Loss of hypocretin (orexin) neurons with traumatic brain injury
Open accessAbstract
Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake‐promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson disease and other disorders. We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI. This observation highlights the often overlooked hypothalamic injury in TBI and provides new insights into the causes of chronic sleepiness in patients with TBI. Ann Neurol 2009;66:555–559
AI snapshot
Written from the paper’s full text.
TL;DR
In postmortem hypothalami from 4 patients with severe TBI versus 4 controls, hypocretin neuron number was significantly reduced by 27%. This suggests that hypothalamic hypocretin neuron loss may contribute to chronic sleepiness after TBI.
Key findings
- TBI subjects had 27% fewer hypocretin neurons than controls (23,655 ± 5,035 vs. 32,318 ± 3,060 neurons, p = 0.001).
- MCH neurons were 31% fewer in TBI subjects (39,540 ± 10,900 vs. 57,176 ± 24,016), but this was not quite statistically significant (p = 0.06); excluding one female control with low MCH neuron numbers, TBI subjects had 29% fewer hypocretin neurons (p = 0.002) and 40% fewer MCH neurons (p = 0.003).
- GFAP-labeled astrocyte density was higher in TBI patients than controls (21 ± 12 vs. 7 ± 2 per mm², p < 0.001), and patients with more severe hypocretin neuron loss had more GFAP-labeled astrocytes (r = −0.46, p = 0.01).
- TBI hypothalami also showed intense perivascular hypocretin immunoreactivity, and many hypocretin neurons were small and pyknotic with reduced hypocretin fiber density.
Methods
- Autopsy brains from 4 patients who died 7 to 42 days (mean 19) after severe TBI and 4 control subjects with no clinical evidence of TBI or other neurological disorders; TBI patients were younger (51 ± 19 years) than controls (69 ± 18 years), and all subjects were male except one woman in the control group.
- Immunohistochemistry for hypocretin-1, MCH, and GFAP; hypocretin and MCH neurons were counted across a 1:24 series of the entire hypothalamus with Abercrombie correction, and GFAP-immunolabeled astrocytes were counted in 30 randomly selected 400 by 400 µm sites within the lateral and posterior hypothalamus.
- Cell counts were compared between groups using Student’s t-tests.
Limitations
- Stated by the paper: the study examined a small number of brains, control subjects were not fully matched, other wake-promoting systems were not examined, and the patients had fatal TBI, probably introducing selection bias; non-fatal TBI may be associated with less severe hypocretin neuron loss.
- Evident from the text: this is described as a pilot study with severe/fatal TBI cases, so findings may not generalize to milder or non-fatal TBI, and the autopsy design cannot directly establish that hypocretin loss causes chronic sleepiness.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
16 of 32 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Injury to ascending arousal pathways from the brainstem may contribute to chronic sleepiness after head trauma.
“Injury to ascending arousal pathways from the brainstem may contribute, but recent findings suggest a key role for the neuropeptides hypocretin-1 and -2 (also known as orexin-A and -B).2,4,5”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [2] Baumann CR Werth E Stocker R Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study Brain 2007 130 1873 1883 17584779 source
The section on clinical characteristics and potential causes proposes that TBI may damage hypocretin neurons or their axons, contributing to post-traumatic sleepiness. It does not identify injury to ascending arousal pathways from the brainstem as that mechanism. The risk-factors section reports no association between lesion location and sleep-wake disturbances; outcomes in patients with visible brainstem or hypothalamic lesions did not differ from those of other patients. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [4] Baumann CR Stocker R Imhof HG Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury Neurology 2005 65 147 149 16009905 source
- cites [5] España RA Scammell TE Sleep neurobiology for the clinician Sleep 2004 27 811 820 15283019 source
The review’s Arousal Network section says lesions of the rostral reticular formation can disrupt wakefulness because they also damage arousal fibers. Its introductory discussion reports excessive sleepiness after injury to wake-promoting regions, but it does not establish that brainstem pathway injury contributes to chronic sleepiness specifically after head trauma. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Even after 6 months recovery, many TBI patients with EDS have persistently low hypocretin-1 levels.
“Even after 6 months recovery, many TBI patients with EDS have persistently low hypocretin-1 levels.2”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] Baumann CR Werth E Stocker R Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study Brain 2007 130 1873 1883 17584779 source
The Laboratory studies section reports that hypocretin-1 remained low in 4 of 21 patients at six months, while it was normal in 17. The Clinical characteristics section says levels were lower in patients with EDS, but does not establish that many patients with EDS had persistently low levels. The claim overstates the prevalence of persistent deficiency. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Selective loss of hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy.
“Selective loss of the hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy,5–9”
Quote in the paperSubstantial claim2 of 5 sources checked- cites [5] España RA Scammell TE Sleep neurobiology for the clinician Sleep 2004 27 811 820 15283019 source
The Orexin/Hypocretin section (page unavailable) links loss of orexin neurons to difficulty maintaining wakefulness and describes cataplexy with deficient orexin signaling. But its figure is about 90% of patients with narcolepsy *and cataplexy* having undetectable cerebrospinal-fluid orexin—not over 90% of all patients with narcolepsy having selective neuronal loss that causes both symptoms. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [6] Adamantidis AR Zhang F Aravanis AM Neural substrates of awakening probed with optogenetic control of hypocretin neurons Nature 2007 450 420 424 17943086 PMC6744371 source
- cites [7] Peyron C Faraco J Rogers W A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains Nat Med 2000 6 991 997 10973318 source
- cites [8] Thannickal TC Moore RY Nienhuis R Reduced number of hypocretin neurons in human narcolepsy Neuron 2000 27 469 474 11055430 PMC8760623 source
- cites [9] Crocker A España RA Papadopoulou M Concomitant loss of dynorphin, NARP, and orexin in narcolepsy Neurology 2005 65 1184 1188 16247044 PMC2254145 source
The Conclusions (page unavailable) say that narcolepsy with cataplexy is likely caused by loss of orexin-producing neurons, and the Discussion links disrupted orexin signaling to sleepiness and cataplexy. The paper does not establish that this occurs in over 90% of patients: its Results report roughly 90% or greater neuron loss in two people with narcolepsy and cataplexy, not a percentage of patients. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Even after 6 months recovery, 43% of patients have symptoms of sleep disorders.
“Coma and obtundation are common during the acute period, but even after 6 months recovery, 43% of patients have symptoms of sleep disorders.2,3”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [2] Baumann CR Werth E Stocker R Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study Brain 2007 130 1873 1883 17584779 source
The Fig. 3 caption (Single patient reports; page unavailable) reports that 28 of 65 patients (43%) had sleep–wake disturbances for which no cause other than traumatic brain injury was identified. But it reports sleep–wake disturbances in 47 of 65 patients overall, so 43% is the rate for a narrower group, not the overall rate implied by the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [3] Castriotta RJ Wilde MC Lai JM Prevalence and consequences of sleep disorders in traumatic brain injury J Clin Sleep Med 2007 3 349 356 17694722 PMC1978308 source
The Discussion reports that 47% of the TBI sample had a diagnosed sleep disorder, and Table 4 includes patients studied more than six months after injury. It does not report that 43% had symptoms after six months of recovery; the stated percentage, measure, and time-specific estimate are unsupported. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
Patients with more severe loss of hypocretin neurons had more GFAP-labeled astrocytes (r=−0.46, p=0.01).
“Double immunofluorescence staining showed that patients with more severe loss of hypocretin neurons had more GFAP-labeled astrocytes (r=−0.46, p=0.01).”
Quote in the paperNot a substantial claim
- Findingown data
In TBI brains, hypocretin neurons were distributed in a normal pattern.
“Though TBI brains contained fewer hypocretin neurons, the neurons were distributed in a normal pattern, thus demonstrating the reliability and completeness of the cell counts (Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
The number of hypocretin neurons in TBI subjects was 27% less than in controls (23,655±5,035 vs. 32,318±3,060 neurons, p = 0.001).
“The number of hypocretin neurons in TBI subjects was 27% less than in controls (23,655±5,035 vs. 32,318±3,060 neurons, p = 0.001) (Figure 1).”
- Also stated in: § Abstract · plain
“We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI.”
- Also stated in: § Discussion · plain
“In this pilot study, we found that patients with severe TBI have a significant loss of hypocretin-producing neurons.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
The density of astrocytes as assessed by GFAP staining was significantly higher in TBI patients than in controls (21±12 vs. 7±2 per mm2, p<0.001).
“The density of astrocytes as assessed by GFAP staining was significantly higher (21±12 vs. 7±2 per mm2, p<0.001) in TBI patients than in controls (Supplemental Figure B).”
Quote in the paperNot a substantial claim - Findingown data
The perivascular hypocretin immunoreactivity was present around small vessels in the posterior and lateral hypothalamus but not elsewhere.
“This amorphous staining was present around small vessels in the posterior and lateral hypothalamus but not elsewhere.”
Quote in the paperNot a substantial claim - Findingown data
Hypothalami from TBI patients contained intense perivascular hypocretin immunoreactivity.
“Hypothalami from TBI patients also contained intense perivascular hypocretin immunoreactivity (Figure 3).”
Quote in the paperNot a substantial claim - Premisecitation
TBI patients have a marked reduction in CSF hypocretin-1 levels in the first days after injury.
“We recently found that TBI patients have a marked reduction in CSF hypocretin-1 levels in the first days after injury.4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Baumann CR Stocker R Imhof HG Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury Neurology 2005 65 147 149 16009905 source
- Premisecitation
Injury to the hypothalamus is common in patients with TBI.
“Injury to the hypothalamus is common in patients with TBI,11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Crompton MR Hypothalamic lesions following closed head injury Brain 1971 94 165 172 5552160 source
- Study design and conductcitation
The specificity of the hypocretin-1 antiserum was tested and confirmed in hypothalamic tissue from hypocretin-knockout mice.
“The specificity of the antiserum was tested and confirmed in hypothalamic tissue from hypocretin-knockout mice.12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Baumann CR Clark EL Pedersen NP Hecht JL Scammell TE Do enteric neurons make hypocretin? Regul Pept 2008 147 1 3 18191238 PMC2276606 source
- Interpretationreasoning
Reduced hypocretin signaling may contribute to the persistent sleepiness often seen in TBI patients.
“These findings demonstrate that TBI can injure the hypothalamus and suggest that reduced hypocretin signaling may contribute to the persistent sleepiness often seen in TBI patients.”
Quote in the paperSubstantial claim - Interpretationcitation
Loss of MCH neurons may also contribute to the pathophysiology of posttraumatic sleep-wake disturbances.
“Loss of the MCH neurons may also contribute to the pathophysiology of posttraumatic sleep-wake disturbances as these cells are hypothesized to regulate REM sleep.22,23”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [22] Hassani OK Lee MG Jones BE Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep-wake cycle Proc Natl Acad Sci U S A 2009 106 2418 2422 19188611 PMC2650171 source
- cites [23] Adamantidis A de Lecea L Physiological arousal: a role for hypothalamic systems Cell Mol Life Sci 2008 65 1475 1488 18351292 PMC11131926 source
- Interpretationreasoning
Partial loss of hypocretin neurons may contribute to chronic sleepiness after TBI.
“We believe that partial loss of hypocretin neurons may contribute to chronic sleepiness after TBI.”
Quote in the paperSubstantial claim - Interpretationreasoning
Persistent sleepiness in some TBI patients is likely due to a combination of reduced hypocretin signaling and injury to other sleep-wake regulating systems.
“Overall, it seems likely that the persistent sleepiness in some TBI patients is due to a combination of reduced hypocretin signaling and injury to other sleep-wake regulating systems.”
Quote in the paperSubstantial claim - Study design and conductnone given
The study studied patients with fatal TBI, which probably introduced some selection bias.
“Last, we studied patients with fatal TBI, which probably introduced some selection bias.”
Quote in the paperNot a substantial claim - Interpretationown data
TBI can injure the hypothalamus.
“These findings demonstrate that TBI can injure the hypothalamus and suggest that reduced hypocretin signaling may contribute to the persistent sleepiness often seen in TBI patients.”
Quote in the paperSubstantial claim - Interpretationown data
The non-significant reduction in MCH neurons was probably because of variable numbers of MCH neurons.
“TBI patients also had 31% fewer MCH neurons than controls (39,540±10,900 vs. 57,176±24,016), but this reduction was not quite statistically significant (p = 0.06), probably because of variable numbers of MCH neurons.”
Quote in the paperNot a substantial claim - Interpretationown data
The loss of hypocretin neurons, coupled with gliosis and intense perivascular hypocretin-immunoreactive debris, strongly suggests that severe TBI can directly or indirectly kill hypocretin neurons.
“In our patients, the loss of hypocretin neurons, coupled with gliosis and intense perivascular hypocretin-immunoreactive debris, strongly suggests that severe TBI can directly or indirectly kill hypocretin neurons.”
Quote in the paperSubstantial claim - Interpretationreasoning
It is likely that reduced hypocretin signalling is not the only factor to cause sleepiness after TBI.
“Still, it is likely that reduced hypocretin signalling is not the only factor to cause sleepiness after TBI.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 17
- May combine two claims. 14
Classified as probably not a substantial claim.
PremisecitationIdentical symptoms occur in mice genetically lacking hypocretins.
“and identical symptoms occur in mice genetically lacking hypocretins.10”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Chemelli RM Willie JT Sinton CM Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation Cell 1999 98 437 451 10481909 source
The Discussion reports that mice lacking orexin (hypocretin) have narcoleptic attacks and sleep dysregulation remarkably similar to human narcolepsy. It does not establish that the symptoms are identical: the authors say they cannot clearly distinguish the mice’s narcoleptic from cataplectic episodes and note an EEG feature not reported in humans or dogs. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationChronic daytime sleepiness is a major disabling symptom for many patients with TBI, and its etiology is not well understood.
“Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood.”
- Also stated in: § Introduction · plain
“Though chronic sleepiness is common after head trauma, the cause remains unclear.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [2] Baumann CR Werth E Stocker R Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study Brain 2007 130 1873 1883 17584779 source
- cites [3] Castriotta RJ Wilde MC Lai JM Prevalence and consequences of sleep disorders in traumatic brain injury J Clin Sleep Med 2007 3 349 356 17694722 PMC1978308 source
The Discussion reports a high prevalence of excessive daytime sleepiness after TBI and poorer cognitive and vigilance performance in sleepy subjects. It says functional disability is possible but that the impact on day-to-day functioning has not been established; it also cannot determine whether some sleep disorders preceded the injury. The paper therefore supports the prevalence and uncertainty about cause, but not the stronger claim that chronic sleepiness is an established major disabling symptom. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Also stated in: § Introduction · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn a prospective study of 65 TBI patients, 1 in 4 patients reported excessive daytime sleepiness irrespective of the location or severity of the head trauma.
“In a prospective study of 65 TBI patients, 1 in 4 patients reported excessive daytime sleepiness (EDS) irrespective of the location or severity of the head trauma.2”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] Baumann CR Werth E Stocker R Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study Brain 2007 130 1873 1883 17584779 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn another study of 87 patients, sleepiness occurred in 25% after TBI.
“Another study of 87 patients revealed similar results, with sleepiness in 25% after TBI.3”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [3] Castriotta RJ Wilde MC Lai JM Prevalence and consequences of sleep disorders in traumatic brain injury J Clin Sleep Med 2007 3 349 356 17694722 PMC1978308 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationHypocretins are made by a small cluster of neurons in the lateral hypothalamus that play an essential role in promoting wakefulness.
“Hypocretins are made by a small cluster of neurons in the lateral hypothalamus that play an essential role in promoting wakefulness.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] España RA Scammell TE Sleep neurobiology for the clinician Sleep 2004 27 811 820 15283019 source
The Orexin/Hypocretin section says hypocretins are produced by neurons in the lateral and posterior hypothalamus and that these neurons play an essential role in stabilizing wakefulness. It does not establish that they form a small cluster, and it names the posterior hypothalamus as well as the lateral hypothalamus. (LLM, conf=0.79)
Experimental — accuracy not yet measured
May combine two claims.
Study design and conductcitationIn controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.
“In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.7,8,14,15”
Quote in the paperNot a substantial claim2 of 4 sources checked- cites [7] Peyron C Faraco J Rogers W A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains Nat Med 2000 6 991 997 10973318 source
- cites [8] Thannickal TC Moore RY Nienhuis R Reduced number of hypocretin neurons in human narcolepsy Neuron 2000 27 469 474 11055430 PMC8760623 source
- cites [14] Fronczek R Overeem S Lee SY Hypocretin (orexin) loss in Parkinson's disease Brain 2007 130 1577 1585 17470494 source
The Hypocretin-1 cell number section reports a control median of 36,842 neurons, and the Hypocretin-1 histochemistry section says their distribution matched an earlier description in the perifornical lateral hypothalamus. Our copy does not compare the control total with prior reports or explicitly describe a distribution across both the lateral and posterior hypothalamus. Page numbers were not available in the indexed passages. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [15] Thannickal TC Lai YY Siegel JM Hypocretin (orexin) cell loss in Parkinson's disease Brain 2007 130 1586 1595 17491094 PMC8762453 source
The Materials and methods and Quantitative analysis sections say the authors examined five normal brains and determined hypocretin-cell number and distribution. The passages available from our copy do not give a total control-neuron count or say that the count and lateral/posterior hypothalamic distribution were similar to prior reports (pages not provided). (LLM, conf=0.70)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOther reports describe pituitary and hypothalamic dysfunction after TBI.
“Other reports describe pituitary and hypothalamic dysfunction,17,18”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [17] Karavitaki N Wass J Henderson Slater JD Wade D A case of post-traumatic isolated ACTH deficiency with spontaneous recovery 9 months after the event J Neurol Neurosurg Psychiatry 2006 77 276 277 16421141 PMC2077606 source
The case report describes isolated ACTH deficiency after traumatic brain injury, supporting pituitary dysfunction. The Discussion mentions the hypothalamus as a possible site of injury but does not report hypothalamic dysfunction; page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [18] Schneider HJ Aimaretti G Kreitschmann-Andermahr I Hypopituitarism Lancet 2007 369 1461 1470 17467517 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenThe pattern of gliosis differed across the TBI patients.
“The pattern of gliosis differed across the TBI patients.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMany hypocretin neurons in TBI patients were small and pyknotic, and the density of hypocretin fibers appeared reduced.
“Many hypocretin neurons in TBI patients were small and pyknotic, and the density of hypocretin fibers appeared reduced.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong TBI patients, the number of hypocretin neurons differed moderately between the left and right sides of the hypothalamus and between individuals.
“Among the TBI patients, the number of hypocretin neurons differed moderately between the left and right sides of the hypothalamus and between individuals, reflecting the asymmetry and heterogeneity of TBI.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe TBI patients had significantly fewer hypocretin neurons even though they were younger than the controls.
“However, our TBI patients had significantly fewer hypocretin neurons even though they were younger than the controls.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTBI patients had 31% fewer MCH neurons than controls (39,540±10,900 vs. 57,176±24,016), but this reduction was not quite statistically significant (p = 0.06).
“TBI patients also had 31% fewer MCH neurons than controls (39,540±10,900 vs. 57,176±24,016), but this reduction was not quite statistically significant (p = 0.06), probably because of variable numbers of MCH neurons.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataExcluding the female control subject with surprisingly low numbers of MCH neurons, TBI subjects had 29% fewer hypocretin neurons than controls (33,342±2,785; p=0.002) and 40% fewer MCH neurons (66,434±18,730; p=0.003).
“If one excludes the female control subject with surprisingly low numbers of MCH neurons (control subject 2), then the TBI subjects had 29% fewer hypocretin neurons than controls (33,342±2,785; p=0.002) and 40% fewer MCH neurons (66,434±18,730; p=0.003).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe perivascular staining may represent phagocytized hypocretin peptide following damage to the hypocretin neurons.
“The perivascular staining may represent phagocytized hypocretin peptide following damage to the hypocretin neurons.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe study did not examine other wake-promoting systems.
“In addition, we did not examine other wake-promoting systems, and the extent of injury to other arousal pathways should be further investigated in larger human and animal studies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe study examined a small number of brains, and the control subjects were not fully matched.
“We examined a small number of brains, and the control subjects were not fully matched.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOne early study showed damage to the hypothalamus in 42% of deceased TBI patients.
“One early study showed damage to the hypothalamus in 42% of deceased TBI patients.11”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Crompton MR Hypothalamic lesions following closed head injury Brain 1971 94 165 172 5552160 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataTBI patients were younger (51 ± 19 years) than controls (69 ± 18 years), and all subjects were male except for one woman in the control group.
“In this pilot study, the TBI patients were younger (51 ± 19 years) than the controls (69 ± 18 years), and all subjects were male except for one woman in the control group.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductcitationAbercrombie corrections based on the size of cell nuclei in each subject were performed to estimate numbers of hypocretin and MCH neurons.
“To estimate accurately the numbers of hypocretin and MCH neurons in each section, we performed Abercrombie corrections based on the size of the cell nuclei in each subject.13”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Guillery RW On counting and counting errors J Comp Neurol 2002 447 1 7 11967890 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataPostmortem delays were similar in both groups (TBI: 12±3 hours, controls: 13±3 hours).
“Postmortem delays were similar in both groups (TBI: 12±3 hours, controls: 13±3 hours) (Supplemental Table).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenOnly clearly immunolabeled neurons with neuronal morphology, outgoing axons and dendrites, and a nuclear void were counted.
“Only clearly-immunolabeled neurons with neuronal morphology, outgoing axons and dendrites, and a nuclear void were counted.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTBI injury was not limited to hypocretin neurons as there was a partial loss of neurons producing MCH and patchy gliosis throughout the hypothalamus.
“This injury was not limited to the hypocretin neurons as there was a partial loss of neurons producing MCH and patchy gliosis throughout the hypothalamus.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningNon-fatal TBI may be associated with a less severe loss of hypocretin neurons.
“It is possible that non-fatal TBI is associated with a less severe loss of hypocretin neurons.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenA fine-scale counting grid encompassing no more than 10 neurons per grid sector was used to prevent miscounting.
“To prevent miscounting, we used a fine-scale counting grid that encompassed no more than 10 neurons per grid sector.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationHypersomnolence is common with hypothalamic and rostral brainstem injuries, but is uncommon with selective loss of the hypocretin neurons.
“Hypersomnolence is common with hypothalamic and rostral brainstem injuries, but is uncommon with selective loss of the hypocretin neurons.21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Scammell TE Culebras A Secondary Narcolepsy Sleep Disorders and Neurologic Diseases 2007 2nd edition New York Informa Healthcare 117 134
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationAbout one-third of TBI patients have brainstem injuries, often near the midbrain tegmentum, that may disrupt ascending monoaminergic or cholinergic wake-promoting pathways.
“About one-third of TBI patients have brainstem injuries, often near the midbrain tegmentum, that may disrupt ascending monoaminergic or cholinergic wake-promoting pathways.20”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Crompton MR Brainstem lesions due to closed head injury Lancet 1971 1 669 673 4101614 source
May combine two claims.
Study design and conductown dataThe normal distribution of hypocretin neurons in TBI brains demonstrates the reliability and completeness of the cell counts.
“Though TBI brains contained fewer hypocretin neurons, the neurons were distributed in a normal pattern, thus demonstrating the reliability and completeness of the cell counts (Figure 2).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenIn all subjects, the complete hypocretin neuron field was examined.
“In all subjects, the complete hypocretin neuron field was examined (Supplemental Figure A).”
Quote in the paperSubstantial claim
The authors state this as an assumption.
Partial loss of hypocretin neurons causes the generally milder sleepiness of narcolepsy without cataplexy and Parkinson's disease.
“some hypothesize that a partial loss of these cells causes the generally milder sleepiness of narcolepsy without cataplexy and Parkinson’s disease.14,15,19”
“This assumption is supported by our recent finding of reduced CSF hypocretin-1 levels in sleepy TBI patients who survived their injury.2”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In Baumann et al. 2009, the number of hypocretin neurons was decreased by 27% compared to controls in 4 TBI patients.
“Baumann et al. 2009 found that in 4 TBI patients, the number of hypocretin neurons was decreased by 27% compared to controls.47”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [47]
Some studies have evidence of reduced numbers of MCH neurons after injury, observed after severe TBI.
“some studies have evidence of reduced numbers of MCH neurons after injury. However, this outcome was observed after severe TBI,46,47”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [47]
Cites
Narcolepsy in orexin Knockout Mice
Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., Richardson, J. A., Williams, S. C., Xiong, Y., Kisanuki, Y., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)81973-x · Cited by 3,095 · cited 1× · see citing works
“Selective loss of the hypocretin-producing neurons causes sleepiness and cataplexy in 90% of patients with narcolepsy, and identical symptoms occur in mice genetically lacking hypocretins.(10) Injury to the hypothalamus is common in patients with TBI,(11) but its clinical impact remains unclear.”
BackgroundSelf-citationPeyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., et al. (2000) · Nature Medicine · doi:10.1038/79690 · Cited by 2,118 · cited 1× · see citing works
“In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.(7,8,14,15) Hypothalami from TBI patients also contained intense perivascular hypocretin immunoreactivity (Fig 3).”
ResultReduced Number of Hypocretin Neurons in Human Narcolepsy
Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M., & Siegel, J. M. (2000) · Neuron · doi:10.1016/s0896-6273(00)00058-1 · Cited by 2,089 · see citing works
Neural substrates of awakening probed with optogenetic control of hypocretin neurons
Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K., & de Lecea, L. (2007) · Nature · doi:10.1038/nature06310 · Cited by 1,341 · see citing works
Incidence of Traumatic Brain Injury in the United States, 2003
Rutland-Brown, W., Langlois, J. A., Thomas, K. E., & Xi, Y. L. (2006) · Journal of Head Trauma Rehabilitation · doi:10.1097/00001199-200611000-00009 · Cited by 836 · see citing works
Hypocretin (orexin) cell loss in Parkinson's disease
Thannickal, T. C., Lai, Y.-Y., & Siegel, J. M. (2007) · Brain · doi:10.1093/brain/awm097 · Cited by 566 · cited 2× · see citing works
“Clearly, extensive loss of hypocretin neurons is sufficient to cause the sleepiness of narcolepsy with cataplexy, and some hypothesize that a partial loss of these cells causes the generally milder sleepiness of narcolepsy without cataplexy and Parkinson disease.(14,15,19) This assumption is supported by our recent fi…”
ResultHypocretin (orexin) loss in Parkinson's disease
Fronczek, R., Overeem, S., Lee, S. Y. Y., Hegeman, I. M., van Pelt, J., van Duinen, S. G., Lammers, G. J., & Swaab, D. F. (2007) · Brain · doi:10.1093/brain/awm090 · Cited by 463 · cited 2× · see citing works
“Clearly, extensive loss of hypocretin neurons is sufficient to cause the sleepiness of narcolepsy with cataplexy, and some hypothesize that a partial loss of these cells causes the generally milder sleepiness of narcolepsy without cataplexy and Parkinson disease.(14,15,19) This assumption is supported by our recent fi…”
ResultHassani, O. K., Lee, M. G., & Jones, B. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811400106 · Cited by 451 · cited 1× · see citing works
“Loss of the MCH neurons may also contribute to the pathophysiology of post-traumatic sleep-wake disturbances, as these cells are hypothesized to regulate rapid eye movement sleep.(22,23) Overall, it seems likely that the persistent sleepiness in some TBI patients is due to a combination of reduced hypocretin signaling…”
BackgroundSleep-wake disturbances 6 months after traumatic brain injury: a prospective study
Baumann, C. R., Werth, E., Stocker, R., Ludwig, S., & Bassetti, C. L. (2007) · Brain · doi:10.1093/brain/awm109 · Cited by 380 · cited 7× · see citing works
“Injury to ascending arousal pathways from the brainstem may contribute, but recent findings suggest a key role for the neuropeptides hypocretin-1 and -2 (also known as orexin-A and -B).(2,4,5) Hypocretins are made by a small cluster of neurons in the lateral hypothalamus that play an essential role in promoting wakefu…”
BackgroundMethodResultInfluentialSelf-citationOn counting and counting errors
Guillery, R. W. (2002) · Journal of Comparative Neurology · doi:10.1002/cne.10221 · Cited by 343 · cited 1× · see citing works
“To estimate accurately the numbers of hypocretin and MCH neurons in each section, we performed Abercrombie corrections based on the size of the cell nuclei in each subject.(13) We then calculated the total numbers of hypocretin and MCH neurons by multiplying the cell counts per section by the section sampling frequenc…”
MethodSchneider, H. J., Aimaretti, G., Kreitschmann-Andermahr, I., Stalla, G.-K., & Ghigo, E. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60673-4 · Cited by 336 · see citing works
Prevalence and Consequences of Sleep Disorders in Traumatic Brain Injury
Castriotta, R. J., Wilde, M. C., Lai, J. M., Atanasov, S., Masel, B. E., & Kuna, S. T. (2007) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.26855 · Cited by 334 · cited 6× · see citing works
“For example, stimulants such as modafinil that are helpful in narcolepsy and other hypocretin-deficient disorders should be studied systematically in affected TBI patients.24 Even better, hypocretin agonists could become an elegant and tailored treatment option not only for sleepy individuals with narcolepsy but also…”
BackgroundResultInfluentialConcomitant loss of dynorphin, NARP, and orexin in narcolepsy
Crocker, A., España, R. A., Papadopoulou, M., Saper, C. B., Faraco, J., Sakurai, T., Honda, M., Mignot, E., & Scammell, T. E. (2005) · Neurology · doi:10.1212/01.wnl.0000168173.71940.ab · Cited by 301 · cited 2× · see citing works
“We immunostained sections for hypocretin-1 (orexin A) as described previously.(9) Briefly, after treatment with 3% hydrogen peroxide and blocking in 3% normal horse serum, we incubated sections overnight in goat anti–hypocretin-1 antiserum (1:5,000; Santa Cruz Biotechnology, Santa Cruz, CA) and then in biotinylated do…”
MethodSelf-citationHypothalamic lesions following closed head injury
CROMPTON, M. R. (1971) · Brain · doi:10.1093/brain/94.1.165 · Cited by 243 · cited 2× · see citing works
“One early study showed damage to the hypothalamus in 42% of deceased TBI patients.(11) Other reports describe pituitary and hypothalamic dysfunction,(17,18) though to our knowledge, ours is the first to describe injury to specific types of hypothalamic neurons.”
BackgroundHypocretin-1 (orexin A) deficiency in acute traumatic brain injury
Baumann, C. R., Stocker, R., Imhof, H. G., Trentz, O., Hersberger, M., Mignot, E., & Bassetti, C. L. (2005) · Neurology · doi:10.1212/01.wnl.0000167605.02541.f2 · Cited by 191 · cited 2× · see citing works
“Injury to ascending arousal pathways from the brainstem may contribute, but recent findings suggest a key role for the neuropeptides hypocretin-1 and -2 (also known as orexin-A and -B).(2,4,5) Hypocretins are made by a small cluster of neurons in the lateral hypothalamus that play an essential role in promoting wakefu…”
BackgroundSelf-citationSleep Neurobiology for the Clinician
(2004) · Sleep · doi:10.1093/sleep/27.4.811 · Cited by 151 · cited 1× · see citing works
“Injury to ascending arousal pathways from the brainstem may contribute, but recent findings suggest a key role for the neuropeptides hypocretin-1 and -2 (also known as orexin-A and -B).(2,4,5) Hypocretins are made by a small cluster of neurons in the lateral hypothalamus that play an essential role in promoting wakefu…”
BackgroundSelf-citationThe "specialty" of general practitioner obstetrics.
Marsh, G. N. (1982) · PubMed · Cited by 131 · see citing works
(2006) · CRC Press eBooks · doi:10.3109/9781420019254 · Cited by 95 · see citing works
Physiological arousal: a role for hypothalamic systems
Adamantidis, A., & de Lecea, L. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7521-8 · Cited by 95 · cited 1× · see citing works
“Loss of the MCH neurons may also contribute to the pathophysiology of post-traumatic sleep-wake disturbances, as these cells are hypothesized to regulate rapid eye movement sleep.(22,23) Overall, it seems likely that the persistent sleepiness in some TBI patients is due to a combination of reduced hypocretin signaling…”
BackgroundBRAINSTEM LESIONS DUE TO CLOSED HEAD INJURY
Rufus Crompton, M. (1971) · The Lancet · doi:10.1016/s0140-6736(71)92680-8 · Cited by 90 · cited 1× · see citing works
“About 1 3 of TBI patients have brainstem injuries, often near the midbrain tegmentum, that may disrupt ascending monoaminergic or cholinergic wake-promoting pathways.(20) In addition, some TBI patients have hypersomnolence, with excessively large amounts of sleep each day.”
BackgroundThe Frustrating and Mostly Fruitless Search for an Autoimmune Cause of Narcolepsy
Scammell, T. E. (2006) · SLEEP · doi:10.1093/sleep/29.5.601 · Cited by 52 · cited 1× · see citing works
“Clearly, extensive loss of hypocretin neurons is sufficient to cause the sleepiness of narcolepsy with cataplexy, and some hypothesize that a partial loss of these cells causes the generally milder sleepiness of narcolepsy without cataplexy and Parkinson disease.(14,15,19) This assumption is supported by our recent fi…”
ResultSelf-citationAcute traumatic midbrain hemorrhage
Ropper, A. H., & Miller, D. C. (1985) · Annals of Neurology · doi:10.1002/ana.410180114 · Cited by 34 · see citing works
Do enteric neurons make hypocretin?
Baumann, C. R., Clark, E. L., Pedersen, N. P., Hecht, J. L., & Scammell, T. E. (2008) · Regulatory Peptides · doi:10.1016/j.regpep.2007.11.006 · Cited by 26 · see citing works
Self-citationA case of post-traumatic isolated ACTH deficiency with spontaneous recovery 9 months after the event
Karavitaki, N. (2006) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2005.070482 · Cited by 14 · cited 1× · see citing works
“Perhaps the hypocretin neurons are injured by the same shearing forces that often damage the midbrain, but vasospasm, or elevated intracranial pressure leading to compression or reduced perfusion of the hypothalamus, may also contribute.(11,17,18) Chronic excessive daytime sleepiness is a major disabling symptom for m…”
BackgroundSleep Disorders and Neurologic Diseases
(2007) · CRC Press eBooks · doi:10.3109/9781420014693 · Cited by 5 · see citing works
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Control of sleep and wakefulness
Brown, R. E., Basheer, R., McKenna, J. T., Strecker, R. E., & McCarley, R. W. (2012) · Physiological Reviews · doi:10.1152/physrev.00032.2011 · Cited by 1,477 · see citing works
Narcolepsy — clinical spectrum, aetiopathophysiology, diagnosis and treatment
Bassetti, C. L., Adamantidis, A., Burdakov, D., Han, F., Gay, S., Kallweit, U., Khatami, R., Koning, F., Kornum, B. R., Lammers, G. J., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0226-9 · Cited by 651 · see citing works
Self-citationOrexin Receptors: Pharmacology and Therapeutic Opportunities
Scammell, T. E., & Winrow, C. J. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010510-100528 · Cited by 379 · see citing works
Self-citationSleep Neurobiology from a Clinical Perspective
España, R. A., & Scammell, T. E. (2011) · SLEEP · doi:10.5665/sleep.1112 · Cited by 282 · see citing works
Self-citationSleep disturbance and melatonin levels following traumatic brain injury
Shekleton, J. A., Parcell, D. L., Redman, J. R., Phipps‐Nelson, J., Ponsford, J. L., & Rajaratnam, S. M. W. (2010) · Neurology · doi:10.1212/wnl.0b013e3181e0438b · Cited by 248 · see citing works
Ponsford, J. L., Ziino, C., Parcell, D. L., Shekleton, J. A., Roper, M., Redman, J. R., Phipps‐Nelson, J., & Rajaratnam, S. M. W. (2012) · Journal of Head Trauma Rehabilitation · doi:10.1097/htr.0b013e31824ee1a8 · Cited by 235 · see citing works
Sleep-wake disturbances after traumatic brain injury
Ouellet, M.-C., Beaulieu-Bonneau, S., & Morin, C. M. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00068-x · Cited by 231 · see citing works
Sleep-wake disturbances 3 years after traumatic brain injury
Kempf, J., Werth, E., Kaiser, P. R., Bassetti, C. L., & Baumann, C. R. (2010) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2009.201913 · Cited by 207 · see citing works
“In a recent pilot study, we found a significant decrease of neurons producing the wake-promoting neurotransmitter hypocretin (orexin) in the hypothalamus of deceased TBI patients, when compared with controls.(15) This loss and other structural changes in sleepewake regulations neuronal systems might contribute to slee…”
BackgroundSelf-citationSleep-Wake Disturbances After Traumatic Brain Injury: Synthesis of Human and Animal Studies
Sandsmark, D. K., Elliott, J. E., & Lim, M. M. (2017) · Sleep · doi:10.1093/sleep/zsx044 · Cited by 183 · see citing works
Sleep in the United States Military
Good, C. H., Brager, A. J., Capaldi, V. F., & Mysliwiec, V. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0431-7 · Cited by 191 · see citing works
“Both studies implicated deficits in the orexin system, which is consistent with the destabilization of waking during the active period [174].”
BackgroundWickwire, E. M., Williams, S. G., Roth, T. G., Capaldi, V. F., Jaffe, M., Moline, M. L., Motamedi, G. K., Morgan, G. W., Mysliwiec, V., Germain, A., et al. (2016) · Neurotherapeutics · doi:10.1007/s13311-016-0429-3 · Cited by 162 · see citing works
Modafinil ameliorates excessive daytime sleepiness after traumatic brain injury
Kaiser, P. R., Valko, P. O., Werth, E., Thomann, J., Meier, J., Stocker, R., Bassetti, C. L., & Baumann, C. R. (2010) · Neurology · doi:10.1212/wnl.0b013e3181fd62a2 · Cited by 150 · see citing works
Self-citationGrima, N., Rajaratnam, S. M. W., Mansfield, D. R., Sletten, T. L., Spitz, G., & Ponsford, J. L. (2018) · BMC Medicine · doi:10.1186/s12916-017-0995-1 · Cited by 149 · see citing works
“While melatonin was found to be effective in alleviating sleep disturbances, it is acknowledged that the mechanisms underpinning sleep disturbances in TBI involve multiple biological and psychological systems, such as alterations in monoaminergic neurons [45, 46] and wake-promoting hypocretin-1 neurons [47], and alter…”
BackgroundImbach, L. L., Valko, P. O., Li, T., Maric, A., Symeonidou, E.-R., Stover, J. F., Bassetti, C. L., Mica, L., Werth, E., & Baumann, C. R. (2015) · Brain · doi:10.1093/brain/awu391 · Cited by 142 · see citing works
“However, fatal TBI is associated with a partial loss of wake-promoting hypocretin (orexin)- and histamine-producing neurons (Baumann et al., 2009; Valko et al., 2014).”
BackgroundSelf-citationNarcolepsy: Neural Mechanisms of Sleepiness and Cataplexy
Burgess, C. R., & Scammell, T. E. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2630-12.2012 · Cited by 136 · see citing works
“, 2007) and traumatic brain injury (Baumann et al., 2009), disorders that often produce sleepiness but no cataplexy.”
Self-citationSleep disorders, obesity, and aging: The role of orexin
Nixon, J. P., Mavanji, V., Butterick, T. A., Billington, C. J., Kotz, C. M., & Teske, J. A. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.11.001 · Cited by 134 · see citing works
Sleep disturbances, TBI and PTSD: Implications for treatment and recovery
Stavitsky, K., Kark, S. M., Gehrman, P., & Bogdanova, Y. (2015) · Clinical Psychology Review · doi:10.1016/j.cpr.2015.05.008 · Cited by 136 · see citing works
“Low cerebrospinal fluid (CSF) hypocretin (orexin) has been reported in patients following TBI (Baumann et al., 2009; Baumann et al., 2005).”
BackgroundSleep Disturbances in Traumatic Brain Injury: A Meta-Analysis
Grima, N., Ponsford, J. L., Rajaratnam, S. M. W., Mansfield, D. R., & Pase, M. P. (2016) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.5598 · Cited by 121 · see citing works
“Postmortem investigations in TBI patients have identified significant reductions in wake-promoting hypocretin 53 and histaminergic neuronal populations, 54 which may underpin increased sleep drive.”
Semple, B. D., Zamani, A., Rayner, G., Shultz, S. R., & Jones, N. C. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.018 · Cited by 123 · see citing works
Wickwire, E. M., Schnyer, D. M., Germain, A., Smith, M. T., Williams, S. G., Lettieri, C. J., McKeon, A. B., Scharf, S. M., Stocker, R., Albrecht, J. S., et al. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5243 · Cited by 106 · see citing works
Self-citationBrown, J. A., Woodworth, H. L., & Leinninger, G. M. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00009 · Cited by 100 · see citing works
“OX neurons are also reduced after traumatic brain injury, which similarly results in chronic daytime sleepiness and reduced locomotor activity (Baumann et al., 2005, 2009; Willie et al., 2012).”
BackgroundChristensen, J., Yamakawa, G. R., Shultz, S. R., & Mychasiuk, R. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101917 · Cited by 105 · see citing works
Piantino, J. A., Lim, M. M., Newgard, C. D., & Iliff, J. J. (2019) · Current Pain and Headache Reports · doi:10.1007/s11916-019-0799-4 · Cited by 94 · see citing works
Changes in Sleep Patterns Following Traumatic Brain Injury
Ponsford, J. L., Parcell, D. L., Sinclair, K. L., Roper, M., & Rajaratnam, S. M. W. (2013) · Neurorehabilitation and neural repair · doi:10.1177/1545968313481283 · Cited by 92 · see citing works
“It also supports the contention that hypersomnia occurs following TBI, possibly caused by a loss of hypocretin neurons.(13,14,18,19) Recent studies have also found lower levels of evening melatonin in people with TBI, which may contribute to the increased sleep onset latency and nighttime awakenings.”
BackgroundInflammatory Signaling in Post-Stroke Fatigue and Depression
Wen, H., Weymann, K. B., Wood, L. J., & Wang, Q. M. (2018) · European Neurology · doi:10.1159/000494988 · Cited by 92 · see citing works
Wallace, D. M., Shafazand, S., Ramos, A. R., Carvalho, D. Z., Gardener, H., Lorenzo, D., & Wohlgemuth, W. K. (2011) · Sleep Medicine · doi:10.1016/j.sleep.2011.06.004 · Cited by 83 · see citing works
“As most of our patients presented with multiple and mixed aetiology head injury, it is conceivable that damage to the hypothalamus with loss of hypocretin neurons and damage to other diffusely distributed arousal systems may have occurred as a consequence of shear stress/diffuse axonal injury sometimes seen in closed…”
BackgroundPain and sleep in post-concussion/mild traumatic brain injury
Lavigne, G. J., Khoury, S., Chauny, J., & Désautels, A. (2015) · Pain · doi:10.1097/j.pain.0000000000000111 · Cited by 82 · see citing works
“This was associated with hypocretin (Hcrt; orexin) reduction; Hcrt is a neuropeptide essential for maintaining consolidated sleep/ wake states.(10,11,130) No single gene can explain the complex interrelations between”
BackgroundA Model of Fatigue Following Traumatic Brain Injury
Ponsford, J. L., Schönberger, M., & Rajaratnam, S. M. W. (2014) · Journal of Head Trauma Rehabilitation · doi:10.1097/htr.0000000000000049 · Cited by 82 · see citing works
Excessive sleep need following traumatic brain injury: a case–control study of 36 patients
Sommerauer, M., Valko, P. O., Werth, E., & Baumann, C. R. (2013) · Journal of Sleep Research · doi:10.1111/jsr.12068 · Cited by 76 · see citing works
“Accordingly, we found partial loss of hypocretin neurones in the hypothalamus of deceased TBI patients (Baumann et al., 2009).”
BackgroundSelf-citationSleep–wake disorders persist 18 months after traumatic brain injury but remain underrecognized
Imbach, L., Büchele, F., Valko, P. O., Li, T., Maric, A., Stover, J., Bassetti, C. L., Mica, L., Werth, E., & Baumann, C. R. (2016) · Neurology · doi:10.1212/wnl.0000000000002697 · Cited by 76 · see citing works
“In this line, we hypothesize that any type of TBI could induce damage to highly vulnerable sleep-relevant cerebral centers.(16,17) However, we cannot rule out that other factors contribute to chronic posttraumatic pleiosomnia, and further studies are needed to improve our understanding of the pathophysiologic mechanis…”
BackgroundSelf-citationPrevalence and predictors of fatigue in glioblastoma: a prospective study
Valko, P. O., Siddique, A., Linsenmeier, C., Zaugg, K., Held, U., & Höfer, S. (2014) · Neuro-Oncology · doi:10.1093/neuonc/nou127 · Cited by 74 · see citing works
Self-citationWillie, J. T., Lim, M. M., Bennett, R. E., Azarion, A. A., Schwetye, K. E., & Brody, D. L. (2012) · Journal of Neurotrauma · doi:10.1089/neu.2012.2404 · Cited by 79 · see citing works
“Furthermore, an autopsy study demonstrated significant reduction of orexin neurons in brains obtained following lethal TBI compared with control brains (Baumann et al., 2009).”
InfluentialValko, P. O., Gavrilov, Y. V., Yamamoto, M., Finn, K., Reddy, H., Haybaeck, J., Weis, S., Scammell, T. E., & Baumann, C. R. (2015) · Annals of Neurology · doi:10.1002/ana.24298 · Cited by 78 · see citing works
“Surprisingly little is known about injury to the hypothalamus and other wake-promoting brain regions in TBI, but in a pilot study of 4 TBI patients and 4 controls without head injury, we found a 27% loss of wake-promoting orexin (hypocretin) neurons.(7) To improve our understanding of injury to wake-promoting circuitr…”
BackgroundSelf-citationSkopin, M. D., Kabadi, S. V., Viechweg, S. S., Mong, J. A., & Faden, A. I. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2014.3664 · Cited by 71 · see citing works
“Clinical studies have observed increases in hypersomnia such as excessive daytime sleepiness (EDS) in approximately 25% of patients with TBI.5,6 Other retrospective studies indicate that approximately half of the patients experience some form of EDS with half of those having severe hypersomnia.5,6 Fur- ther, changes i…”
BackgroundInfluentialBassetti, C. L., Ferini‐Strambi, L., Brown, S. A., Adamantidis, A., Benedetti, F., Bruni, O., Cajochen, C., Dolenc‐Grošelj, L., Ferri, R., Gais, S., et al. (2015) · European Journal of Neurology · doi:10.1111/ene.12781 · Cited by 68 · see citing works
“Related research suggested a role of impaired hypocretin neurotransmission in other neuropsychiatric disorders such as head trauma, Parkinson’s disease and Alzheimer’s disease and improvement of insomnia following antagonization of the hypocretin system [19,41,66,67].”
BackgroundSelf-citationTraumatic Brain Injury and Disturbed Sleep and Wakefulness
Baumann, C. R. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8178-x · Cited by 66 · see citing works
“1) (Baumann et al. 2009).”
Self-citationBowirrat, A., Chen, T. J. H., Blum, K., Madigan, M. A., Bailey, J. A., Chen, A. L. C., Downs, B. W., Braverman, E. R., Shahien, R., Waite, R. L., et al. (2010) · Current Neuropharmacology · doi:10.2174/157015910793358123 · Cited by 69 · see citing works
Traumatic Brain Injury and Incidence Risk of Sleep Disorders in Nearly 200,000 US Veterans
Leng, Y., Byers, A. L., Barnes, D. E., Peltz, C. B., Li, Y., & Yaffe, K. S. (2021) · Neurology · doi:10.1212/wnl.0000000000011656 · Cited by 65 · see citing works
“For instance, hypothalamic injury could contribute to sleep-wake disorders through loss of wake-promoting histaminergic or orexin/hypocretin neurons.(41,42) Risk of sleep apnea might be increased as a result of mechanical changes of craniofacial anatomy, although the exact pathways linking TBI and different forms of s…”
BackgroundGreen, T. R. F., Ortiz, J. B., Wonnacott, S., Williams, R. J., & Rowe, R. K. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00894 · Cited by 63 · see citing works
“Extensive loss of orexin neurons and consequent excessive daytime sleepiness have been observed both pre-clinically and clinically after TBI (Baumann et al., 2009; Thomasy et al., 2017; Thomasy and Opp, 2019).”
BackgroundIntrathecal Baclofen Associated With Improvement of Consciousness Disorders in Spasticity Patients
Margetis, K. D., Korfias, S. I., Gatzonis, S. D., Boutos, N., Stranjalis, G., Boviatsis, E., & Sakas, D. E. (2013) · Neuromodulation Technology at the Neural Interface · doi:10.1111/ner.12147 · Cited by 62 · see citing works
“The above data taken together with the fact that severe TBI can result in loss of orexin neurons (24) support the notion that ITB can modulate a damaged orexin pathway in brain-injured patients.”
Almorexant Promotes Sleep and Exacerbates Cataplexy in a Murine Model of Narcolepsy
Wurts, S. W., Morairty, S. R., Fisher, S. P., Chen, T.-M., Warrier, D. R., & Kilduff, T. S. (2013) · SLEEP · doi:10.5665/sleep.2442 · Cited by 60 · see citing works
Sleep Quantity and Quality during Acute Concussion: A Pilot Study
Raikes, A. C., & Schaefer, S. Y. (2016) · SLEEP · doi:10.5665/sleep.6314 · Cited by 59 · see citing works
Hou, L., Han, X., Sheng, P. X., Tong, W., Li, Z., Xu, D., Yu, M., Huang, L., Zhao, Z., Yi-cheng, L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076087 · Cited by 59 · see citing works
“revealed reduced number of hypothalamic hypocretin (orexin) neurons in patients who died of severe TBI, low and undetectable cerebrospinal fluid levels of hypocretin (orexin) in the acute period after TBI and an association between low hypocretion levels and posttraumatic sleepiness [14,35,36].”
BackgroundBüchele, F., Morawska, M. M., Schreglmann, S. R., Penner, M., Muser, M. H., Baumann, C. R., & Noaín, D. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.4001 · Cited by 55 · see citing works
“15,16 To better understand the link between histological damage and SWD after TBI, we need an appropriate experimental rodent TBI model that both replicates human patterns of histological as well as behavioral sequelae and allows for long-term recordings of sleep-wake states.”
Self-citationActigraphic Assessment of Sleep Disturbances following Traumatic Brain Injury
Sinclair, K. L., Ponsford, J. L., & Rajaratnam, S. M. W. (2012) · Behavioral Sleep Medicine · doi:10.1080/15402002.2012.726203 · Cited by 49 · see citing works
“Reductions in both hypocretin (Baumann et al., 2009; Baumann et al., 2005; Baumann et al., 2007) and melatonin (Shekleton, Parcell, Redman, Ponsford, & Rajaratnam, 2010), have been reported in TBI groups.”
BackgroundElliott, J. E., De Luche, S. E., Churchill, M. J., Moore, C., Cohen, A. S., Meshul, C. K., & Lim, M. M. (2018) · Sleep · doi:10.1093/sleep/zsx212 · Cited by 63 · see citing works
“compared with noninjured control brains [41].”
Cortical Excitability Changes in Patients with Sleep-Wake Disturbances after Traumatic Brain Injury
Nardone, R., Bergmann, J., Kunz, A., Caleri, F., Seidl, M., Tezzon, F., Gerstenbrand, F., Trinka, E., & Golaszewski, S. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1748 · Cited by 49 · see citing works
Sabir, M., Gaudreault, P.-O., Freyburger, M., Massart, R., Blanchet-Cohen, A., Jaber, M., Gosselin, N., & Mongrain, V. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2014.12.023 · Cited by 47 · see citing works
“Alternatively, these changes may be linked to alterations in other neuronal circuits involved in sleep-wake regulation, such as hypothalamic orexin neurons or the thalamic reticular nucleus that were both shown to be modified by TBI (Baumann et al., 2009; Hazra et al., 2014; Willie et al., 2012).”
BackgroundSleep and Fatigue Following Traumatic Brain Injury
Ponsford, J. L., & Sinclair, K. L. (2014) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2013.10.001 · Cited by 44 · see citing works
Babiloni, A. H., Baril, A., Charlebois‐Plante, C., Jodoin, M., Sanchez, E., Baets, L. D., Arbour, C., Lavigne, G. J., Gosselin, N., & Beaumont, L. D. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12051793 · Cited by 43 · see citing works
“Another sleep-related consequence of TBI is increased sleepiness, especially in early stages, and research has highlighted the damage of orexin/hypocretin neurons, whose activation involve wakefulness, as a possible contributor of the association between this association [68].”
BackgroundRaikes, A. C., Bajaj, S., Dailey, N. S., Smith, R. S., Alkozei, A., Satterfield, B. C., & Killgore, W. D. S. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00468 · Cited by 41 · see citing works
Sleep Disorders Associated With Traumatic Brain Injury—A Review
Singh, K., Morse, A. M., Tkachenko, N., & Kothare, S. V. (2016) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2016.02.013 · Cited by 40 · see citing works
Sleep Disturbances in Traumatic Brain Injury: Associations With Sensory Sensitivity
Elliott, J. E., Opel, R. A., Weymann, K. B., Chau, A. Q., Papesh, M. A., Callahan, M. L., Storzbach, D. M., & Lim, M. M. (2018) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.7220 · Cited by 39 · see citing works
“These included determining (1) the number of TBIs; (2) the recency of the subjects’ TBI (determined from year of most recent TBI if > 1 TBI was identified); (3) whether or not the TBI(s) was caused by blast exposure; (4) whether the TBI caused loss of consciousness, confusion, posttraumatic amnesia, or postconcussive…”
Sleep disorders in traumatic brain injury
Wolfe, L. F., Sahni, A., & Attarian, H. P. (2018) · Neurorehabilitation · doi:10.3233/nre-182583 · Cited by 40 · see citing works
Adeghate, E. A., Fernández-Cabezudo, M. J., Rashed, H., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008587 · Cited by 40 · see citing works
“Founder orexin deficient (OX) mice were on a C57BL/6J-129/SvEV background, and their offspring were backcrossed with C57BL/6J mice for 6–8 generations [25].”
MethodThe Trouble with Tribbles: Do Antibodies Against TRIB2 Cause Narcolepsy?
Lim, A. S. P., & Scammell, T. E. (2010) · SLEEP · doi:10.1093/sleep/33.7.857 · Cited by 39 · see citing works
Self-citationBrain interrupted: Early life traumatic brain injury and addiction vulnerability
Cannella, L. A., McGary, H. M., & Ramirez, S. H. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.03.003 · Cited by 39 · see citing works
A review of sleep disturbances following traumatic brain injury
Zuzuárregui, J. R. P., Bickart, K. C., & Kutscher, S. J. (2018) · Sleep Science and Practice · doi:10.1186/s41606-018-0020-4 · Cited by 38 · see citing works
Sleep disorders in children with traumatic brain injury: a case of serious neglect
Stores, G., & Stores, R. (2013) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.12163 · Cited by 36 · see citing works
Hypocretin Mediates Sleep and Wake Disturbances in a Mouse Model of Traumatic Brain Injury
Thomasy, H. E., & Opp, M. R. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.5810 · Cited by 35 · see citing works
“Hypocre-tin, 37,38,45,46 histamine, 36,44 serotonin, 49 noradrenaline, 49 acetylcholine, 37,47,73 and melatonin 50 are the transmitters for which data suggest potential roles as mediators of post-TBI sleep and wake disturbances.”
Markovic, S. J., Fitzgerald, M., Peiffer, J. J., Scott, B. R., Rainey‐Smith, S. R., Sohrabi, H. R., & Brown, B. M. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101322 · Cited by 37 · see citing works
Thomasy, H. E., Febinger, H. Y., Ringgold, K. M., Gemma, C., & Opp, M. R. (2017) · Neurobiology of Sleep and Circadian Rhythms · doi:10.1016/j.nbscr.2016.03.001 · Cited by 37 · see citing works
“Furthermore, the number of hypocretin neurons are reduced in post-mortem brains of patients who died from TBI (Baumann et al., 2009).”
BackgroundInfluentialNeuropathological investigation of hypocretin expression in brains of dementia with Lewy bodies
Kasanuki, K., Iseki, E., Kondo, D., et al. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.03.020 · Cited by 34 · see citing works
Vu, P. A., Tucker, L. B., Liu, J., McNamara, E. H., Tran, T., Fu, A. H., Kim, Y., & McCabe, J. T. (2018) · Brain Research · doi:10.1016/j.brainres.2018.08.034 · Cited by 32 · see citing works
Acute Post-Traumatic Sleep May Define Vulnerability to a Second Traumatic Brain Injury in Mice
Rowe, R. K., Harrison, J. L., Morrison, H. W., Subbian, V., Murphy, S. M., & Lifshitz, J. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.5980 · Cited by 34 · see citing works
Lu, W. Y.-R., Krellman, J. W., & Dijkers, M. P. J. M. (2016) · Neurorehabilitation · doi:10.3233/nre-151296 · Cited by 33 · see citing works
“TBI can damage neural regions that subserve sleep regulation, including the suprachiasmatic nucleus, hypothalamus, midbrain, and ascending reticular activating system (Baumann et al., 2009; Frieboes et al., 1999), with associated alterations in the level of neurotransmitters such as hypocretin-1 (Baumann, Werth, Stock…”
BackgroundGao, X., & Hermes, G. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00142 · Cited by 30 · see citing works
“Therefore, it is reasonable to postulate that hypocretin neurons may undergo some plastic changes during intensive activation according to Hebbian theory.”
BackgroundExpression and Localization of the Orexin-1 Receptor (OX1R) After Traumatic Brain Injury in Mice
Mihara, Y., Dohi, K., Yofu, S., Nakamachi, T., Ohtaki, H., Shioda, S., & Aruga, T. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-010-9438-6 · Cited by 31 · see citing works
Traumatic Head Injury in Cluster Headache: Cause or Effect?
Lambru, G., & Matharu, M. S. (2012) · Current Pain and Headache Reports · doi:10.1007/s11916-012-0248-0 · Cited by 27 · see citing works
“[46] have shown selective injury and loss of hypocretin-producing neurons in the posterolateral hypothalamus in people with severe brain injury, possibly explaining the excessive daytime sleepiness of these patients.”
BackgroundMelanin concentrating hormone in central hypersomnia
Peyron, C., Valentin, F., Bayard, S., Hanriot, L., Bedetti, C., Rousset, B., Luppi, P., & Dauvilliers, Y. A. (2011) · Sleep Medicine · doi:10.1016/j.sleep.2011.04.002 · Cited by 26 · see citing works
“This observation seems of major interest since histological data recently reported a 30% loss of MCH neurons in patients with traumatic brain injury [28].”
BackgroundDiagnosis and Management of Narcolepsy
Schneider, L. D., & Mignot, E. J.-M. (2017) · Seminars in Neurology · doi:10.1055/s-0037-1605554 · Cited by 26 · see citing works
Neurobiology of Arousal and Sleep: Updates and Insights Into Neurological Disorders
Lim, M. M., & Szymusiak, R. S. (2015) · Current Sleep Medicine Reports · doi:10.1007/s40675-015-0013-0 · Cited by 26 · see citing works
Yamakawa, G. R., Brady, R. D., Sun, M., McDonald, S. J., Shultz, S. R., & Mychasiuk, R. (2020) · Neurobiology of Sleep and Circadian Rhythms · doi:10.1016/j.nbscr.2020.100058 · Cited by 25 · see citing works
“Autopsied brain tissue from patients with severe TBI showed significant loss of hypothalamic orexin neurons (Baumann et al., 2009).”
BackgroundMachaalani, R., Hunt, N. J., & Waters, K. A. (2013) · Brain Research · doi:10.1016/j.brainres.2013.06.035 · Cited by 28 · see citing works
Targets for migraine treatment: beyond calcitonin gene-related peptide
Moreno‐Ajona, D., Villar‐Martínez, M. D., & Goadsby, P. J. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000935 · Cited by 24 · see citing works
Sleep complications following traumatic brain injury
Grima, N., Ponsford, J. L., & Pase, M. P. (2017) · Current Opinion in Pulmonary Medicine · doi:10.1097/mcp.0000000000000429 · Cited by 24 · see citing works
Clinical Approach to Commonly Encountered Problems
Hines, M. T. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-44329-6.00007-3 · Cited by 24 · see citing works
Yassin, W., Sugihara, G., Oishi, N., Kubota, M., Ubukata, S., Murai, T., & Ueda, K. (2015) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.4710 · Cited by 22 · see citing works
Haynes, Z. A., Collen, J. F., Poltavskiy, E. A., Walker, L. E., Janak, J. C., Howard, J. T., Werner, J. K., Wickwire, E. M., Holley, A. B., Zarzabal, L. A., et al. (2021) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.9276 · Cited by 20 · see citing works
“33,34 Sleep-wake disturbances have been reported in up to 85% of patients with TBI in prior studies, and this population is known to have higher rates of insomnia diagnoses.”
El-Khatib, H., Arbour, C., Sanchez, E., Dumont, M., Duclos, C., Blais, H., Carrier, J., Paquet, J., & Gosselin, N. (2018) · Sleep Medicine · doi:10.1016/j.sleep.2018.11.012 · Cited by 20 · see citing works
“maintaining this sleep-wake pattern during the chro nic stage of TBI [15,36].”
BackgroundRowe, R. K., & Griesbach, G. S. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.04.017 · Cited by 20 · see citing works
Lu, W. Y.-R., Cantor, J. B., Aurora, R. N., Gordon, W. A., Krellman, J. W., Nguyen, M., Ashman, T. A., Spielman, L. A., & Ambrose, A. F. (2015) · Brain Injury · doi:10.3109/02699052.2015.1043947 · Cited by 19 · see citing works
“that previous work suggests that at least some individuals with TBI exhibit a hypocretin (orexin) deficiency due to loss of hypocretin-producing neurons, which play an important role in promoting wakefulness [48].”
BackgroundNew insights in post-traumatic headache with cluster headache phenotype: a cohort study
Grangeon, L., O’Connor, E., Chan, C.-K., et al. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2019-322725 · Cited by 19 · see citing works
Adeghate, E. A. (2012) · Vitamins and hormones · doi:10.1016/b978-0-12-394623-2.00007-x · Cited by 19 · see citing works
Elliott, J. E., McBride, A. A., Balba, N. M., Thomas, S. V., Pattinson, C. L., Morasco, B. J., Wilkerson, A. M., Gill, J., & Lim, M. M. (2022) · PLoS ONE · doi:10.1371/journal.pone.0262955 · Cited by 18 · see citing works
Feng, Z., Zhong, Y.-J., Wang, L., et al. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.155433 · Cited by 18 · see citing works
“It has been reported that orexin was reduced in cerebrospinal fluid in 95% of patients during 2 months after traumatic brain injury, and led to narcolepsy (Baumann et al., 2009; Ramanjaneya et al., 2009; Jeter et al., 2013).”
BackgroundRecovery from Coma Post-Cardiac Arrest Is Dependent on the Orexin Pathway
Kang, Y., Tian, G., Bazrafkan, A. K., et al. (2017) · Journal of Neurotrauma · doi:10.1089/neu.2016.4852 · Cited by 17 · see citing works
Du, M. K., Hunt, N. J., Waters, K. A., et al. (2015) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2015.10.007 · Cited by 17 · see citing works
“Yet, in traumatic brain injury or extreme HH, there was a 3-fold loss of Ox neuropeptide (Baumann et al., 2009).”
BackgroundBotchway-Commey, E. N., Godfrey, C., Anderson, V. A., Nicholas, C. L., & Catroppa, C. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2018.5743 · Cited by 17 · see citing works
“16,17 One theory on the etiology of SWD attributes insomnia to failure of the filtering mechanism used by the corticothalamocortical loop to prevent excitatory inputs from reaching the cortex during sleep.”
Sleep in Traumatic Brain Injury
Vermaelen, J., Greiffenstein, P. P., & deBoisblanc, B. P. (2015) · Critical Care Clinics · doi:10.1016/j.ccc.2015.03.012 · Cited by 16 · see citing works
Secondary Narcolepsy in Children
Madan, R., Pitts, J., Patterson, M. C., et al. (2020) · Journal of Child Neurology · doi:10.1177/0883073820954617 · Cited by 16 · see citing works
Borniger, J. C., Ungerleider, K., Zhang, N., Karelina, K., Magalang, U. J., & Weil, Z. M. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.01.064 · Cited by 15 · see citing works
“Finally, there have been reports of the loss of arousal-promoting orexin/hypocretin neurons as well as other hypothalamic arousal-modulating cells (e.g., histamine and melanin-concentrating hormone) in TBI patients (Baumann et al., 2009; Valko et al., 2015).”
Excessive daytime sleepiness after traumatic brain injury
Crichton, T., Singh, R. K., Abosi-Appeadu, K., & Dennis, G. (2020) · Brain Injury · doi:10.1080/02699052.2020.1810316 · Cited by 16 · see citing works
Palomba, M. L., Etet, P. F. S., & Veronesi, C. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.03.069 · Cited by 15 · see citing works
Traumatic Brain Injury and Behavior
McGee, J. C., Alekseeva, N., Chernyshev, O. Y., & Minagar, A. (2015) · Neurologic Clinics · doi:10.1016/j.ncl.2015.08.004 · Cited by 14 · see citing works
Mild Traumatic Brain Injury Affects Orexin/Hypocretin Physiology Differently in Male and Female Mice
Somach, R. T., Jean, I. D., Farrugia, A. M., & Cohen, A. S. (2023) · Journal of Neurotrauma · doi:10.1089/neu.2023.0125 · Cited by 13 · see citing works
Increased dopaminergic function in the thalamus is associated with excessive daytime sleepiness
Yousaf, T., Pagano, G., Niccolini, F., & Politis, M. (2017) · Sleep Medicine · doi:10.1016/j.sleep.2017.11.1137 · Cited by 13 · see citing works
“18 neurons in the hypothalamus [50], cholinergic neuro ns in the basal forebrain and serotoninergic neurons in the raphe [51].”
BackgroundThe orexin/hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms
Fronczek, R., Schinkelshoek, M. S., Shan, L., & Lammers, G. J. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-820107-7.00021-5 · Cited by 13 · see citing works
Potential for the development of light therapies in mild traumatic brain injury
Raikes, A. C., & Killgore, W. D. S. (2018) · Concussion · doi:10.2217/cnc-2018-0006 · Cited by 12 · see citing works
Narcolepsy and traumatic brain injury: Cause or consequence?
Poryazova, R., Hug, D., & Baumann, C. R. (2011) · Sleep Medicine · doi:10.1016/j.sleep.2011.04.007 · Cited by 12 · see citing works
“After traumatic brain injury (TBI), hypocretin neurons are partially reduced [2], and excessive daytime sleepiness (EDS) belongs to the most common posttraumatic sleep–wake disturbances [3].”
BackgroundSelf-citation
- Authors
- Baumann, C. R., Bassetti, C. L., Valko, P. O., Haybaeck, J., Keller, M., Clark, E., Stocker, R., Tolnay, M., & Scammell, T. E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- University Hospital Zurich (CH)
- Corresponding author
- Baumann, Christian R.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2009-10
- Volume
- 66
- Issue
- 4
- Pages
- 555-559
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2770195
- OpenAlex
- W2025705478
- Semantic Scholar
- 1dbac4f5e899ccafddf7329f779db1028a085914
- Cited by
- 185
- References
- 25
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 4 · 2022: 13 · 2021: 10 · 2020: 13 · 2019: 11 · 2018: 22 · 2017: 10 · 2016: 10 · 2015: 19 · 2014: 12 · 2013: 10 · 2012: 12
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.zora.uzh.ch
- Licence
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- PubMed Central (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute of Mental Health (R01 MH062589, MH062589)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- orexin, traumatic brain injury, hypothalamic neurons, narcolepsy, Parkinson's disease, wakefulness
- MeSH terms
- Orexins, Adult, Aged, Aged, 80 and over, Brain Injuries, Cell Count, Female, Humans, Hypothalamus, Male, Middle Aged, Neurons, Neuropeptides, Pilot Projects, Wakefulness, Intracellular Signaling Peptides and Proteins
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