from https://www.sciencedaily.com/releases/2012/04/120424142109.htm

 

Decreased basal ganglia activation in subjects with chronic fatigue syndrome: association with symptoms of fatigue

Abstract:

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation.

In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses.

Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects.

These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

 

Source: Miller AH, Jones JF, Drake DF, Tian H, Unger ER, Pagnoni G. Decreased basal ganglia activation in subjects with chronic fatigue syndrome: association with symptoms of fatigue. PLoS One. 2014 May 23;9(5):e98156. doi: 10.1371/journal.pone.0098156. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032274/ (Full article)

 

Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome

Abstract:

Fatigue is a common symptom of neurological diseases that affect basal ganglia function. We used proton magnetic resonance spectroscopy ((1)H MRS) to study the metabolic functions of the basal ganglia in chronic fatigue syndrome (CFS) to test the hypothesis that fatigue in CFS may have a neurogenic component. (1)H MRS of left basal ganglia was carried out in eight non-psychiatric patients with CFS and their results were compared to age- and sex-matched healthy asymptomatic healthy controls. A highly significant increase in the spectra from choline-containing compounds was seen in the CFS patient group (p < 0.001). In the absence of regional structural or inflammatory pathology, increased choline resonance in CFS may be an indicator of higher cell membrane turnover due to gliosis or altered intramembrane signalling.

 

Source: Chaudhuri A, Condon BR, Gow JW, Brennan D, Hadley DM. Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport. 2003 Feb 10;14(2):225-8. http://www.ncbi.nlm.nih.gov/pubmed/12598734

 

Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a severely disabling illness of uncertain aetiology. It is characterized by a chronic, sustained or fluctuating sense of debilitating fatigue without any other known underlying medical conditions. It is also associated with both somatic and neuropsychological symptoms. Both physical and laboratory findings are usually unremarkable.

Regional cerebral blood flow (rCBF) was assessed in 60 clinically defined CFS patients and 14 normal control (NC) subjects using 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) single photon emission computed tomography (SPECT). Compared with the NC group, the CFS group showed significantly lower cortical/cerebellar rCBF ratios, throughout multiple brain regions (P < 0.05). Forty-eight CFS subjects (80%) showed at least one or more rCBF ratios significantly less than normal values.

The major cerebral regions involved were frontal (38 cases, 63%), temporal (21 cases, 35%), parietal (32 cases, 53%) and occipital lobes (23 cases, 38%). The rCBF ratios of basal ganglia (24 cases, 40%) were also reduced. 99Tcm-HMPAO brain SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects. The findings may not be diagnostic of CFS but 99Tcm-HMPAO SPECT may play an important role in clarifying the pathoaetiology of CFS. Further studies are warranted.

 

Source: Ichise M, Salit IE, Abbey SE, Chung DG, Gray B, Kirsh JC, Freedman M. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nucl Med Commun. 1992 Oct;13(10):767-72. http://www.ncbi.nlm.nih.gov/pubmed/1491843