id
stringlengths 11
17
| article_id
stringlengths 8
11
| path
stringlengths 11
60
| section_title
stringlengths 1
1.33k
| educational_score
float64 0
5.16
| domain
stringclasses 4
values | document_type
stringclasses 5
values | domain_scores
listlengths 0
3
| document_type_scores
listlengths 0
4
| text
stringlengths 1
110k
| authors
listlengths 0
8.02k
| article_url
stringlengths 3
63
| license_type
stringclasses 1
value | license_url
stringclasses 15
values | language
stringclasses 45
values | language_score
float64 0
1
|
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PMC11278015_p92
|
PMC11278015
|
sec[3]/p[11]
|
4. Discussion
| 4.042969 |
biomedical
|
Study
|
[
0.99951171875,
0.00023639202117919922,
0.0002627372741699219
] |
[
0.99853515625,
0.0002529621124267578,
0.0009398460388183594,
0.000059604644775390625
] |
Soares et al. conducted a meta-analysis on children with sleep bruxism in the global population, showing a prevalence rate of 31.16% . In our study, it turned out that sleep bruxism affects 21%, including both adults and minors. When divided among minors, bruxism was reported in 9% of minor females and males. Observable differences are likely associated with the period included in the analysis. In the study by Soares et al., this period was 10 years , whereas in our study, it was 20 years. However, analysis restricted to polysomnographic studies revealed a prevalence of sleep bruxism at 43%. Due to the small sample size, these results should be interpreted cautiously, and further analyses should be conducted in the future. This underscores the ongoing need to monitor the occurrence of bruxism in the population.
|
[
"Grzegorz Zieliński",
"Agnieszka Pająk",
"Marcin Wójcicki"
] |
https://doi.org/10.3390/jcm13144259
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278015_p93
|
PMC11278015
|
sec[3]/p[12]
|
4. Discussion
| 3.041016 |
biomedical
|
Study
|
[
0.998046875,
0.00028634071350097656,
0.0015726089477539062
] |
[
0.97900390625,
0.0089569091796875,
0.0116729736328125,
0.00024271011352539062
] |
Archer et al. conducted a meta-analysis on the prevalence of awake bruxism in adults, finding a prevalence rate of 15.44% . These results are similar to what we obtained. The global prevalence of awake bruxism was estimated at 23%. Among adult females, it was 18%, and among males, 9%.
|
[
"Grzegorz Zieliński",
"Agnieszka Pająk",
"Marcin Wójcicki"
] |
https://doi.org/10.3390/jcm13144259
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278015_p94
|
PMC11278015
|
sec[3]/p[13]
|
4. Discussion
| 3.845703 |
biomedical
|
Study
|
[
0.9990234375,
0.00018656253814697266,
0.0007824897766113281
] |
[
0.93505859375,
0.0021572113037109375,
0.062469482421875,
0.0001786947250366211
] |
The meta-analysis by Ferrari-Piloni et al. investigated the occurrence of bruxism in children residing in Brazil, revealing a prevalence of 25.8% in both sleep and awake states. Additionally, Ferrari-Piloni et al. observed regional differences in Brazil: Northeast—35.2%, Southeast—45.0%, and South—19.8% . The meta-analysis by Ferrari-Piloni et al. provided grounds to suggest that bruxism is associated with geographic factors.
|
[
"Grzegorz Zieliński",
"Agnieszka Pająk",
"Marcin Wójcicki"
] |
https://doi.org/10.3390/jcm13144259
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278015_p95
|
PMC11278015
|
sec[3]/sec[0]/p[0]
|
Limitations of the Study
| 4 |
biomedical
|
Study
|
[
0.99951171875,
0.00029754638671875,
0.0003631114959716797
] |
[
0.9990234375,
0.00037598609924316406,
0.00043892860412597656,
0.0000661015510559082
] |
Among the limitations of the study is the lack of analysis of the prevalence of bruxism (sleep and awake bruxism) on the continents of Africa and Australia. As mentioned in the methodology, this was due to not collecting an adequate sample for analysis (one study concerning Australia and three studies concerning Africa ). This illustrates a dependency that was already observed in an earlier meta-analysis concerning the occurrence of TMDs . An additional limitation is the lack of analyses regarding awake bruxism in North America. At that time, an adequate number of studies needed to conduct the meta-analysis was also not collected. This indicates a research gap and underscores the need to conduct high-quality dental research on the epidemiology of diseases and parafunctions of the stomatognathic system on these continents . Another limitation is the failure to consider the division in the pediatric population into permanent and mixed dentition. We suggest including these variables in subsequent analyses.
|
[
"Grzegorz Zieliński",
"Agnieszka Pająk",
"Marcin Wójcicki"
] |
https://doi.org/10.3390/jcm13144259
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278015_p96
|
PMC11278015
|
sec[3]/sec[0]/p[1]
|
Limitations of the Study
| 4.054688 |
biomedical
|
Study
|
[
0.99951171875,
0.00024378299713134766,
0.00047087669372558594
] |
[
0.9970703125,
0.00025343894958496094,
0.0025768280029296875,
0.00005811452865600586
] |
Another limitation of the study is what was observed in the analysis of the JBI questionnaire, specifically Q3, regarding the selection of an appropriate sample size, Q9, addressing the adequacy of the response rate, and Q7, concerning the diagnostic method for bruxism. Most studies relied on custom-made research questionnaires and self-reports from participants or their caregivers (in the case of children). Probably contributing to the high heterogeneity of results in this meta-analysis. Of course, both non-instrumental approaches (e.g., self-reports) and instrumental methods (e.g., electromyography) can be used to assess bruxism . However, different research questionnaires create the potential for errors (for example, studies by Raphael et al. and Restrepo et al. highlight the risk of potential error associated with self-reported and parent-reported bruxism). Therefore, we highlight this potential risk. With the emergence of the standardized diagnostic tool BruxScreen , we hope that future epidemiological studies will be conducted using this tool among others.
|
[
"Grzegorz Zieliński",
"Agnieszka Pająk",
"Marcin Wójcicki"
] |
https://doi.org/10.3390/jcm13144259
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278015_p97
|
PMC11278015
|
sec[3]/sec[0]/p[2]
|
Limitations of the Study
| 2.380859 |
biomedical
|
Study
|
[
0.98828125,
0.0006170272827148438,
0.0112457275390625
] |
[
0.9833984375,
0.01345062255859375,
0.002780914306640625,
0.0002180337905883789
] |
The final limitation of this meta-analysis is the use of a single database. Despite conducting additional searches using an internet search engine and employing snowball sampling, there is a risk of selection bias.
|
[
"Grzegorz Zieliński",
"Agnieszka Pająk",
"Marcin Wójcicki"
] |
https://doi.org/10.3390/jcm13144259
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p0
|
PMC11278030
|
sec[0]/p[0]
|
1. Introduction
| 3.890625 |
biomedical
|
Review
|
[
0.99169921875,
0.0036106109619140625,
0.00485992431640625
] |
[
0.005401611328125,
0.00201416015625,
0.9921875,
0.0003170967102050781
] |
Traumatic brain injury (TBI) is a leading cause of injury-related deaths and disabilities worldwide, exerting a devastating impact on patients and their families . One recent systematic review reported that an estimated sixty-nine million individuals worldwide suffer from TBI from any cause each year. Although the vast majority of these are mild (81%) or moderate (11%) , severe TBI nevertheless constitutes a significant health and socioeconomic problem.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278030_p1
|
PMC11278030
|
sec[0]/p[1]
|
1. Introduction
| 4.035156 |
biomedical
|
Review
|
[
0.99853515625,
0.0007290840148925781,
0.0005049705505371094
] |
[
0.1502685546875,
0.029937744140625,
0.81884765625,
0.0010843276977539062
] |
There is currently no available treatment for primary brain injury, defined as the direct destruction of the brain parenchyma and blood vessels. Therefore, treatments for TBI focus on mitigating secondary injury, which is triggered by a cascade of destructive events and processes beginning at the cellular level within minutes to hours following the initial injury. The duration and magnitude of the secondary injury cascade are highly variable depending on the TBI subtype. Excitotoxicity, neuroinflammation, apoptosis, free radical production, seizure activity, blood/brain barrier disruption, blood vessel leakage, and cerebral thermopooling may all develop to varying degrees . Accordingly, TBI is termed “the most complicated disease of the most complex organ of the body” .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p2
|
PMC11278030
|
sec[0]/p[2]
|
1. Introduction
| 3.935547 |
biomedical
|
Review
|
[
0.998046875,
0.0010080337524414062,
0.0007090568542480469
] |
[
0.159423828125,
0.00140380859375,
0.8388671875,
0.0005016326904296875
] |
To date, no specific neuroprotective pharmacological treatment options with proven clinical efficacy are available for patients with TBI . Importantly, all the harmful processes are temperature-dependent, meaning that they are all stimulated by fever and can be mitigated or blocked by hypothermia treatment . Early preclinical studies have shown that a slight reduction in brain temperature after moderate-to-severe TBI reduces histopathological damage and neurological deficits. Investigative clinical studies have also reported reductions in multiple post-traumatic attenuated secondary injury mechanisms . However, numbers of clinical studies have failed to demonstrate the benefits of hypothermia.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278030_p3
|
PMC11278030
|
sec[1]/p[0]
|
2. Methods
| 3.994141 |
biomedical
|
Study
|
[
0.99951171875,
0.0004878044128417969,
0.00018990039825439453
] |
[
0.9453125,
0.0027294158935546875,
0.0513916015625,
0.0004048347473144531
] |
This study comprises three sections: a narrative review on neuroprotection and history of therapeutic hypothermia (TH), a summary of prior meta-analyses, and a meta-analysis of preoperative early TH for young patients with surgically evacuated hematoma.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p4
|
PMC11278030
|
sec[1]/p[1]
|
2. Methods
| 4.039063 |
biomedical
|
Study
|
[
0.99951171875,
0.00027751922607421875,
0.0002224445343017578
] |
[
0.998046875,
0.00047588348388671875,
0.001308441162109375,
0.0000718235969543457
] |
A systemic search for Pubmed, Medline, and the Cochrane Central Register of Clinical Trials was performed from 1 January 2000 to 12 December 2023 using the following search terms: “hypothermia OR cooling” AND “traumatic brain injury OR TBI” AND “RCT”. The author also hand-searched the bibliographies of relevant citations and reviews. The analyses were referenced to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA); however, this study was conducted by a single author and does not fulfill the PRISMA requirement, and was not registered in the International Prospective Register of Systematic Reviews (PROSPERO).
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p5
|
PMC11278030
|
sec[1]/p[2]
|
2. Methods
| 3.958984 |
biomedical
|
Study
|
[
0.99951171875,
0.0003445148468017578,
0.00016307830810546875
] |
[
0.99267578125,
0.0010356903076171875,
0.006244659423828125,
0.00017964839935302734
] |
The author conducted a meta-analysis of the retrieved literature on young patients with acute subdural hematoma who underwent the preoperative induction of hypothermia and early surgery using Review Manager (RevMan, Cochrane Collaboration, London, UK, version 5.3).
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p6
|
PMC11278030
|
sec[2]/p[0]
|
3. Terminology
| 3.816406 |
biomedical
|
Study
|
[
0.9990234375,
0.0006928443908691406,
0.0002510547637939453
] |
[
0.96044921875,
0.00899505615234375,
0.029998779296875,
0.0005679130554199219
] |
TH has been widely used for patients with various types of severe brain injury; however, the definition of “mild”, “moderate”, and “deep” hypothermia shows some discrepancies between studies. To avoid confusion related to these terms, five intensive care societies sponsored an expert review and analyzed the existing knowledge. The jury opined that the term “targeted temperature management (TTM)” should replace “therapeutic hypothermia”, and that the descriptions should be replaced with explicit TTM profiles . In this study, TH was used as the TTM at 32–34 °C unless otherwise stated.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p7
|
PMC11278030
|
sec[3]/p[0]
|
4. Mechanism of Hypothermic Neuroprotection
| 3.667969 |
biomedical
|
Other
|
[
0.9990234375,
0.00027942657470703125,
0.0005536079406738281
] |
[
0.327392578125,
0.3359375,
0.3349609375,
0.0016565322875976562
] |
Cerebral metabolism decreases by 6% to 10% for each 1 °C reduction in body temperature. Thus, early studies used profound hypothermia below 30 °C as lower temperatures were believed to be more effective. Currently, it is recognized that reducing body temperature by a few degrees can protect the brain through various early and late mechanisms of action .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p8
|
PMC11278030
|
sec[3]/p[1]
|
4. Mechanism of Hypothermic Neuroprotection
| 4.300781 |
biomedical
|
Review
|
[
0.99853515625,
0.0007390975952148438,
0.0006699562072753906
] |
[
0.2308349609375,
0.010589599609375,
0.7578125,
0.0009188652038574219
] |
The broad range of beneficial effects of hypothermia includes the inhibition of various destructive processes following ischemia/reperfusion injury, including ion pump dysfunction and neuroexcitotoxicity, free radical production, mitochondrial injury, cell membrane leakage, formation of cytotoxic edema, and intracerebral acidosis. The late mechanisms of TH include the inhibition of apoptosis, calpain-mediated proteolysis, reduction in vascular permeability, blood/brain barrier disruption, and edema formation.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278030_p9
|
PMC11278030
|
sec[4]/p[0]
|
5. History of Therapeutic Hypothermia in Brief
| 3.601563 |
biomedical
|
Review
|
[
0.98779296875,
0.006011962890625,
0.006313323974609375
] |
[
0.006328582763671875,
0.30078125,
0.6884765625,
0.004119873046875
] |
The documentation of the therapeutic effects of hypothermia can be traced back several millennia. The earliest recorded evidence of the use of cooling for disease was found in the Edwin Smith Papyrus, written in ancient Egypt. More than a millennium later, Hippocrates described the use of whole-body cooling in patients suffering from tetanus , and local cooling with ice and snow before operation work . Areteus, a Greek physician in the second century AD, recommended prompt action and burr hole opening to remove hematomas, diuretics, and hypothermia for brain injury . Thereafter, the beneficial effects of cooling have been repeatedly reported from the Renaissance until the 20th century .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p10
|
PMC11278030
|
sec[4]/p[1]
|
5. History of Therapeutic Hypothermia in Brief
| 4.003906 |
biomedical
|
Study
|
[
0.982421875,
0.0173492431640625,
0.00038814544677734375
] |
[
0.54638671875,
0.1663818359375,
0.1419677734375,
0.1451416015625
] |
In 1938, following vigorous laboratory investigations, Temple Fay first induced generalized refrigeration in a young woman with metastatic breast cancer who experienced systemic pain due to widespread metastasis . Subsequently, the therapeutic use of hypothermia in patients with TBI was first reported in 1943 in a 22-year-old woman suffering from a cerebral contusion and laceration who had remained unconscious and developed a fever above 40 °C with tachycardia and tachypnea. She remained in a coma with a high fever around 40 °C despite local cooling. Finally, 4 weeks after the injury, she received whole body refrigeration at 33 °C for 48 h. She recovered fully and returned to work seven months later . Fay et al. subsequently applied generalized refrigeration to 124 patients and developed a local cooling device .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p11
|
PMC11278030
|
sec[4]/p[2]
|
5. History of Therapeutic Hypothermia in Brief
| 3.607422 |
biomedical
|
Review
|
[
0.9970703125,
0.0018186569213867188,
0.0011444091796875
] |
[
0.02178955078125,
0.273681640625,
0.70166015625,
0.0028514862060546875
] |
In the 1950s, following experimental evidence showing the beneficial effects of hypothermia on brain protection , it was used in cardiac surgery , cerebral aneurysm surgery , and resuscitation . Although early experiments investigating hypothermia appeared promising, deep hypothermia ≤30 °C aiming at lowering metabolism was abandoned because of serious adverse events .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278030_p12
|
PMC11278030
|
sec[5]/p[0]
|
6. Reviving Clinical Use of Hypothermia for Severe Traumatic Brain Injury
| 3.912109 |
biomedical
|
Review
|
[
0.9970703125,
0.0014963150024414062,
0.0013303756713867188
] |
[
0.01531982421875,
0.025177001953125,
0.95849609375,
0.0009341239929199219
] |
A revival of hypothermia therapy began in 1987 following the finding that lowering the brain temperature by only a few degrees conferred a marked brain-protective effect in rat ischemic models . Many preclinical studies have since reported the efficacy of mild hypothermia in various aspects. These studies have encouraged the clinical use of TH in the treatment of various severe brain injuries.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p13
|
PMC11278030
|
sec[5]/p[1]
|
6. Reviving Clinical Use of Hypothermia for Severe Traumatic Brain Injury
| 4.140625 |
biomedical
|
Study
|
[
0.998046875,
0.001750946044921875,
0.00032448768615722656
] |
[
0.94775390625,
0.0027523040771484375,
0.04888916015625,
0.00051116943359375
] |
In the 1990s and the early 2000s, TH was widely used to treat severe TBI. In 1993, the first randomized controlled trials (RCTs) on TH for TBI were published . Marion et al. used TH at 32 °C to 33 °C for severe TBI patients. Forty consecutive patients aged 16–75 years with GCS scores of 3–7, admitted between February 1991 and August 1992, were randomized to either the TH or normothermia group. TH was initiated within a mean of 10 h after injury and maintained for 24 h, after which the patients were rewarmed to 37 to 38 °C over 12 h. TH significantly reduced intracranial pressure (ICP) and cerebral blood flow (CBF) during cooling. This study showed a trend toward better outcomes in the TH group than in the normothermia group, without increased systemic complications . Clifton et al. further conducted a phase II study on TH enrolling 46 patients with severe TBI. Patients aged 16 to 60 years with GCS scores of 4–7 were randomized to TH (32 to 33 °C) or standard management (37 °C). Cooling was begun within 6 h of injury using cooling blankets and the patients were rewarmed at a rate of 1 °C/4 h after maintaining 33 °C for 48 h. TH was associated with improved neurologic outcomes with minimal toxicity . Shiozaki et al. reported that TH at 34 °C for 48 h significantly improved survival rate and reduced ICP, CBF, and cerebral metabolic rates for oxygen (CMRO 2 ) for TBI patients with a GCS score of ≤8 and ICP > 20 mmHg . They later recommended normothermia, in which the ICP could be maintained at <20 mmHg using conventional therapies .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278030_p14
|
PMC11278030
|
sec[5]/p[2]
|
6. Reviving Clinical Use of Hypothermia for Severe Traumatic Brain Injury
| 4.117188 |
biomedical
|
Study
|
[
0.99951171875,
0.0006055831909179688,
0.0001176595687866211
] |
[
0.99609375,
0.0014162063598632812,
0.002239227294921875,
0.00020992755889892578
] |
A clinical study on severe TBI showed that TH reduced CMRO 2 by approximately 45% without inducing significant changes in cerebral blood flow (CBF) or normalized cerebral metabolic rate of lactate, thereby preventing secondary brain damage . TH reduces prostanoid production after TBI, thereby attenuating the imbalance between thromboxane A 2 and prostaglandin I 2 and improving outcomes .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p15
|
PMC11278030
|
sec[6]/p[0]
|
7. Major Phase III Randomized Controlled Trials
| 3.59375 |
biomedical
|
Study
|
[
0.99853515625,
0.0008020401000976562,
0.0005331039428710938
] |
[
0.476806640625,
0.045196533203125,
0.476806640625,
0.0011167526245117188
] |
Based on early studies that demonstrated the potential benefits of TH in TBI, numerous phase III trials on the topic have been planned since the 1990s. Figure 2 provides an overview of the major RCTs on TH for adult TBI , together with child TBI , and postcardiac arrest . Patient recruitment periods and years of the publication are shown.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p16
|
PMC11278030
|
sec[6]/p[1]
|
7. Major Phase III Randomized Controlled Trials
| 2.369141 |
biomedical
|
Study
|
[
0.9951171875,
0.001865386962890625,
0.0031490325927734375
] |
[
0.70849609375,
0.04644775390625,
0.24365234375,
0.0014705657958984375
] |
The characteristics of the RCTs on adult TBI are summarized in Table 1 . Contrary to expectations, most studies have failed to demonstrate the efficacy of TH. A summary of each RCT is provided below.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p17
|
PMC11278030
|
sec[6]/sec[0]/p[0]
|
7.1. Marion1997
| 4.089844 |
biomedical
|
Study
|
[
0.99609375,
0.003757476806640625,
0.0002541542053222656
] |
[
0.96484375,
0.01055908203125,
0.023773193359375,
0.0009403228759765625
] |
In one single-center RCT conducted in Pittsburgh, USA, TH (a temperature of 32 or 33 °C) for 24 h, initiated a mean of 10 h after severe TBI, significantly improved the outcomes at 3 and 6 months in patients with GCS scores of 5 to 7, but not in those with GCS scores of 3 to 4. TH did not increase the incidence of complications. Therefore, TH appears to be a promising treatment option for severe TBI .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p18
|
PMC11278030
|
sec[6]/sec[1]/p[0]
|
7.2. Clifton: NABIS:H
| 3.910156 |
biomedical
|
Other
|
[
0.76513671875,
0.2315673828125,
0.003314971923828125
] |
[
0.453857421875,
0.52978515625,
0.0031642913818359375,
0.0131378173828125
] |
This landmark multicenter RCT, involving 11 sites across the USA, assigned 193 patients to the control group and 199 to the TH group (33 °C). The mean time from injury to achieving the target temperature of 33 °C was 8.4 ± 3.0 h in the TH group.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p19
|
PMC11278030
|
sec[6]/sec[1]/p[1]
|
7.2. Clifton: NABIS:H
| 4.148438 |
biomedical
|
Study
|
[
0.99755859375,
0.0022449493408203125,
0.00023543834686279297
] |
[
0.99755859375,
0.0011758804321289062,
0.001132965087890625,
0.00022161006927490234
] |
The study revealed no differences between the TH and normothermia groups in the primary outcome measure; 57% of the patients in both groups had a poor outcome (severe disability, vegetative state, or death), while mortality was 28% in the TH group and 27% in the normothermia groups. The lack of the benefits of TH in severe TBI had a profound impact on the management strategies. However, a significant decrease in poor outcomes was noted among the patients ≤45 years who had hypothermia on admission; 52% of those assigned to the TH group had poor outcomes, as compared with 76% of the normothermia group ( p = 0.02) . Poor outcomes ranged widely in low-enrollment centers, and the participation of small centers resulted in an increase in the intercenter variance and diminished the quality of the data . This study was criticized for its slow achievement of the target body temperature and unstable circulatory dynamics, which led to future studies.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p20
|
PMC11278030
|
sec[6]/sec[2]/p[0]
|
7.3. Shiozaki
| 4.101563 |
biomedical
|
Study
|
[
0.98095703125,
0.0184173583984375,
0.0005865097045898438
] |
[
0.9873046875,
0.01087188720703125,
0.0005679130554199219,
0.0010585784912109375
] |
In this study conducted at 11 medical centers in Osaka, Japan, 91 TBI patients with GCS scores ≤8 were assigned to either the TH group (45 patients) or the normothermia group (46 patients), provided that ICP remained <25 mmHg after the conventional ICP reduction therapies. Using a cooling mat, the TH group was maintained at 34 °C for 2 days and then rewarmed at a rate of 1 °C/day, whereas the normothermic group was maintained at 37 °C for 5 days.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p21
|
PMC11278030
|
sec[6]/sec[2]/p[1]
|
7.3. Shiozaki
| 3.822266 |
biomedical
|
Study
|
[
0.98974609375,
0.00968170166015625,
0.00045299530029296875
] |
[
0.99072265625,
0.006572723388671875,
0.00156402587890625,
0.0010395050048828125
] |
Although there was no difference in the outcomes between the two groups, complications were significantly more frequent in the TH group. This study concluded that TH should not be used to treat patients with severe TBI in whom ICP can be maintained at <25 mmHg using conventional therapies .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p22
|
PMC11278030
|
sec[6]/sec[3]/p[0]
|
7.4. Jiang
| 3.947266 |
biomedical
|
Study
|
[
0.7919921875,
0.2061767578125,
0.0017223358154296875
] |
[
0.78173828125,
0.1993408203125,
0.0019683837890625,
0.017059326171875
] |
At three medical centers in China, 215 patients aged 18–45 years with an admission GCS score ≤8 within 4 h after injury, frontotemporoparietal contusion with midline shift >1 cm, and ICP >20 mmHg were randomly divided into a long-term TH group ( n = 108) and short-term mild TH group ( n = 107). When the patient’s rectal temperature reached 33 °C to 35 °C, this temperature was maintained for 5 ± 1.3 days for the long-term TH group and 2 ± 0.6 days for the short-term TH group.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278030_p23
|
PMC11278030
|
sec[6]/sec[3]/p[1]
|
7.4. Jiang
| 4.074219 |
biomedical
|
Study
|
[
0.974609375,
0.024688720703125,
0.000732421875
] |
[
0.99169921875,
0.006496429443359375,
0.0009737014770507812,
0.0010652542114257812
] |
Favorable outcomes at 6 months were observed in 43.5% of the long-term TH group and 29.0% of the short-term TH group ( p < 0.05). ICP significantly rebounded after rewarming in the short-term TH group but not in the long-term TH group ( p < 0.05). No significant difference in the frequency of complications was noted between the groups .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p24
|
PMC11278030
|
sec[6]/sec[4]/p[0]
|
7.5. Clifton: NABIS:H II
| 4.128906 |
biomedical
|
Study
|
[
0.984375,
0.01507568359375,
0.0004968643188476562
] |
[
0.9912109375,
0.00688934326171875,
0.0006127357482910156,
0.0010471343994140625
] |
This study aimed to assess whether the very early induction of hypothermia in patients with severe TBI improved outcomes, involving more rapid induction and the strict maintenance of TH levels under stable hemodynamics. Ninety-seven patients (fifty-two in the TH group and forty-five in the normothermia group) aged 16–45 years were enrolled from six sites in the USA. The mean time to reach 35 °C in the TH group was 2.6 h, and to 33 °C was 4.4 h. Body temperature was precisely controlled by automated temperature feedback and adjustment systems using gel pads.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p25
|
PMC11278030
|
sec[6]/sec[4]/p[1]
|
7.5. Clifton: NABIS:H II
| 4.097656 |
biomedical
|
Study
|
[
0.998046875,
0.0014886856079101562,
0.00026798248291015625
] |
[
0.9951171875,
0.0017871856689453125,
0.0028858184814453125,
0.00018584728240966797
] |
The study, again, showed no differences in poor outcomes (60% vs. 56%, p = 0.67) or mortality (23% vs. 18%, p = 0.52) between the TH and normothermia groups. However, the patients who underwent the surgical removal of intracranial hematomas with hypothermia had significantly fewer poor outcomes than the patients who had normothermia ( p = 0.02). Furthermore, there was weak evidence that the patients with diffuse brain injury treated with TH had poorer outcomes than the patients in the normothermic group ( p = 0.09). However, this trial did not confirm the utility of TH as a primary neuroprotective strategy in patients with severe TBI .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p26
|
PMC11278030
|
sec[6]/sec[5]/p[0]
|
7.6. Maekawa: B-HYPO Study
| 4.140625 |
biomedical
|
Study
|
[
0.99072265625,
0.0088043212890625,
0.0004677772521972656
] |
[
0.9951171875,
0.0041351318359375,
0.00036597251892089844,
0.0004973411560058594
] |
The B-HYPO study, which involved 36 hospitals in Japan, was conducted between December 2002 and September 2008. This study aimed to avoid the limitations of the previous studies by implementing the following rules: patients were cooled as soon as possible, hypothermia was maintained for at least 72 h while ICP was in the normal range, and patients were rewarmed at a rate of <1 °C/day with strict hemodynamic monitoring. An arterial catheter, a pulmonary arterial catheter, and an ICP-monitoring probe were inserted to maintain optimal hemodynamic status and ICP. Thus, this study only recruited patients with TBI and GCS scores of 4–8, aged 15–69 years, who were able to undergo cooling within 2 h after injury. The patients were allocated to either the TH (32–34 °C) or fever control (35.5–37.0 °C) groups at a ratio of 2:1. Core body temperature was primarily measured using a thermistor coupled to an internal jugular venous catheter, and the jugular venous oxygen saturation (SjO 2 ) was continuously monitored. Biochemical data were recorded before and after the induction of hypothermia and rewarming. The CT images of all the patients were collected and classified according to the Traumatic Coma Data Bank (TCDB) classification. The principal investigator conducted site visits to each participating hospital for quality control.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p27
|
PMC11278030
|
sec[6]/sec[5]/p[1]
|
7.6. Maekawa: B-HYPO Study
| 4.074219 |
biomedical
|
Study
|
[
0.98681640625,
0.01236724853515625,
0.0005869865417480469
] |
[
0.9931640625,
0.00545501708984375,
0.0006613731384277344,
0.0006165504455566406
] |
The target sample size was set at 300 patients, but enrollment slowed after the amendment of the Japanese Road Traffic Law in 2007 to make drinking and driving strictly punishable. Eventually, 98 patients were enrolled in the TH group and 50 in the temperature control group. The overall rates of poor neurological outcome were 53% and 48% in the TH and fever control groups, respectively. This study concluded that tight hemodynamic management and slow rewarming, together with prolonged TH for severe TBI, did not improve neurological outcomes or the risk of mortality compared to strict temperature control .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p28
|
PMC11278030
|
sec[6]/sec[5]/p[2]
|
7.6. Maekawa: B-HYPO Study
| 4.191406 |
biomedical
|
Study
|
[
0.9990234375,
0.0008134841918945312,
0.0002524852752685547
] |
[
0.9931640625,
0.0005049705505371094,
0.0061187744140625,
0.000164031982421875
] |
A dozen post hoc analyses were published from the data obtained in the B-HYPO study, the results of which are as follows: Diverse effects of TH were observed based on TCDB classification. Increased favorable outcomes in young patients (≤50 years old) with evacuated mass lesions in the TH group (77.8%) compared with the fever control group (33.3%), whereas the patients with diffuse injury III who were treated with TH had significantly higher mortality than the patients treated with fever control . Among the patients with an Abbreviated Injury Scale score of 3–4, the fever control group demonstrated significantly lower mortality and a trend toward more favorable outcomes compared to those of the TH group . Based on the analysis of the initial potassium level, fever control may be considered instead of TH in patients with normokalemia upon admission . Initial stress hyperglycemia was sustained in the TH group compared to the fever control group. Blood glucose levels on the day after admission were significant prognostic indicators in both the TH and control groups . Early-stage hyperoxia was associated with favorable neurological outcomes and survival . TH did not negatively affect the outcomes in patients with coagulopathy and severe TBI . Slow rewarming for >48 h may improve the neurological outcomes of prolonged TH in patients with TBI and evacuated hematomas . A mild decrease in heart rate during the early phase of TH following tachycardia at admission could predict unfavorable neurological outcomes . A reduction in the difference between the mixed venous oxygen saturation (SvO 2 ) and jugular venous oxygen saturation (SjvO 2 ) on day three was associated with high mortality . High hemoglobin levels during the early phase were also significantly associated with favorable neurological outcomes . Among the young adults (≤50 years) who underwent early surgical evacuation for acute subdural hematoma (ASDH), the TH group had better outcomes than the normothermia group despite similar CT findings . The temperature difference between the jugular bulb and pulmonary artery (ΔTjb-pa) trended significantly higher in the favorable outcome patients than in the unfavorable outcome patients throughout the 120 h following the onset of severe TBI. The variation in Tjb-pa from 0 to 72 h was significantly lower in patients with favorable outcomes .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p29
|
PMC11278030
|
sec[6]/sec[6]/p[0]
|
7.7. Andrews: Eurotherm3235
| 4.101563 |
biomedical
|
Study
|
[
0.92529296875,
0.07318115234375,
0.0014219284057617188
] |
[
0.77587890625,
0.2158203125,
0.00275421142578125,
0.00555419921875
] |
The Eurotherm 3235 Trial was an international, multicenter RCT that examined the effects of titrated TH (32 to 35 °C) for intracranial hypertension. Adult TBI patients with ICP >20 mmHg despite mechanical ventilation and sedation were assigned to either the control or TH group. The study enrolled 387 patients, of whom 54% were in the control group and 44% were in the TH group. More than 90% of the patients in both groups were enrolled >12 h after the injury; however, there were no significant between-group differences according to the time from injury to the initiation of hypothermia (<12 or ≥12 h).
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p30
|
PMC11278030
|
sec[6]/sec[6]/p[1]
|
7.7. Andrews: Eurotherm3235
| 4.140625 |
biomedical
|
Study
|
[
0.958984375,
0.040130615234375,
0.0008459091186523438
] |
[
0.98291015625,
0.01377105712890625,
0.0016040802001953125,
0.0017242431640625
] |
Favorable outcomes (Extended Glasgow Coma Scale [GOS-E] score of 5–8, indicating moderate disability or good recovery) occurred in 25.7% of the patients in the TH group and 36.5% of the control group ( p = 0.03). The risk of death (hazard ratio, 1.45; 95% CI, 1.01 to 2.10; p = 0.047) was superior in the control group; further, serious adverse events were reported more frequently in the TH group than in the control group (33 vs. 10 events). TH plus standard care successfully reduced ICP but did not improve functional recovery compared with standard care alone .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278030_p31
|
PMC11278030
|
sec[6]/sec[6]/p[2]
|
7.7. Andrews: Eurotherm3235
| 3.751953 |
biomedical
|
Review
|
[
0.998046875,
0.0012912750244140625,
0.0006709098815917969
] |
[
0.3994140625,
0.037689208984375,
0.5615234375,
0.001262664794921875
] |
TH is an effective addition to ICP management that can reduce the number of hyperosmolar therapies required . However, later proportional hazard analysis for death indicated that TH, as a first-line measure to reduce ICP to <20 mmHg, is harmful in patients with a lower severity of injury, while no clear benefit exists in patients with more severe injuries .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p32
|
PMC11278030
|
sec[6]/sec[7]/p[0]
|
7.8. Cooper: POLAR-ACT
| 3.998047 |
biomedical
|
Other
|
[
0.87109375,
0.1263427734375,
0.002437591552734375
] |
[
0.396484375,
0.59326171875,
0.0027103424072265625,
0.007381439208984375
] |
The Prophylactic Hypothermia Trial to Lessen trAumatic bRain injury—randomized controlled trial (POLAR-RCT), conducted in six countries, recruited 511 patients: 266 in the TH group and 245 in the normothermia group. Prophylactic TH targeted the early induction of hypothermia (33–35 °C) for at least 72 h, and up to 7 days if ICPs were elevated. Eligible patients aged 18 to 60 with a GCS score ≤8 were recruited.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278030_p33
|
PMC11278030
|
sec[6]/sec[7]/p[1]
|
7.8. Cooper: POLAR-ACT
| 4.125 |
biomedical
|
Study
|
[
0.947265625,
0.0521240234375,
0.0008001327514648438
] |
[
0.9697265625,
0.0254058837890625,
0.001678466796875,
0.0030269622802734375
] |
Although TH was initiated rapidly after injury (median time, 1.8 h), the time to reach the final temperature target of 33 °C took a median of 10.1 h (IQR, 6.8 to 15.9). A total of 85 evaluable patients (33%) in the TH group received hypothermia for less than 48 h (33 °C–35 °C), and 27% of the patients in the TH group never reached the final target temperature of 33 °C. Favorable outcomes (GOS-E score, 5–8) at 6 months occurred in 48.8% of the TH group and 49.1% of the normothermia group (risk difference, 0.4% [95% CI, −9.4% to 8.7%]; relative risk with TH, 0.99 [95%CI, 0.82–1.19]; p = 0.94).
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p34
|
PMC11278030
|
sec[6]/sec[7]/p[2]
|
7.8. Cooper: POLAR-ACT
| 3.738281 |
biomedical
|
Study
|
[
0.96923828125,
0.0297393798828125,
0.0009746551513671875
] |
[
0.9873046875,
0.0101165771484375,
0.0010814666748046875,
0.0013408660888671875
] |
Compared to those with normothermia, early prophylactic TH did not improve neurological outcomes at 6 months. No significant interactions were noted between the treatment group and any of the pre-specified subgroups: the presence of surgically evacuated cranial hematomas and any intracranial hematoma (surgically evacuated or not). The patients’ age and timing of surgery in relation to body temperature were not mentioned .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278030_p35
|
PMC11278030
|
sec[6]/sec[8]/p[0]
|
7.9. Hui: LTH-1
| 4.019531 |
biomedical
|
Other
|
[
0.833984375,
0.1627197265625,
0.003192901611328125
] |
[
0.332275390625,
0.65673828125,
0.00246429443359375,
0.00836181640625
] |
The Long-Term Hypothermia trial (LTH-1), conducted in 14 hospitals in China, was a prospective multicenter RCT conducted to examine the safety and efficacy of hypothermia in adults with severe TBI. Eligible patients included those aged 18–65, with a GCS score of 4 to 8, and an initial ICP ≥25 mmHg. Patients were randomly assigned to the long-term TH group (34–35 °C for 5 days) or normothermia group at 37 °C.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278030_p36
|
PMC11278030
|
sec[6]/sec[8]/p[1]
|
7.9. Hui: LTH-1
| 4.132813 |
biomedical
|
Study
|
[
0.9853515625,
0.0141754150390625,
0.00048470497131347656
] |
[
0.99462890625,
0.003910064697265625,
0.0009212493896484375,
0.0006508827209472656
] |
There were no differences between the groups in terms of favorable outcomes or mortality. However, TH significantly increased favorable outcomes over the normothermia group in patients with an initial ICP ≥30 mm Hg (60.8% and 42.7%, respectively; OR 1.861, 95%CI 1.031–3.361; p = 0.039). Of note, ICH removal was conducted in 91.8% of the normothermia group and 92.3% of the TH group, and decompressive craniectomy was performed in this order in 71.2% and 68.0% of the patients, respectively .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p37
|
PMC11278030
|
sec[6]/sec[9]/p[0]
|
7.10. Hergenroeder: HOPES
| 4.046875 |
biomedical
|
Other
|
[
0.84912109375,
0.148681640625,
0.002422332763671875
] |
[
0.4404296875,
0.54638671875,
0.003398895263671875,
0.0095977783203125
] |
The HypOthermia for Patients requiring Evacuation of Subdural hematoma (HOPES) trial was a multicenter RCT designed based on previous studies, in which the early induction of TH and early hematoma removal in young adults provided favorable outcomes. This RCT was conducted in the USA and Japan, enrolling patients with ASDH requiring evacuation within 6 h of injury. Patients in the TH group were cooled by an endovascular device to reach 35 °C by the time of dural opening and sustained for 48 h. Patients in the control group were maintained at 37 °C.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278030_p38
|
PMC11278030
|
sec[6]/sec[9]/p[1]
|
7.10. Hergenroeder: HOPES
| 4.03125 |
biomedical
|
Other
|
[
0.85302734375,
0.1427001953125,
0.004108428955078125
] |
[
0.4130859375,
0.5771484375,
0.00209808349609375,
0.007709503173828125
] |
The trial design aimed to enroll 120 patients; however, due to slow accrual, an early futility interim analysis was added after 31 participants completed the 6-month follow-up. There were no significant differences in favorable 6-month GOS-E between the TH and the normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = 0.35) in this analysis. The plasma levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase did not differ between the two groups .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p39
|
PMC11278030
|
sec[7]/p[0]
|
8. Review of Prior Meta-Analyses
| 3.986328 |
biomedical
|
Study
|
[
0.9990234375,
0.0004935264587402344,
0.00038504600524902344
] |
[
0.744140625,
0.0017843246459960938,
0.253662109375,
0.0004382133483886719
] |
A PubMed/MEDLINE literature search and citations from references yielded 25 meta-analyses assessing TH for adult TBI . The highlights of each study are summarized in Table 2 . These meta-analyses have found conflicting results, with few studies indicating the benefits of TH. However, some studies have shown the benefits of long-term TH compared to short-term TH . TH is effective in lowering elevated ICP ; however, decreased ICP does not result in favorable outcomes .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p40
|
PMC11278030
|
sec[7]/p[1]
|
8. Review of Prior Meta-Analyses
| 3.966797 |
biomedical
|
Review
|
[
0.99853515625,
0.000789642333984375,
0.0006690025329589844
] |
[
0.494140625,
0.0013828277587890625,
0.50390625,
0.0004515647888183594
] |
Several studies have previously reported on the quality of RCTs, with results showing that low-quality RCTs overestimate the benefits of TH, while high-quality RCTs showed no difference in outcome between the TH and the normothermia groups, or even worse outcomes in the TH group . Indeed, two RCTs with a low risk of bias showed significantly higher mortality, poorer outcomes, and an equal incidence of new-onset pneumonia in the TH group. In contrast, other RCTs with a high risk of bias showed the opposite, with higher mortality and worse outcomes, but fewer new pneumonia cases in the control group .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p41
|
PMC11278030
|
sec[7]/p[2]
|
8. Review of Prior Meta-Analyses
| 4.015625 |
biomedical
|
Study
|
[
0.99951171875,
0.00038433074951171875,
0.0003204345703125
] |
[
0.93115234375,
0.0007109642028808594,
0.06793212890625,
0.0002206563949584961
] |
Several studies have addressed the heterogeneity of TBI . One study used a cooling index calculated from the target cooling temperature, cooling duration, and speed of rewarming to standardize and assess the quality of TH. Although inter-study heterogeneity was high, TH was beneficial in severe TBI only if the cooling index was sufficiently high. As independent factors, milder and longer cooling, and rewarming at <0.25 °C/h were associated with better outcomes . A cooling index-based meta-analysis, including the recent POLAR-ACT study, strengthened the results regarding the benefits of TH .
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p42
|
PMC11278030
|
sec[8]/p[0]
|
9. A Meta-Analysis of Young Patients with Surgically Evacuated Hematoma
| 4.015625 |
biomedical
|
Study
|
[
0.99951171875,
0.0002942085266113281,
0.0002065896987915039
] |
[
0.98583984375,
0.0005431175231933594,
0.0136871337890625,
0.00014388561248779297
] |
Animal experiments investigating ASDH have shown brain swelling after hematoma removal , while early preoperative TH reduced ischemia/reperfusion injury following surgical evacuation . Early TH may therefore offer potential benefits in attenuating ischemia/reperfusion injury in patients requiring ASDH removal . In the existing RCTs, the benefits of early TH have also been suggested for young patients with evacuated mass lesions, although individual RCTs included only a small number of eligible patients . Thus, a meta-analysis including the NABIS:H I, NABIS:H II, B-HYPO, and HOPES trials was performed.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p43
|
PMC11278030
|
sec[8]/p[1]
|
9. A Meta-Analysis of Young Patients with Surgically Evacuated Hematoma
| 4.117188 |
biomedical
|
Study
|
[
0.9990234375,
0.0009307861328125,
0.0002353191375732422
] |
[
0.99462890625,
0.0009250640869140625,
0.004016876220703125,
0.0001939535140991211
] |
The resulting forest plot showed a significant increase in favorable outcomes in the TH group compared with the control group (RR = 0.70, [95% CI = 0.53, 0.92], p = 0.01). Although the mortality rates for this subgroup were not described in NABIS:H I, a trend toward lower mortality rates was observed in the TH group. (PR = 0.47, [95% CI = 0.21, 1.04], p = 0.07) . The assessment of the risk of bias is shown in Table S1 . Although some differences in age and time to surgery were noted in each RCT (age ≤ 45, the induction of HT to 35 °C within 1.5 h of surgery start time in NABIS:H I and II study ; age ≤ 50, time to 35.5 °C 280 min in B-HYPO study ; average age of 43.9, 35 °C prior to dura opening in HOPES trial ), cooling was commonly initiated early before surgery. The meta-analysis indicated that TH would be suitable for the following patients: (1) relatively young, (2) with evacuated mass lesions, (3) with early cooling, and (4) with early hematoma evacuation.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278030_p44
|
PMC11278030
|
sec[9]/p[0]
|
10. Limitations of RCTs
| 4.015625 |
biomedical
|
Study
|
[
0.998046875,
0.0012054443359375,
0.0005822181701660156
] |
[
0.56298828125,
0.002368927001953125,
0.43408203125,
0.0005402565002441406
] |
Similar limitations were noted across most existing large multicenter RCTs, including a variable timing of TH initiation, poor adherence to the temperature range, different rewarming rates, a variable duration of hypothermia, and poor design and methodology . Furthermore, a few essential issues have not been discussed in the existing RCTs. The first concern is the localization of brain injury. As the brain is functionally localized, functional recovery is closely dependent on the damaged region. Favorable outcomes seem unlikely in patients with severe damage to the eloquent areas. Although it would be challenging to conduct RCTs on this topic, the topographical assessment of brain damage is an essential concern. The second concern is rehabilitation. Early and appropriate rehabilitation positively affects patient recovery. The extent and duration of rehabilitation during and after TH are therefore likely to affect patient outcomes. The third is management strategies other than TH, although it may be impractical to standardize all the management procedures and medications across facilities.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p45
|
PMC11278030
|
sec[10]/p[0]
|
11. Future Prospects
| 3.957031 |
biomedical
|
Review
|
[
0.99609375,
0.0020580291748046875,
0.002071380615234375
] |
[
0.0156707763671875,
0.0014429092407226562,
0.982421875,
0.0003466606140136719
] |
A systematic review and meta-analysis of experimental TBI showed that TH appeared to be an effective treatment, although it should be noted that these studies had limitations in terms of quality and design . Discrepancies between experimental and clinical approaches should therefore be considered when translating animal experiments into clinical practice. For example, TH was introduced very early in animal studies compared to in clinical trials. This is important as the maxim “time lost is brain lost” commonly used to describe stroke also applies to TH for severe TBI.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278030_p46
|
PMC11278030
|
sec[10]/p[1]
|
11. Future Prospects
| 4.011719 |
biomedical
|
Review
|
[
0.9833984375,
0.0121612548828125,
0.004634857177734375
] |
[
0.003047943115234375,
0.0052947998046875,
0.99072265625,
0.0008196830749511719
] |
The essential question in the field of TH is “how early, how deep, how long, and how to rewarm”, which unfortunately remains unresolved. The specific pitfalls associated with the clinical management of TH, such as stress-induced insulin-resistant hyperglycemia and unstable systemic circulation, require particular attention . One umbrella review of the treatment options for TBI indicated that TH is the only clinical practice with evidence of benefit . Therefore, TH should not be abandoned in the treatment of severe TBI with hematomas. However, a one-size-fits-all treatment is not applicable to patients with severe TBI composed of heterogeneous lesions. Biomarkers may be valuable for stratifying the severity of TBI and assessing the effects of TH. Patients with severe TBI require individualized treatment for the underlying pathophysiology of brain injury. The meticulous management of neurocritical care is also essential for the successful completion of TH with minimal adverse events.
|
[
"Hitoshi Kobata"
] |
https://doi.org/10.3390/jcm13144221
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p0
|
PMC11278044
|
sec[0]/p[0]
|
1. Introduction
| 4.097656 |
biomedical
|
Review
|
[
0.9970703125,
0.0013570785522460938,
0.0014171600341796875
] |
[
0.04345703125,
0.002498626708984375,
0.95361328125,
0.00038433074951171875
] |
Sleep and brain health are tightly linked, with better sleep correlating with favorable objective and subjective measures of brain structure and function . Throughout the aging process, there is a progressive loss of “healthy” features of sleep macro- and micro-architecture, characterized by reductions in N3 sleep, sleep efficiency, and delta power. These alterations are more pronounced in certain neurological disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). It is noteworthy that a substantial proportion, ranging from 40% to 60%, of individuals with PD report experiencing sleep disturbances . These aging-associated sleep disturbances are independent risk factors that appear to contribute to and reflect both impaired cognitive function and mortality in older adults . There is a critical need for (1) practical and precise ways to track the effect of interventions that aim to improve brain health, and (2) non-pharmacological approaches to improve sleep and thus positively impact brain health.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p1
|
PMC11278044
|
sec[0]/p[1]
|
1. Introduction
| 4.011719 |
biomedical
|
Review
|
[
0.99365234375,
0.0027313232421875,
0.003604888916015625
] |
[
0.0125579833984375,
0.0012493133544921875,
0.98583984375,
0.0002586841583251953
] |
Exercise is an attractive intervention of key interest, as accumulating evidence shows beneficial effects on both sleep quality and measures of cognitive health in older adults . Previous work has suggested that exercise increases N3 sleep, which has been linked to brain aging and fast-sigma power and reduces sleep fragmentation . However, other studies have found minimal effects of exercise on N3 sleep . In addition, the extent to which exercise improves cognitive function in older adults with dementia remains a topic of investigation . Recent AAN (American Academy of Neurology), ACSM (American College of Sports Medicine), and WHO guidelines recommend that older individuals exercise 150–300 min weekly to maintain brain health . However, the optimal frequency, intensity, time, and type (FITT) of aerobic exercise are debatable. Overall, the differences in exercise regimen design, target population, and sleep and cognitive assessments in previous exercise intervention trials leave open the question of whether and to what extent exercise is able to improve brain health.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p2
|
PMC11278044
|
sec[0]/p[2]
|
1. Introduction
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
0.00020503997802734375,
0.0001971721649169922
] |
[
0.998046875,
0.0003070831298828125,
0.0017337799072265625,
0.00006878376007080078
] |
Our team recently developed a brain health biomarker called “Brain Age” (BA) derived from sleep EEG and recordings . BAI is the estimated BA minus chronological age (BAI = BA − CA), i.e., the difference between apparent (predicted) age and biological age. BAI is increased in individuals with neuropsychiatric (mild cognitive impairment or dementia) and cardiometabolic diseases . However, no study has evaluated whether BAI can be reduced through interventions that improve brain health. In addition, the practical challenges associated with the large-scale and longitudinal application of BAI within lab settings, including high costs, night-to-night variability of sleep, and the first-night effect in sleep laboratory testing, pose limitations. Despite recent advancements, such as the introduction of the sleep headband Dreem 2 aimed at improving sleep monitoring with fewer interferences mentioned above in home settings, the comparability of BAI computed from home sleep EEG recordings (e.g., captured by Dreem2) with BAI determined from the gold standard polysomnography (PSG) method for sleep monitoring remains uncertain.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p3
|
PMC11278044
|
sec[0]/p[3]
|
1. Introduction
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
0.0004029273986816406,
0.00021350383758544922
] |
[
0.9990234375,
0.00034928321838378906,
0.00031685829162597656,
0.00007718801498413086
] |
Here, we conducted an exploratory study (1) to evaluate whether the combination of a home sleep headband and BAI was able to track brain health in healthy middle-aged and older adults long term; and (2) to investigate whether a 12-week, 150 min weekly moderate-intensity aerobic exercise regimen designed to improve aerobic fitness could improve brain health, as reflected by an improvement in cognition, a reduction in BAI, and the enhancement of key features of sleep macro- and micro-architecture.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p4
|
PMC11278044
|
sec[1]/sec[0]/p[0]
|
2.1. Study Design and Participants
| 4.164063 |
biomedical
|
Study
|
[
0.99462890625,
0.005069732666015625,
0.0003323554992675781
] |
[
0.99755859375,
0.0017213821411132812,
0.0004448890686035156,
0.00042057037353515625
] |
We conducted a pre–post-interventional study. Adults aged 50 to 75 years old were recruited from the greater Boston area through online advertisements, flyers, and outpatient clinics at the Massachusetts General Hospital. Participants were included if physically inactive (average time spent exercising was less than 60 min per week in the past 6 months) and if they received clearance from their primary care physician to participate in the 12-week moderate-intensity exercise program. A pre-screening survey was used to select eligible participants with the following exclusion criteria: (1) a history of neurological illness (e.g., poorly controlled epilepsy with >1 seizure per month in the last 6 months, stroke with residual motor language deficits, multiple sclerosis, PD, dementia, head trauma in the past 6 months with a loss of consciousness >30 min, cerebral palsy, brain tumor, normal-pressure hydrocephalus, or Huntington’s disease; (2) a history of untreated or poorly controlled neuropsychiatric illness; (3) diagnosed with moderate or severe sleep apnea (apnea–hypopnea index ≥ 15/hour of sleep) or using a continuous positive airway pressure machine (CPAP); (4) HIV infection; (5) a history of falling within the past 6 months; (6) the inability to safely exercise (e.g., coronary heart disease, heart failure, osteoarthritis, or chronic fatigue syndrome) or the inability to perform any of the tests, e.g., failure to complete cardiopulmonary exercise testing (CPET) due to the development of cardiac symptoms during testing, or a lack of English proficiency, which would limit cognitive testing; and (7) the inability to complete the daily workout schedule. Written informed consent was obtained prior to participation in the study, which was approved by the Mass General Brigham Review Board . On the day of consent, participants completed CPET, cognitive testing, and a blood draw. Participants returned to the hospital within one week to undergo in-lab diagnostic polysomnography (PSG). These procedures were repeated at the end of the study. After the initial PSG, participants were instructed to begin a program of moderate-intensity exercise. Details of the exercise program are described below. The study design is shown in Figure 1 .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278044_p5
|
PMC11278044
|
sec[1]/sec[0]/p[1]
|
2.1. Study Design and Participants
| 4 |
biomedical
|
Study
|
[
0.9990234375,
0.0003941059112548828,
0.0004138946533203125
] |
[
0.99853515625,
0.0013570785522460938,
0.00017547607421875,
0.00005936622619628906
] |
Power analysis suggested that a minimum of 34 subjects (80% power, 0.5 mean of paired differences, 1.0 standard deviation of differences ) would be needed to evaluate whether a 12-week moderate-intensity exercise program can improve BAI and cognitive scores. We proposed the recruitment of 35 subjects to complete all assessments over a 1-year period to establish adequate power and to minimize Type II errors.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p6
|
PMC11278044
|
sec[1]/sec[1]/p[0]
|
2.2. Cardiopulmonary Exercise Testing
| 4.226563 |
biomedical
|
Study
|
[
0.998046875,
0.0016870498657226562,
0.00021278858184814453
] |
[
0.998046875,
0.0009064674377441406,
0.0009646415710449219,
0.00025916099548339844
] |
Aerobic exercise capacity (maximal oxygen consumption, VO 2 max), resting heart rate, and cardiac-event risk were measured at the Brigham and Women’s Hospital CPET laboratory by a clinical exercise physiologist. Prior to the visit, participants were instructed to refrain from smoking, eating, and drinking caffeinated or alcoholic beverages for an 8–12 h period overnight. During the exam, participants’ VO 2 max was determined by the following ramp cycle protocol: cycle ergometer (Lode Corival, Lode BV, Groningen, The Netherlands) intensity was set to 10–25 watts/minute (depending on the subject’s capacity) at the speed of 60 rpms until exhaustion or clinical concerns were voiced. Otherwise, termination criteria are listed below as follows: (1) participant heart rate reached the maximal value of (220 − age); (2) oxygen intake reached a plateau despite an increase in work rate; and (3) participants who indicated exhaustion or the BORG scale was equal to or larger than 17. Respiratory measurements and electrocardiogram (ECG) were recorded by the Ultima CPX system (Medgraphics, Saint Paul, MN, USA). For two participants who refused to complete the final assessment of their VO 2 max due to COVID-19 concerns, VO 2 max was estimated by a 1-mile walk test on an outdoor track. Briefly, participants were instructed to walk as quickly as possible while avoiding jogging or running. Post-walking heart rate, walk time, body weight, age, and sex were used to calculate VO 2 max as described in a previous study . In the context of the pandemic, where many participants expressed reluctance to visit hospitals due to concerns regarding viral transmission, utilization of the 1-mile walk test as a substitute for standard measurements was felt to be justified. A previous study validated that the correlation of VO 2 max measurements between the 1-mile walk test and graded treadmill testing was 0.8 among middle-aged and older adults, suggesting that the 1-mile walk test provides a reasonable estimate of VO 2 max .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p7
|
PMC11278044
|
sec[1]/sec[2]/p[0]
|
2.3. Cognitive Testing
| 4.0625 |
biomedical
|
Study
|
[
0.99951171875,
0.0002789497375488281,
0.0003604888916015625
] |
[
0.9990234375,
0.0006084442138671875,
0.0002980232238769531,
0.00005894899368286133
] |
The National Institutes of Health (NIH) Toolbox Cognition Battery was administered in a quiet and private environment by a trained study staff member . This battery is one of the core domains of the NIH Toolbox for Assessment of Neurological and Behavioral Function and consists of seven instruments. Fluid cognition is a measure of five of these instruments Dimensional Change Card Sort (DCCS), flanker inhibitory control and attention (FICA), list sorting working memory (LSWM), pattern comparison processing speed (PCPS), and Picture Sequence Memory (PSM), whereas crystallized cognition is a composite of two of these instruments (Picture Vocabulary Test (PVT) and Oral Reading Recognition (ORR)). Total cognition is a composite of fluid and crystallized scores. Absolute scores for each of the seven tests and the three composite scores were used for analyses (all non-age adjusted). Further explanation of the individual tests and scoring procedures is available in the Supplementary Materials .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p8
|
PMC11278044
|
sec[1]/sec[3]/p[0]
|
2.4. Plasma Biomarkers Level Assessment
| 4.136719 |
biomedical
|
Study
|
[
0.99951171875,
0.0004992485046386719,
0.00015807151794433594
] |
[
0.9990234375,
0.0005254745483398438,
0.0003724098205566406,
0.00010001659393310547
] |
On the morning of the CPET appointment, overnight fasting blood samples were drawn between 8 AM and 11 AM by a phlebotomist at the Mass General Brigham Center for Clinical Investigation. Blood was centrifuged at 2000× g for 15 min. Plasma was aliquoted and stored in a −80° freezer for protein analysis. Levels of cytokines were measured using the established electrochemi-luminescence-based multi-array method through the Quickplex SQ 120 system (by the Meso Scale Diagnostics LLC, Rockville, MD, USA) using previously reported methods . In brief, the system utilizes a 96-well-based high-throughput readout. Human proinflammatory multi-plex kits were utilized, which enabled the detection of 8 cytokines in our samples, including INF-γ, TNF-α, IL-2, IL-4, IL-6, IL-8, IL-10, and IL-13. Procedures for measuring cytokines levels followed manufacturer protocols. In brief, our samples and standard proteins provided by the manufacturer were prepared and incubated at 4 °C overnight. Then, the mixed solutions were placed on a shaker for 2 h, followed by washing and then incubation with detection of antibodies for another 2 h. Next, the electrochemi-luminescence signals were captured through the SQ 120 system. Finally, protein concentrations (pg/mL) were calculated using manufacturer-provided standard concentrations.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p9
|
PMC11278044
|
sec[1]/sec[4]/p[0]
|
2.5. Diagnostic Polysomnography (PSG)
| 4.171875 |
biomedical
|
Study
|
[
0.99755859375,
0.002262115478515625,
0.000202178955078125
] |
[
0.998046875,
0.0011053085327148438,
0.00041747093200683594,
0.0002841949462890625
] |
PSG was performed at the American Academy of Sleep Medicine (AASM)-Accredited Massachusetts General Hospital Sleep Disorders Unit. During the COVID-19 pandemic, all participants were cleared with PCR COVID-19 testing 72 h prior to the study. A minimum of six hours of overnight sleep was monitored using conventional in-lab polysomnography (Compumedics, Charlotte, NC, USA) with a 250 Hz sampling rate and a 0.3–35 Hz bandpass filter. EEG data were recorded from frontal (F3 and F4), central (C3 and C4), and occipital (O1 and O2) electrodes, and then referenced to contralateral mastoid electrodes (M2 and M1). Electrooculogram (EOG), electromyogram (EMG), ECG, pulse oximetry, respiration, and nasal flowmeter were used to assess sleep apnea and leg movements. Sleep was staged as non-rapid eye movement (NREM) stages 1 to 3, R (REM), or awake (W) stages in consecutive 30 s epochs following AASM criteria by Registered Polysomnographic Technologists . The final sleep report was reviewed by a physician with board certification in Sleep Medicine. Two participants who completed the initial assessment and exercise program declined to complete the final PSG assessment because of COVID-19 concerns. Their final sleep EEGs were recorded by Dreem 2, which is comparable to PSG to acquire physiological sleep signals .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p10
|
PMC11278044
|
sec[1]/sec[5]/p[0]
|
2.6. 12-Week Exercise Regimen
| 4.113281 |
biomedical
|
Study
|
[
0.97119140625,
0.0281524658203125,
0.0008449554443359375
] |
[
0.97900390625,
0.018768310546875,
0.0009899139404296875,
0.001201629638671875
] |
Participants completed a 12-week exercise regimen designed as follows: maintenance of 50–75% maximal heart rate (HRmax = 220 − age) intensity for 30 min per day, 5 days per week. Participants began with 15 min/day × 3 days in week 1, 20 min/day × 4 days in week 2, and then 30 min/day × 5 days over weeks 3–12. If they were unable to exercise for 30 min continuously, participants were allowed to split the 30 min of exercise into sessions of 10–15 min with 5 min rest intervals. For feasibility, the type and timing of exercise were not restricted; however, participants were encouraged to exercise around the same time each day. Participants were given a physical activity tracker (Fitbit, San Francisco, CA, USA) to monitor their exercising heart rate to ensure that exercise time and intensity met the requirements. Additionally, participants were instructed to log each physical activity session. High-intensity interval training (HIIT) and strength training were not allowed. According to the logs, 84% of participants’ exercise type was jogging or fast walking, 8% was elliptical running, and the remainder was cycling. The study team met in person or via teleconference (during the COVID-19 pandemic) bi-weekly with participants to answer questions and to verify that exercise duration adhered to the stipulated requirements.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278044_p11
|
PMC11278044
|
sec[1]/sec[6]/p[0]
|
2.7. Home Data Collection
| 4.101563 |
biomedical
|
Study
|
[
0.9990234375,
0.0007262229919433594,
0.0002713203430175781
] |
[
0.9990234375,
0.0007505416870117188,
0.0002052783966064453,
0.00008487701416015625
] |
Participants were asked to wear the Fitbit 24 × 7 and to sync the device every 5 days to upload the data to the cloud, allowing the study team to check adherence to the exercise program. Additionally, overnight sleep EEG was recorded using a home sleep headband (Dreem 2, France, or Prodigy, Canada) 2 nights per week throughout the 12-week exercise program. The Dreem 2 headband records via five EEG dry electrodes (Fpz, F7, F8, O1, and O2) at a 250 Hz sampling rate with a 0.4–35 Hz bandpass filter. The Prodigy sleep monitor records via six snap forehead electrodes (left/right frontal EEG sensors, left/right EOG sensors, mastoid, and chin sensors) at a 120 Hz sampling rate with a 0.33–35 Hz bandpass filter . Each subject used the same device throughout the study for consistency. Heart rate and EEG data were checked by the study team weekly to ensure adherence.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p12
|
PMC11278044
|
sec[1]/sec[7]/p[0]
|
2.8. Exercising Time and Sleeping Heart Rate
| 4.105469 |
biomedical
|
Study
|
[
0.9990234375,
0.00045371055603027344,
0.00028896331787109375
] |
[
0.99951171875,
0.0003657341003417969,
0.00021147727966308594,
0.0000655055046081543
] |
Continuous heart rate was tracked using a Fitbit via an optical sensor every 10 to 15 s. We set three timepoints to determine the time of exercise: T1 (peak heart rate timepoint), T2 (45 min before T1), and T3 (45 min after T1). Periods of exercise sessions were defined as compliant with the study protocol when the heart rate during T2 and T3 was ≥50–75% HRmax for at least 10 min. The sum of all such sessions was defined as the total exercise time. In the absence of Fitbit data, the exercise log was used. Fitbit automatically records sleep and wake timepoints. Sleeping heart rate was defined as the average heart rate across the entire night of sleep. We empirically identified periods during sleep when the heart rate was lower than the 20th percentile as representing stage N3, and periods with heart rate greater than the 80th percentile as REM.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p13
|
PMC11278044
|
sec[1]/sec[8]/p[0]
|
2.9. EEG Preprocessing and Artifact Removal
| 4.1875 |
biomedical
|
Study
|
[
0.99951171875,
0.00033473968505859375,
0.00020945072174072266
] |
[
0.9990234375,
0.00028228759765625,
0.00039196014404296875,
0.0000870823860168457
] |
For both in-lab PSG and at-home sleep measurements, EEG signals were notch-filtered at 60 Hz to reduce line noise and bandpass filtered from 0.5 Hz to 20 Hz to reduce myogenic artifact. The signals were then segmented into 30 s epochs. Epochs with artifacts were excluded in two steps. In the first step, we removed “definite” artifacts by excluding epochs with a maximum absolute amplitude larger than 500 µV or a flat (standard deviation < 1 µV) amplitude that lasted 2 s or longer. In the second step, for the remaining epochs, we trained a linear discriminant analysis (LDA) classifier to classify each epoch into artifact vs. not artifact. We used the total power and 2nd-order difference (for abrupt non-physiological changes; see the Supplementary Materials ) of the spectrum as inputs to the LDA classifier. To train the classifier, we manually labeled each epoch in randomly selected EEGs (two channels: F7-O1, F8-O2) with different ratios of definite artifact per epoch across the night: 10 EEGs with a ratio of 25–50%; 10 EEGs with a ratio > 50%. After training, the LDA classifier labeled each epoch as artifact or not artifact. By comparing these with manually assigned labels, we derived a receiver operating characteristic (ROC) curve . We used this ROC curve to find a threshold that achieved a false negative rate (FNR) of 10%, as visual analysis suggested that this cutoff produced an acceptable tradeoff between retaining high-quality signals and rejecting artifactual epochs. The EEG artifact removal model mentioned above was implemented using Python 3.7 (Python Software Foundation, Wilmington, DE, USA) and the MNE package . Please check Supplemental Methods S1 for details regarding the artificial removal of EEG.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p14
|
PMC11278044
|
sec[1]/sec[9]/p[0]
|
2.10. Brain Age Computation and Spindle Analysis
| 4.222656 |
biomedical
|
Study
|
[
0.99951171875,
0.00033402442932128906,
0.00027370452880859375
] |
[
0.9990234375,
0.0002219676971435547,
0.000518798828125,
0.00007927417755126953
] |
The BAI was computed as described previously, with minor changes . Briefly, BAI was calculated using a machine learning model with overnight sleep EEG features. For each 30 s epoch, we extracted 96 features from both time and frequency domains, including line length (signal complexity) and signal kurtosis (extent of extreme values); max, min, mean, and standard deviation of relative delta, theta, alpha band powers, and delta-to-theta, delta-to-alpha, and theta-to-alpha power ratio computed across 2 s sub-epochs; and kurtosis of spectral power in delta, theta, alpha, and sigma bands. We averaged these features within each of the five sleep stages separately (REM, N1, N2, N3, and Wake) over time, and concatenated them, to finally arrive at 96 × 5 = 480 features to represent physiologic information in a night of sleep. Here, we extracted 96 features, whereas our previous study used 102 features. The 6 fewer features are the sample entropy of the EEG from each of the 6 electrodes. Further examination showed that these features had zero coefficients in the original BAI model. Therefore, we dropped them. Note that the 96 features are for computing BAI from overnight in-lab PSG at the beginning and the end of the study, which includes 6 EEG electrodes. When computing BAI from at-home sleep EEGs (Dreem and Prodigy), we used the available 2 frontal EEG electrodes. Hence, the feature number was 96/3 = 32. The brain age model for frontal EEG only was trained using the same training dataset from the original brain age model, while limiting features to the 2 frontal EEG electrodes only. Sleep EEG data with an artifact ratio < 0.5 were computed for the BAI. In addition, sleep spindles, delta or slow oscillations, and their coupling during N2 sleep were detected and their summary features were quantified using Luna software V0.27 . In detail, the signal is first bandpass filtered at 0.2–4.5 Hz using Luna, and then SOs are detected using zero-crossing rules. The signal for detecting SO is the raw signal from the device; there is no high-pass filtering performed. Spindle features included spindle density, average peak frequency, average amplitude, and average duration. The delta or slow oscillation features include their density, average amplitude, average duration, positive-to-negative slope, and negative-to-positive peak. The coupling features included magnitude of coupling, number of spindles overlapping a detected delta or slow oscillation, and average delta or slow oscillation phase at the spindle peak.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p15
|
PMC11278044
|
sec[1]/sec[10]/p[0]
|
2.11. Sleep Metrics Analysis
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
0.0003325939178466797,
0.00018084049224853516
] |
[
0.9990234375,
0.0007543563842773438,
0.0003371238708496094,
0.00007683038711547852
] |
Sleep stages and conventional sleep metrics were analyzed for in-lab PSG measurements and home sleep assessments. Sleep staging of in-lab PSGs was performed as described above. Prodigy headband data were staged using a previously described automated algorithm . Dreem headband data were staged using the manufacturer’s automated system . Additionally, conventional sleep metrics were calculated as follows: Sleep efficiency = TST/TIB × 100%; Awakening index = (# of transitions sleep to wake)/TIB; WASO = total wake time after sleep and before final awakening; where TST = total sleep time; TIB = time in bed; WASO = wake after sleep onset.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p16
|
PMC11278044
|
sec[1]/sec[11]/p[0]
|
2.12. Statistical Analysis
| 4.066406 |
biomedical
|
Study
|
[
0.99951171875,
0.00030517578125,
0.0002372264862060547
] |
[
0.9990234375,
0.00023865699768066406,
0.000476837158203125,
0.00006508827209472656
] |
The change in various metrics from pre- to post-exercise, including BAI, sleep macro- and micro-architecture, cognitive scores, VO 2 max, and heart rate, were analyzed with paired t-tests. Effect size (ES, Cohen’s d) was calculated as the mean change of pre-exercise and post-exercise values divided by pooled standard deviation (no adjustment of covariates, as the study compared pre- and post-exercise values within the same subjects). Associations were measured using Pearson’s correlation coefficients . Shapiro–Wilk tests were used to verify the normal distribution requirement of Pearson’s correlation analysis. A linear mixed effects model (LMEM) was employed to examine the effects of age, gender, BAI, VO 2 max, heart rate, cognitive scores, and cytokines that model both pre-to-post within-person effects and cross-sectional effects. The mixed effect models used a random intercept and random slope. Benjamini and Hochberg False Discovery Rate (FDR) method to control the proportion of false discoveries when conducting multiple hypothesis tests. Data are presented as mean ± standard error (SE), mean difference (ME, post-pre data), and 95% confidence interval (CI), except where otherwise specified. Statistical significance was defined as p < 0.05. Statistical analyses were performed with Python 3.7 (Python Software Foundation, Wilmington, DE, USA), Rstudio 1.1.0 , and GraphPad Prism 8.0 (San Diego, CA, USA).
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p17
|
PMC11278044
|
sec[2]/sec[0]/p[0]
|
3.1. Participant Characteristics
| 3.742188 |
biomedical
|
Study
|
[
0.958984375,
0.03961181640625,
0.0014448165893554688
] |
[
0.97021484375,
0.0269927978515625,
0.0006432533264160156,
0.0022678375244140625
] |
Thirty-one eligible participants were enrolled between November 2019 and June 2021 . Five were subsequently excluded: one withdrew because of cardiovascular risk detected by CPET; two withdrew for personal reasons related to the COVID-19 pandemic; and two withdrew due to stated inability to exercise resources during the pandemic. Of the remaining twenty-six participants, two declined to complete the final in-lab PSG and CPET assessments due to COVID-19 concerns. Their final sleep EEG and VO 2 max were assessed outside of the hospital (see Section 2 above). Prior to reaching the pre-defined target sample size of 34, recruitment was discontinued due to unanticipated enrollment and budget challenges related to the COVID-19 pandemic. Thus, all analyses reported herein are based on the participants who completed the study (N = 26), except where otherwise specified.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p18
|
PMC11278044
|
sec[2]/sec[0]/p[1]
|
3.1. Participant Characteristics
| 4.054688 |
biomedical
|
Study
|
[
0.99853515625,
0.00106048583984375,
0.00034165382385253906
] |
[
0.99951171875,
0.0003695487976074219,
0.00015616416931152344,
0.00010323524475097656
] |
Our final sample included 20 females and 6 males with an average age of 60 ± 7.37 years (mean ± standard deviation, SD). All subjects completed at least college-level education, averaging 17.19 ± 2.8 (mean ± SD) years of education. The average body mass index (BMI) was not significantly different between pre- and post-exercise time points. Average apnea–hypopnea indices were 4.05 ± 3.92 (mean ± SD) and 3.06 ± 3.94 (mean ± SD) at initial and final assessments. Participants exercised for approximately 47 ± 13 days (mean ± SD) over the 12-week period and 55 ± 9.8 min/day (mean ± SD), based on their heart rate data and exercise logs. Participant characteristics are presented in Table 1 .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p19
|
PMC11278044
|
sec[2]/sec[1]/p[0]
|
3.2. Physical Fitness
| 3.634766 |
biomedical
|
Study
|
[
0.9990234375,
0.0005002021789550781,
0.0005049705505371094
] |
[
0.9970703125,
0.0020847320556640625,
0.0007233619689941406,
0.0001239776611328125
] |
The 12-week aerobic exercise program improved measures of cardiovascular fitness, as measured by VO 2 max . Relative to baseline measurements, decreases in resting heart rate , sleeping heart rate , and heart rate in N3 sleep were also observed following the exercise program.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p20
|
PMC11278044
|
sec[2]/sec[2]/p[0]
|
3.3. Cognition Performance Score
| 3.914063 |
biomedical
|
Study
|
[
0.998046875,
0.00034618377685546875,
0.0014095306396484375
] |
[
0.99853515625,
0.0005664825439453125,
0.0007042884826660156,
0.000052988529205322266
] |
After the 12-week exercise program, cognitive performance was improved in multiple domains, including the composite domains of crystallized intelligence , fluid intelligence , and total cognition . Additionally, improvements in the subdomains of processing speed, as measured by pattern comparison processing speed , and language skills, as measured by oral reading recognition , were observed. Improvement on the list sort working memory test was marginally significant .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p21
|
PMC11278044
|
sec[2]/sec[3]/p[0]
|
3.4. Plasma Biomarkers
| 3.595703 |
biomedical
|
Study
|
[
0.9990234375,
0.0005483627319335938,
0.0006008148193359375
] |
[
0.9990234375,
0.0008044242858886719,
0.00030517578125,
0.00009304285049438477
] |
Compared to baseline levels of plasma cytokines, the post-exercise IL-8 level was significantly decreased . After 12 weeks of moderate-intensity exercise, plasma IL-4 was significantly elevated compared to baseline. Peripheral IL-13 level borderline significantly increased after the exercise regimen.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11278044_p22
|
PMC11278044
|
sec[2]/sec[4]/p[0]
|
3.5. BAI and Sleep Micro-Architecture
| 4.089844 |
biomedical
|
Study
|
[
0.9990234375,
0.0005860328674316406,
0.00030875205993652344
] |
[
0.99951171875,
0.00020694732666015625,
0.0002186298370361328,
0.00007277727127075195
] |
No differences were seen in BAI measured through in-lab PSG comparing baseline and post-exercise timepoints . Additionally, we did not observe significant changes in sleep micro-architectural features, including delta band power during N3 sleep or alpha band power in the awake state . Likewise, no change was observed in spindle density . After artifact detection and removal, 64% of home sleep headband data exhibited sufficient quality (artifact ratio < 0.5) to compute BAIs. As with in-lab PSG findings, no significant differences were seen in BAI measured by home sleep EEG when comparing baseline to post-exercise data . Similarly, we found no significant changes in delta band power during N3 sleep , alpha band power in the awake state , or spindle density .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p23
|
PMC11278044
|
sec[2]/sec[5]/p[0]
|
3.6. Sleep Macro-Architecture
| 4.09375 |
biomedical
|
Study
|
[
0.9990234375,
0.0004935264587402344,
0.00024330615997314453
] |
[
0.99951171875,
0.000255584716796875,
0.0003426074981689453,
0.0000699758529663086
] |
We analyzed conventional metrics of sleep quality based on sleep macro-architecture from in-lab PSG and home sleep device data, to determine whether the 12-week exercise regimen was able to improve sleep quality. We found no significant differences in sleep stage percentages in the pre–vs.–post-exercise in-lab PSG data for wake , REM , and NREM states . Similarly, we found no significant differences in stage percentages after the 12-week exercise regimen compared to baseline measurement for sleep measured with home EEG for wake , REM , and NREM .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p24
|
PMC11278044
|
sec[2]/sec[5]/p[1]
|
3.6. Sleep Macro-Architecture
| 3.572266 |
biomedical
|
Study
|
[
0.9990234375,
0.0004773139953613281,
0.0004634857177734375
] |
[
0.99853515625,
0.0006222724914550781,
0.0005593299865722656,
0.00008374452590942383
] |
We also found no significant exercise effects on sleep quality metrics derived from sleep macro-architecture measured with in-lab PSG , including sleep efficiency , awakening index , and wake after sleep onset (WASO) . Similarly, no exercise effects were found in home sleep data for sleep efficiency , awakening index , and WASO .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p25
|
PMC11278044
|
sec[2]/sec[6]/p[0]
|
3.7. Associations of the Study Outcomes
| 4.082031 |
biomedical
|
Study
|
[
0.9990234375,
0.00038743019104003906,
0.0003609657287597656
] |
[
0.99951171875,
0.00012433528900146484,
0.00031065940856933594,
0.000056684017181396484
] |
We further analyzed the relationship between the study outcomes by Pearson’s correlation ( Table 2 ). The improvement of VO 2 max was positively related to the enhancement of cognition performance but not related to the change in BAI . Elevated BAI was related to reduced NREM sleep and more fragmented sleep as measured by wake stage percent , sleep efficiency , and WASO . However, we did not observe any statistically significant relations between δVO 2 max and δN3 . In addition, the increment of BAI was associated with lower levels of plasma IL-4 and IL-13 . The improvement of cognitive executive function measured by dimension card change sort was positively related to increased N2 and NREM sleep percentages. Additionally, we found higher levels of IL-13 and IL-4 and lower levels of IL-8 were significantly related to better sleep quality as measured by sleep efficiency , N3 percentage , NREM percentage , awakening index , and delta band power during N3 sleep . Higher levels of IL-4 were also significantly associated with the improvement of cognition performance measured by processing speed and language ability.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p26
|
PMC11278044
|
sec[2]/sec[6]/p[1]
|
3.7. Associations of the Study Outcomes
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.0003681182861328125,
0.0003418922424316406
] |
[
0.99951171875,
0.0001341104507446289,
0.0003199577331542969,
0.0000616312026977539
] |
Results of the linear mixed effects modeling to analyze relations between BAI, VO 2 max, heart rate, cognitions, and plasma cytokines, adjusted for age and sex, are shown in Table 3 . The results were computed from the whole dataset including the five withdrawn participants who only completed baseline assessments. Resting heart rate was negatively associated with VO 2 max ( p = 0.03). Moreover, BAI predicted from PSG data was positively related to plasma IL-8 ( p = 0.035), and inversely related to fluid intelligence ( p = 0.009), processing speed ( p = 0.002), IL-4 ( p = 0.009), IL-13 , and potentially memory performance ( p = 0.103). Additionally, we found a trend between PSG-derived BAI and resting heart rate, a predictor of VO 2 max ( p = 0.087). However, BAI calculated from PSG data was not correlated directly with VO 2 max ( p = 0.564). We did not observe any significant relationships between BAI calculated from home EEG data and VO 2 max, cognitive performance measures, heart rate, or cytokine levels.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11278044_p27
|
PMC11278044
|
sec[3]/p[0]
|
4. Discussion
| 4.121094 |
biomedical
|
Study
|
[
0.94775390625,
0.0509033203125,
0.0013895034790039062
] |
[
0.7470703125,
0.2437744140625,
0.0027256011962890625,
0.006389617919921875
] |
This interventional clinical trial evaluated the feasibility of using home monitoring devices and BAI to track brain health in physically inactive middle-aged and older adults over a 12-week moderate-intensity exercise program. Compared to previous studies that relied on subjective sleep reports or coarse measures of sleep, our study collected abundant physiological data in both in-lab and home settings. Our results suggest that (1) plasma cytokines, cognitive performance, and physical fitness were improved in physically inactive middle-aged and older adults after a 12-week moderate-intensity aerobic exercise regimen; (2) BAI, as currently computed, was not sensitive enough to detect neurophysiologic correlates of these improvements in cognition for this type of population after this level of improved physical fitness; (3) the improvement of cognitive performance was associated with improvements in aerobic fitness and higher circulating IL-4/13, although not with BAI; and (4) lower BAI was associated with less fragmented sleep and higher levels of neuroprotective cytokines (IL-4/13). Additionally, the present study is a feasible and exploratory single-arm trial that evaluated the combination of home devices and BAI to track brain and sleep health in middle-aged and older adults long term. Our physiological assessment suggests that moderate-intensity aerobic exercise may improve brain health and sleep quality in previously physically inactive middle-aged and older adults.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p28
|
PMC11278044
|
sec[3]/sec[0]/p[0]
|
4.1. Improvements in Cognitive Performance
| 4.089844 |
biomedical
|
Study
|
[
0.9990234375,
0.0003790855407714844,
0.0005083084106445312
] |
[
0.9990234375,
0.0001691579818725586,
0.0007171630859375,
0.00005710124969482422
] |
We found that the 12-week, 150 min per-week moderate-intensity exercise program produced measurable improvements in fluid intelligence, crystallized intelligence, and total cognitive performance. Specifically, processing speed and oral reading recognition skills were moderately improved, and improvements in working memory were marginally significant. Our results agree with previous reports showing moderate improvements in processing speed (~7%) following aerobic exercise in older adults . Moreover, our data agree with a recent study that 12-week strength training improves fluid cognition in older adults . In contrast to processing speed, previous studies show mixed results regarding working memory improvement following aerobic exercise , likely due to different sample demographics and assessment methods for working memory. However, one meta-analysis found that healthy participants exhibit improvements in working memory following exercise, which is in line with our findings . Further, to determine whether the improvement of cognitive performance is related to learning or practice effects, we compared the effect size of our cognition performance with a previously published study . We found that the current 12-week exercise program produced higher effect sizes on cognition scores compared to the 7- to 21-day test–retest effect. Additionally, the 12-week interval is long enough to minimize the test–retest practice effect on cognition function according to the previous literature . Therefore, we believe the improvements seen in cognition performance result from the 12-week aerobic exercise regimen.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278044_p29
|
PMC11278044
|
sec[3]/sec[0]/p[1]
|
4.1. Improvements in Cognitive Performance
| 4.367188 |
biomedical
|
Study
|
[
0.99951171875,
0.0004012584686279297,
0.0002033710479736328
] |
[
0.998046875,
0.00034618377685546875,
0.001384735107421875,
0.00014150142669677734
] |
There may be multiple mechanisms by which a moderate-intensity exercise regimen improves cognitive performance, including the following: (1) improved cerebrovascular function ; (2) increase in hippocampal volume and reduction in the burden of white matter lesions ; and (3) regulation of peripheral cytokines and neurotrophic factors, such as Brain-derived Neurotrophic Factor (BDNF) , IL-6, cathepsin B, irisin , and IGF-1 . Here, we found that several plasma cytokines, IL-4, IL-8, and IL-13, were altered after the exercise regimen. Importantly, we further observed that the improvement of processing speed and oral reading recognition skills were related to the increment of IL-4. Our results reinforce the key functions of anti-inflammatory cytokines IL-4/13, which have been shown to exert neuroprotective effects on activated microglia to protect neurons from injury and hippocampal volume loss . Moreover, higher levels of IL-4 in both animal and human trials are associated with better cognitive performance , while increased circulating proinflammatory IL-8 is associated with lower memory and processing speed . The potential principals were IL-4 and receptor-mediated signaling is responsible for neuron growth and survival and promotes other neuron growth factors expression such as nerve growth factor (NGF). The observation of reduced circulating IL-8 over the 12-week exercise program is consistent with the finding of a different exercise regimen, which showed a rapid decrease in IL-8 at 30 min after exercise . Additionally, IL-8 is strongly associated with oxidative stress , which is related to impaired cognition function . Thus, our data suggest that one mechanism for the observed therapeutic effects of exercise on brain cognitive health may be improvements in circulating plasma cytokines. It might also be of interest in the future to measure the effects of physical exercise on biological aging using a DNA methylation epigenetic clock in parallel with the EEG-based BAI . The findings of our current study warrant future research to further characterize the mechanisms by which exercise improves cognitive functions.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p30
|
PMC11278044
|
sec[3]/sec[1]/p[0]
|
4.2. Sleep and Sleep EEG-Based Brain Age Index
| 4.289063 |
biomedical
|
Study
|
[
0.99951171875,
0.0003943443298339844,
0.0002486705780029297
] |
[
0.99853515625,
0.00019884109497070312,
0.000988006591796875,
0.00011110305786132812
] |
When evaluating sleep metrics, we did not observe changes between baseline and post-exercise training evaluations. Similar to previous work, the effects of exercise training on sleep macro- or micro-architectures remain uncertain, especially in people without sleep complaints . For example, acute exercise training has been reported in some studies to increase delta band power and N3 sleep duration . However, another randomized study concluded that a 12-month moderate-intensity exercise program improved several objective measures of sleep but did not change measures of N3 sleep . Unfortunately, we did not observe any changes in BAI over the 12-week study period. Multiple factors (e.g., small sample size, exercise intensity, duration, the time before sleep when exercise was completed, night-to-night variability, and individual differences in participants) could potentially explain these inconsistencies. Although the exercise regimen did not appear to reduce BAI, we did find that younger brain age (lower BAI) was associated with more N2 and N3 sleep and less fragmented sleep, which we interpret as supporting BAI as an indicator of brain health over longer time periods. Additionally, we observed that higher plasma IL-13 is significantly associated with increased sleep efficiency and increased N3 sleep as a percentage of total sleep, while higher IL-8 levels were related to more fragmented sleep. Our findings are in agreement with previous work that circulating IL-8 is significantly increased in sleep-disordered patients compared to healthy controls . Moreover, the higher levels of the neuroprotective cytokines IL-4/13 were significantly associated with younger brain age, which is the first time an association has been shown between circulating biomarkers and BAI. Furthermore, we discovered that circulating IL-4 is positively correlated with N3 sleep power. Recently, there has been increasing interest in augmenting N3 sleep to improve cognition, e.g., through transcranial electrical stimulation and controlled acoustic stimuli . N3 sleep and increased slow wave power during sleep are associated with several desirable physiological effects, including enhanced glymphatic flow , stable breathing, and vagal dominance of heart rate variability . Along with the relationship between sleep microarchitecture and cognitive health, we observed that better brain executive function is associated with more NREM sleep, which is similar to previous findings .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p31
|
PMC11278044
|
sec[3]/sec[1]/p[1]
|
4.2. Sleep and Sleep EEG-Based Brain Age Index
| 3.832031 |
biomedical
|
Study
|
[
0.99951171875,
0.00021767616271972656,
0.0004050731658935547
] |
[
0.9990234375,
0.0005135536193847656,
0.0002677440643310547,
0.00005799531936645508
] |
It is noteworthy that this study was completed during the COVID-19 pandemic. This global pandemic is strongly associated with widespread heightening of anxiety and depression levels , significant changes in lifestyle (increase in daily sedentary time and nap time) , and increased disturbances in sleep patterns and quality . In the present study, the changes in sleeping heart rate and improvements in exercise performance were modest. It is possible that a more vigorous and prolonged program may show changes not evident in our study. Individual differences in brain macro- and micro-architecture during sleep may also be important, with exercise providing greater benefit in those with reduced baseline slow wave power.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p32
|
PMC11278044
|
sec[3]/sec[2]/p[0]
|
4.3. Improvements in Aerobic Fitness
| 4.207031 |
biomedical
|
Study
|
[
0.99951171875,
0.00038886070251464844,
0.00025343894958496094
] |
[
0.9990234375,
0.00018656253814697266,
0.0005359649658203125,
0.0000832676887512207
] |
As hypothesized, the 12-week moderate-intensity aerobic exercise program increased VO 2 max and decreased resting and sleeping heart rate. Notably, our study included two participants whose final VO 2 max values were estimated using the 1-mile walk method, highlighting a gap in directly comparing predictive VO 2 max with CPET-VO 2 max. While the 1-mile walk test is a validated indirect measure correlated with VO 2 peak, we acknowledge its limitations in replacing CPET for VO 2 max determination. CPET remains the gold standard, ensuring a more accurate and comprehensive assessment of VO 2 max. Concerns arise regarding the potentially limited responsiveness of specific individuals to low-intensity endurance training in terms of VO 2 max improvement, as indicated by a meta-analysis . It is noteworthy that the participants included in this meta-analysis predominantly encompass young to middle-aged adults. Conversely, an alternate report suggests a substantial 16.3% enhancement in VO 2 max resulting from endurance training when compared to control groups . We observed that heart rate during N3 sleep was reduced after the exercise regimen compared to baseline measurements. We found that improvements in VO 2 max were associated with improvements in cognitive performance and reduction of sleeping heart rate, but not with a change in BAI and sleep macro- and micro-architecture. Additionally, we did not find any associations between the improvement of VO 2 max and the change of expression of plasma cytokines either, which may suggest that exercise to improve cognition is via other biochemicals rather than the current 8 cytokines. Our data generally align with previous findings that describe increases in physical fitness and brain health following aerobic exercise and a link between elevation of exercise capacity with improvements in cognitive health, suggesting that the current intensity and frequency of workouts promote brain health. However, we acknowledge that our criteria for N3 sleep heart rate were operational, based on a heart rate percentile (<20%). We conducted tests using various percentiles, including 10%, 15%, 20%, and 25%. Our explorations suggested that a cutoff of 20% best matched N3 based on the scored in-lab PSGs.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p33
|
PMC11278044
|
sec[3]/sec[2]/p[1]
|
4.3. Improvements in Aerobic Fitness
| 4.039063 |
biomedical
|
Study
|
[
0.99951171875,
0.00018334388732910156,
0.0004012584686279297
] |
[
0.99951171875,
0.00016832351684570312,
0.00022912025451660156,
0.00004088878631591797
] |
Finally, our mixed effects model result suggested a lack of association between BAI and VO 2 max, but did find significant correlations between BAI, fluid intelligence, processing speed, IL4, IL-13, and IL-8. Processing speed performance changes over the lifespan, peaking during early adulthood and decreasing thereafter . Importantly, processing speed is among the most sensitive cognitive processes influenced by neurological illness . In light of the findings of our investigation, our exploratory data indicate that the current exercise program appears to confer a degree of benefit in enhancing essential cognitive performance. Additionally, IL-4 and IL-13 are critical anti-inflammatory cytokines with effects on sleep and cognitive performance .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p34
|
PMC11278044
|
sec[4]/p[0]
|
5. Limitations and Future Directions
| 4.199219 |
biomedical
|
Study
|
[
0.99951171875,
0.0003688335418701172,
0.0002758502960205078
] |
[
0.99951171875,
0.00019860267639160156,
0.00038743019104003906,
0.0000820159912109375
] |
The lack of change pre- and post-exercise training seen for BAI and other sleep metrics might be due to suboptimal exercise regimen in both intensity and duration, ceiling–floor effects due to the relatively healthy samples , small sample size, and night-to-night variability of sleep measures, including BAI . One major limitation is the limited data quality of home sleep EEG. We employed home sleep headbands to record multiple nights of sleep EEG to account for night-to-night variability of BAI calculations. However, after artifact detection, only 64% of home sleep EEG data had an artifact ratio of <0.5 and only 44% had an artifact ratio of <0.3. Thus, despite collecting abundant longitudinal home sleep EEG data, only a portion of this was suitable for analysis, limiting our ability to average over multiple close-together nights to detect more subtle changes in BAI. Another significant limitation was the absence of a placebo or control group, precluding us from unequivocally attributing the observed enhancements in cognitive function to the exercise intervention. Our rationale for adopting a within-subject before–vs.–after study design was to focus on changes in each participant’s parameters relative to their own baseline. While the inclusion of a control arm could have enhanced methodological rigor, it would have necessitated a larger sample size, a constraint precluded by budgetary considerations. Moreover, randomizing a subset of our limited number of subjects to refrain from exercise could have deterred interest in the study. Given these considerations and the exploratory nature of our research, we deemed the single-arm design to be best. In addition to these limitations, the lack of significant changes in sleep parameters and specific deep brain structures associated with sleep function following aerobic exercise also constitutes a limitation of the present study. Future research could aim to investigate the potential mechanisms underlying these observed effects, including exploring specific neural tracts or pathways modulated by physical activity, and, considering the duration, intensity, and type of exercise. Finally, most participants in this study are white college-educated females. A more diverse population should be included in future work.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p35
|
PMC11278044
|
sec[4]/p[1]
|
5. Limitations and Future Directions
| 3.707031 |
biomedical
|
Study
|
[
0.99853515625,
0.00044035911560058594,
0.0011072158813476562
] |
[
0.99853515625,
0.0011844635009765625,
0.00015735626220703125,
0.00006103515625
] |
We acknowledge that the utilization of a Fitbit for heart rate tracking in the current study presents another limitation. More dependable and precise measurements can be achieved through alternative methods such as chest straps or forehead photoplethysmography (PPG). However, we made a deliberate choice not to employ these alternatives due to practical considerations. Participants were tasked with wearing heart rate monitors continuously, 24/7, over the course of the 12-week study duration, a requirement we anticipated would be challenging to maintain with forehead PPG or a chest strap. Considering budget constraints, user-friendliness, public acceptance, and the feasibility of conducting future large-scale, long-term studies, we opted for a Fitbit over the Polar chest strap or PPG.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278044_p36
|
PMC11278044
|
sec[4]/p[2]
|
5. Limitations and Future Directions
| 3.294922 |
biomedical
|
Study
|
[
0.99853515625,
0.0003917217254638672,
0.0008878707885742188
] |
[
0.998046875,
0.00139617919921875,
0.0002435445785522461,
0.00007104873657226562
] |
Another limitation relates to our measurement of oxygen capacity: our study did not perform VO 2 max verification testing. Implementation of the validation stage poses considerable challenges due to budget limitations, scheduling conflicts among participants, and the limited capacity of CPET laboratories in the hospital setting. It is important to note that no standardized protocol for executing the verification phase exists, necessitating further research efforts to establish a feasible protocol applicable to sedentary older adults .
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p37
|
PMC11278044
|
sec[4]/p[3]
|
5. Limitations and Future Directions
| 3.998047 |
biomedical
|
Study
|
[
0.99755859375,
0.0019989013671875,
0.00044083595275878906
] |
[
0.99365234375,
0.006015777587890625,
0.0002796649932861328,
0.000209808349609375
] |
It is notable that this small sample-size trial was a feasibility and exploratory study to determine whether BAI measured via home sleep monitoring and cognition were influenced by exercise. The commencement of this research occurred a few months prior to the emergence of the COVID-19 pandemic. This situation posed significant difficulties in enrolling a suitable cohort of participants. Unfortunately, owing to financial limitations and external factors, we were obliged to prematurely conclude the study before achieving our target enrollment number. To fully evaluate the effects of exercise on BAI, a larger sample size is essential. Future studies may also evaluate the effects of different intensities (low, medium, high) and duration exercise regimens on sleep and BAI. Our ultimate goal is to develop an affordable and accurate physiological measure for tracking brain health.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278044_p38
|
PMC11278044
|
sec[5]/p[0]
|
6. Conclusions
| 4.078125 |
biomedical
|
Study
|
[
0.99951171875,
0.0004222393035888672,
0.000209808349609375
] |
[
0.9990234375,
0.0002810955047607422,
0.0004184246063232422,
0.00008100271224975586
] |
This exploratory study provided evidence that a 12-week, 150 min per-week moderate-intensity aerobic exercise regimen improves cognitive performance, particularly on cognitive processing speed in association with improved aerobic fitness and higher circulating neuroprotective cytokines (IL-4 and IL-13) among middle-aged and older previously physically inactive adults. Nonetheless, we did not detect significant enhancements in sleep macro- and micro-architectures, cognitive flexibility, attention, or the rapid acquisition and retention of new information.
|
[
"An Ouyang",
"Can Zhang",
"Noor Adra",
"Ryan A. Tesh",
"Haoqi Sun",
"Dan Lei",
"Jin Jing",
"Peng Fan",
"Luis Paixao",
"Wolfgang Ganglberger",
"Logan Briggs",
"Joel Salinas",
"Matthew B. Bevers",
"Christiane Dorothea Wrann",
"Zeina Chemali",
"Gregory Fricchione",
"Robert J. Thomas",
"Jonathan Rosand",
"Rudolph E. Tanzi",
"Michael Brandon Westover"
] |
https://doi.org/10.3390/life14070855
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p0
|
PMC11278058
|
sec[0]/p[0]
|
1. Introduction
| 4.011719 |
biomedical
|
Review
|
[
0.99365234375,
0.0034122467041015625,
0.0030536651611328125
] |
[
0.00670623779296875,
0.00292205810546875,
0.98974609375,
0.0003981590270996094
] |
Invasive Vagus Nerve Stimulation (iVNS) is an approved treatment for refractory epilepsy , depression , and stroke . However, despite its effectiveness, it is an invasive procedure with substantial costs, and only around 30% of implanted patients exhibit a clinical response . Transcutaneous auricular vagus nerve stimulation (taVNS), as an alternative, is a safe and non-invasive stimulation technique that targets the auricular branch of the vagus nerve, placing the electrodes at the concha or tragus of the ear. Several studies, including reviews and meta-analyses , have suggested that taVNS has potential applications in treating different conditions, including epilepsy , depression , anxiety , chronic pain , and stroke , with observed anti-inflammatory and immunomodulating effects .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p1
|
PMC11278058
|
sec[0]/p[1]
|
1. Introduction
| 4.082031 |
biomedical
|
Study
|
[
0.99951171875,
0.00011658668518066406,
0.00019443035125732422
] |
[
0.99267578125,
0.002956390380859375,
0.004001617431640625,
0.00012993812561035156
] |
It has also been demonstrated that taVNS can affect several brain functions by stimulating the vagal afferents. From the vagus nerve, inputs are sent to the nucleus of the solitary tract (NTS), which has connections to the locus coeruleus (LC), a major adrenergic center . The locus coeruleus has projections to several cortical and subcortical structures, including the frontal and parietal cortex, thalamic nucleus, and hippocampus . Together with integrating and processing central impulses, some of these brain areas also control the vagal efferents. Although there is a lack of data regarding taVNS’s effects on the vagal efferent, it could be an intriguing non-invasive intervention with potential to affect the vagal efferent functions .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p2
|
PMC11278058
|
sec[0]/p[2]
|
1. Introduction
| 4.003906 |
biomedical
|
Review
|
[
0.9990234375,
0.00041222572326660156,
0.0003533363342285156
] |
[
0.474853515625,
0.0079498291015625,
0.5166015625,
0.0007224082946777344
] |
One important influence of the vagus nerve efferent function is on the modulation of heart rate through sinoatrial node activity. Heart rate variability (HRV) is a non-invasive way to measure the vagal influence by measuring the variability in time between successive heartbeats . Given this role, HRV has been viewed and investigated as a major biomarker for neurocardiac function, with links to stress, illness, and mortality, as well as an individual’s state of health . Considering that decreased HRV has been related to morbidity and mortality of different diseases through mechanisms such as imbalance of the autonomic nervous system (ANS), inflammatory response, and oxidative stress, restoring this equilibrium through taVNS could have a therapeutic effect .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p3
|
PMC11278058
|
sec[0]/p[3]
|
1. Introduction
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
0.0002065896987915039,
0.0002732276916503906
] |
[
0.970703125,
0.0014171600341796875,
0.027618408203125,
0.000141143798828125
] |
Previous trials have shown and discussed how taVNS affects HRV , suggesting that the stimulation can induce a shift toward greater parasympathetic tonus. One important concept is that the parasympathetic tonus is dependent on several factors such as (i) age, (ii) diseases, and (iii) physiological states (e.g., no movement/resting vs. during movement). The physiological mechanisms of heart rate dynamics can be explained by (i) respiratory gating, which determines the high frequency (HF) (0.18–0.40 Hz) associated with vagal (parasympathetic) activity and central blood pressure ; (ii) sympathetic vasomotor activity that determines the low frequency (LF) (0.03–0.15 Hz) associated with reflex baroreceptor activity ; and sympathovagal balance, which can be measured by the LF/HF ratio .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11278058_p4
|
PMC11278058
|
sec[0]/p[4]
|
1. Introduction
| 4.074219 |
biomedical
|
Study
|
[
0.99951171875,
0.00014770030975341797,
0.00013053417205810547
] |
[
0.9951171875,
0.0004413127899169922,
0.004322052001953125,
0.00008916854858398438
] |
Normal aging is known to be related to decreased global autonomic regulation, which results in a decreased HRV . Umetani et al. demonstrated that healthy subjects older than 65 years old have deterioration in the standard deviation of the R-R intervals (SSDR), the root mean square of the difference between successive R-R intervals (RMSSD), and the percentage of R-R intervals, which differed by more than 50 ms (pNN50) from values in subjects younger than 30 years old . Therefore, given that ANS activity represents an important interface and marker for regulating physiological processes according to a neural response to external events, understanding this marker provides important insights about how the brain responds during normal aging and pathological conditions, such as neurological disorders.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p5
|
PMC11278058
|
sec[0]/p[5]
|
1. Introduction
| 3.632813 |
biomedical
|
Study
|
[
0.9990234375,
0.00035452842712402344,
0.0007333755493164062
] |
[
0.9990234375,
0.0006337165832519531,
0.00018656253814697266,
0.00006407499313354492
] |
Given the importance of HRV markers and the preliminary results showing that taVNS can regulate HRV, we aimed to understand how bilateral taVNS modulates HRV in subjects in a resting state and, in addition, understand whether these effects are modified by demographic characteristics of these individuals, such as age and sex.
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11278058_p6
|
PMC11278058
|
sec[1]/sec[0]/p[0]
|
2.1. Study Design
| 3.347656 |
clinical
|
Other
|
[
0.255126953125,
0.736328125,
0.00846099853515625
] |
[
0.038604736328125,
0.94091796875,
0.0016384124755859375,
0.01861572265625
] |
In this randomized, double-blind, sham–control trial, we recruited 44 healthy subjects who were allocated into two groups (allocation ratio 1:1): active taVNS or sham taVNS. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Partners Human Research Committee . Informed consent was obtained from all subjects involved in the study according to the Declaration of Helsinki . This clinical trial was registered in ClinicalTrials.gov .
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11278058_p7
|
PMC11278058
|
sec[1]/sec[1]/p[0]
|
2.2. Participants
| 3.828125 |
biomedical
|
Study
|
[
0.9970703125,
0.0024662017822265625,
0.0003418922424316406
] |
[
0.99853515625,
0.0011167526245117188,
0.00019800662994384766,
0.0002067089080810547
] |
This study included healthy subjects older than 18 and naïve to stimulation with taVNS. We excluded patients with any unstable medical condition, history of alcohol or drug abuse in the past 6 months, or the presence of any contraindication to taVNS, such as implanted cranial or cardiac devices or metal in the cranium, and we excluded subjects with a score higher than 30 in the Beck Depression Inventory (BDI), which indicates severe depression. All participants signed an online consent form in an encrypted web-based platform (REDCap).
|
[
"Anna Carolyna Gianlorenço",
"Kevin Pacheco-Barrios",
"Marianna Daibes",
"Lucas Camargo",
"Hyuk Choi",
"Jae-Jun Song",
"Felipe Fregni"
] |
https://doi.org/10.3390/jcm13144267
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.