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Cited by 1,063Neuroinflammation and Neurodegeneration MechanismsMedical and Biological SciencesNeuroscience and Neuropharmacology Research

The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting

Open access
von Bartheld, Christopher S., Bahney, Jami, Herculano‐Houzel, Suzana·2016·Journal of Comparative Neurology
DOI 10.1002/cne.24040PMC PMC5063692
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Abstract

For half a century, the human brain was believed to contain about 100 billion neurons and one trillion glial cells, with a glia:neuron ratio of 10:1. A new counting method, the isotropic fractionator, has challenged the notion that glia outnumber neurons and revived a question that was widely thought to have been resolved. The recently validated isotropic fractionator demonstrates a glia:neuron ratio of less than 1:1 and a total number of less than 100 billion glial cells in the human brain. A survey of original evidence shows that histological data always supported a 1:1 ratio of glia to neurons in the entire human brain, and a range of 40–130 billion glial cells. We review how the claim of one trillion glial cells originated, was perpetuated, and eventually refuted. We compile how numbers of neurons and glial cells in the adult human brain were reported and we examine the reasons for an erroneous consensus about the relative abundance of glial cells in human brains that persisted for half a century. Our review includes a brief history of cell counting in human brains, types of counting methods that were and are employed, ranges of previous estimates, and the current status of knowledge about the number of cells. We also discuss implications and consequences of the new insights into true numbers of glial cells in the human brain, and the promise and potential impact of the newly validated isotropic fractionator for reliable quantification of glia and neurons in neurological and psychiatric diseases. J. Comp. Neurol. 524:3865–3895, 2016. © 2016 Wiley Periodicals, Inc.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the human brain does not contain one trillion glial cells or a 10:1 glia:neuron ratio; instead, histological evidence supports about a 1:1 ratio and 40–130 billion glial cells, with the isotropic fractionator finding fewer than 100 billion glial cells and a ratio below 1:1. It traces how the 10:1 claim originated, persisted in textbooks without primary references, and was eventually refuted.

Key findings

  • Historical histological data supported a 1:1 glia:neuron ratio in the entire human brain and a range of 40–130 billion glial cells; the isotropic fractionator reported a glia:neuron ratio of less than 1:1 and fewer than 100 billion glial cells.
  • Neuron estimates converge on 67–86 billion neurons for the entire human brain by isotropic fractionator, with most cerebral cortex studies reporting 10–20 billion neurons and a plausible cerebellar range of 50–70 billion neurons.
  • The glia:neuron ratio is about 1.5 in cerebral cortical grey matter, rises to about 3–4 when white matter is included, and is about 0.05 for the entire cerebellum; only five publications report a whole-brain ratio of 0.7:1–1:1.
  • The 10:1 ratio and one-trillion-glia claim originated in the 1950s, were perpetuated in textbooks and reviews without valid primary references, and were contradicted by primary data that had existed for decades.

Methods

  • Review and historical analysis of published cell counts from 1868/1872 through 2015, compiling reports of neuron numbers, glial numbers, and glia:neuron ratios in the human brain and its major parts.
  • Compares three counting approaches: histology/stereology, DNA extraction, and direct enumeration/isotropic fractionator, including validation studies that compared the isotropic fractionator with stereology and DNA extraction.
  • No new primary cell counts are reported; the paper surveys original evidence and textbook/review claims to examine the origin, perpetuation, and refutation of the one-trillion-glia claim.

Limitations

  • Stated: the review is restricted primarily to literature on cell counts in adult human brains; the isotropic fractionator cannot distinguish glial subtypes or separate glia from endothelial cells, so its non-neuronal:neuron ratio is an upper limit for the glia:neuron ratio; NeuN is not expressed by a small number of neuronal populations; and only macroscopically dissectable regions can be analyzed.
  • Stated: histology/stereology faces challenges with representative sampling, double counting, differential shrinkage, distinguishing small neurons from glia, and the “reference trap”; DNA extraction requires complete recovery, assumes euploidy, and can be affected by fixation and lipid-rich tissue.
  • Evident: as a review, it generates no new experimental data, and its historical tables depend on published studies with inconsistent methods and incomplete primary details; the authors also note that discrepancies between studies are difficult to resolve without full access to primary data and independent re-examination.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/cne.24040

Cites

339 of 339 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 138 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A survey of original evidence shows a range of 40-130 billion glial cells in the human brain.

    “and a range of 40–130 billion glial cells”
    Quote in the paperSubstantial claim
  • Findingcitation

    Recent studies have shown that the cellular composition of the human brain is very different than was believed and taught for almost half a century.

    “Recent studies have shown that the cellular composition of the human brain is very different than was believed and taught for almost half a century”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Azevedo et al., 2009

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    • cites Hilgetag and Barbas, 2009

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    • cites Lent et al., 2012

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  • Findingcitation

    The second phase witnessed the first publications of serious estimates of total numbers of neurons, in the range of 70-85 billion.

    “and neurons (70–85 billion: compiled by Haug, 1986, also reviewed in Williams and Herrup, 1988)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Haug, 1986

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    • cites Williams and Herrup, 1988

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  • Findingreasoning

    The cell density-based estimates of the second phase supported a total glia:neuron ratio of about 1:1.

    “Even though these cell density-based estimates supported a total GNR of about 1:1”
    Quote in the paperSubstantial claim
  • Findingcitation

    The second phase witnessed the first publications of serious estimates of total numbers of glial cells, in the range of 40-130 billion.

    “A second phase witnessed the first publications of serious estimates of total numbers, for both glial cells (40–130 billion: compiled by Blinkov and Glezer, 1968, and Haug, 1986)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Blinkov and Glezer, 1968

      Not checked in the free run.

    • cites Haug, 1986

      Not checked in the free run.

  • May combine two claims. 67
  • Classified as probably not a substantial claim. 33
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingnone given

    The recently validated isotropic fractionator demonstrates a glia:neuron ratio of less than 1:1 and a total number of less than 100 billion glial cells in the human brain.

    “The recently validated isotropic fractionator demonstrates a glia:neuron ratio of less than 1:1 and a total number of less than 100 billion glial cells in the human brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The isotropic fractionator has challenged the notion that glia outnumber neurons and revived a question that was widely thought to have been resolved.

    “A new counting method, the isotropic fractionator, has challenged the notion that glia outnumber neurons and revived a question that was widely thought to have been resolved.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    The first phase of brain cell counting lasted until about the 1970s.

    “This phase lasted until about the 1970s.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The simple mathematical relationship G/N = GNR was neglected on multiple occasions.

    “this relationship was neglected on multiple occasions”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    In the first phase of brain cell counting, data were collected only for parts of the human brain, in particular the cerebral cortex.

    “In the first phase, data were collected only for parts of the human brain, in particular the cerebral cortex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Historically, total neuron numbers, total glia numbers, and the glia-to-neuron ratio followed surprisingly distinct trajectories that seemed to co-exist in agreement on superficial inspection.

    “Historically, these three ways of numerical accounting have followed surprisingly distinct trajectories that seemed to co-exist, on superficial inspection, in agreement.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    To determine numbers of glial cells, most studies have combined astrocytes, oligodendrocytes and microglia.

    “To determine numbers of glial cells, most studies have similarly combined astrocytes, oligodendrocytes and microglia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The original version of the direct enumeration method suffered from rapid degradation of unfixed cells and lack of distinction between cell types.

    “The original version of the “direct enumeration” method suffered from several shortcomings, primarily rapid degradation of unfixed cells and lack of distinction between cell types”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    DNA extraction has been used mostly in the 1950s through the 1970s.

    “DNA extraction has been used mostly in the 1950s through the 1970s”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Modified direct enumeration allowed easy recognition of larger cerebellar neurons, but the distinction between granule cells and glial cells remained problematic.

    “These modifications allowed to easily recognize larger cerebellar neurons, but the distinction between granule cells and glial cells remained problematic.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The isotropic fractionator has the advantages of being easy, fast, and accurate, generating estimates of numbers of cells that are independent of tissue volume or cell density, and overcoming problems of heterogeneity of tissues.

    “the method has the advantages of being easy, fast, and accurate, generating estimates of numbers of cells that are independent of tissue volume or cell density, and overcoming problems of heterogeneity of tissues”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The estimates ranged from 1.2-32 billion neurons for the entire cortex, with a majority of studies reporting between 10 and 20 billion neurons.

    “the estimates ranged from 1.2–32 billion neurons for the entire cortex (right and left hemispheres combined), with a majority of studies reporting between 10 and 20 billion neurons”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    von Economo and Koskinas's numbers became highly controversial and prompted a harsh rebuttal by Agduhr (1941).

    “Ironically, their numbers became highly controversial and prompted a harsh rebuttal by Agduhr (1941).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    There are additional examples where numbers reported by the group of B. Pakkenberg had to be revised.

    “There are additional examples where numbers reported by the group of B. Pakkenberg, one of the pioneers of stereological counting methods, had to be revised”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    More recent work employing computer simulations indicates that considerably more neurons should be counted.

    “while more recent work employing computer simulations indicates that considerably more neurons should be counted”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Schmitz and Hof, 2000

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    • cites Geuna and Herrera-Rincon, 2015

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The group of B. Pakkenberg reported 20-32 billion neurons.

    “On the high end, the group of B. Pakkenberg reported 20–32 billion neurons”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    It still is controversial whether women have a smaller number of neurons than men.

    “It still is controversial whether women have a smaller number of neurons than men”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    It still is controversial whether neocortex loses a small amount of neurons (less than 10% over 80 years).

    “and whether neocortex loses a small amount of neurons (less than 10% over 80 years”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Haug, 1987

      Not checked in the free run.

    • cites Pakkenberg and Gundersen, 1997

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  • May combine two claims.

    Findingcitation

    Actual losses of neurons during normal aging appear to be of a much lesser scale and region-specific.

    “Actual losses appear to be of a much lesser scale and region-specific”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Curcio et al., 1982

      Not checked in the free run.

    • cites West, 1993b

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    • cites Peters et al., 1998

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  • May combine two claims.

    Findingown data

    The range of neuronal numbers in the human brain is by and large within one order of magnitude, with 20/23 authors giving numbers or a median between 10 and 100 billion.

    “Table 6 shows that the range of neuronal numbers in the human brain is by and large within one order of magnitude, with 20/23 authors giving numbers or a median between 10 and 100 billion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Two texts say one trillion neurons, and the authors did not correct this mistake for neuron numbers until subsequent editions of their textbook.

    “Two texts say one trillion (Kandel and Schwartz, 1981, 1985), and the authors did not correct this mistake for neuron numbers until subsequent editions of their textbook (Kandel et al., 1991, 2000, 2013).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Two editions of Principles of Neural Science suggested human brains contain as many as 50 trillion glial cells, despite the largest number ever suggested in primary literature being 130 billion.

    “Accordingly, two editions of the Principles of Neural Science (Kandel and Schwarz, 1981 and 1985) suggested that human brains contain as many as 50 trillion glial cells, despite the fact that the largest number ever suggested in the primary literature was 130 billion (Blinkov and Glezer, 1968).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The first response of many brain scientists to the Azevedo et al. (2009) report was disbelief, and it has taken several years for the new evidence to become accepted.

    “Not surprisingly, the first response of many brain scientists to the “maverick” report by Azevedo et al. (2009) was disbelief (see below and Yuhas and Jabr, 2012), and it has taken several years for the new evidence to become accepted (Table 6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our review of textbooks and other published reports on the GNR and neuron and glia numbers shows that reports can be divided into three types: (1) a few authors remained cautious and stated a wide range, used non-specific terms or said numbers or ratios were unknown; (2) other authors reported numbers based on particular studies and data sets and properly cited the original reference(s); (3) a大型

    “Our review of textbooks and other published reports on the GNR and neuron and glia numbers shows that reports can be divided into three types. (1) A few authors remained cautious and stated a wide range, used non-specific terms (“large number”) or said that numbers or ratios were unknown (Hubel, 1979; Nauta and Feirtag, 1979; Jacobson, 1991). (2) Other authors reported numbers based on particular”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    NINDS narratives mirror the misleading statements about glia-neuron ratios in the textbooks, and are factually wrong, but reflect the "textbook knowledge" of their times.

    “These narratives mirror the misleading statements about glia-neuron ratios in the textbooks, and are factually wrong, but reflect the “textbook knowledge” of their times: “glial cells far outnumber nerve cells in the brain” (NINDS, 2001); “non-neuronal cells … far outnumber nerve cells in the brain” (NINDS, 2011); “non-nerve cells, called glial cells, outnumber nerve cells in the brain” (NINDS, 20”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    The newest (5th) edition of Kandel's textbook has revised the chapter on the cellular composition of the brain from the original "10-50 more glia" statement to "2 to 10 times more glia than neurons"; this is an improvement, but still incorrect, as is the claim of an abundance of glia over neurons in the human brain (4:1 according to Barres et al., 2015).

    “The newest (5th) edition of Kandel’s textbook has revised the chapter on the cellular composition of the brain, which is now co-authored by Barres, from the original “10–50 more glia” statement to “2 to 10 times more glia than neurons” (Kandel et al., 2013). This is an improvement, but still incorrect, as is the claim of an abundance of glia over neurons in the human brain (4:1 according to Barres”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The support for a total glia:neuron ratio of about 1:1 was either not recognized or not effectively communicated.

    “this was either not recognized or not effectively communicated”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    For half a century, the human brain was believed to contain about 100 billion neurons and one trillion glial cells, with a glia:neuron ratio of 10:1.

    “For half a century, the human brain was believed to contain about 100 billion neurons and one trillion glial cells, with a glia:neuron ratio of 10:1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Brain cell counting can be roughly divided into three historical phases.

    “Brain cell counting can be roughly divided into three historical phases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because the published numbers for neuron counts, glia counts, and the assumed glia:neuron ratio of 10:1 contradicted each other, one or more of those components had to be false.

    “and therefore one or more components had to be false”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The DNA extraction approach reveals only total cell number, but not cell type.

    “only total cell number, but not cell type is revealed”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Not all cells are euploid, which is a drawback of the DNA extraction approach.

    “not all cells are euploid”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The DNA extraction approach requires complete recovery of DNA.

    “complete recovery of DNA is required”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The DNA extraction approach can have contamination with other nucleic acids.

    “there can be contamination with other nucleic acids”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The design-based stereology method is unbiased in theory, although bias can arise due to tissue deformation and loss of particles during tissue processing and other errors.

    “Such a method is unbiased in theory, although bias can arise due to tissue deformation and loss of particles during tissue processing and other errors”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites von Bartheld, 1999, 2002

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    • cites Guillery, 2002

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  • May combine two claims.

    Interpretationreasoning

    Inclusion of white matter does not make a significant difference for neuron numbers, although it does make a difference for total cell numbers.

    “Therefore, inclusion of white matter does not make a significant difference for neuron numbers, although it does make a difference for total cell numbers”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This ambiguity explains why Blinkov and Glezer listed Shariff's numbers incorrectly for only one hemisphere, while Haug correctly listed those numbers for total cortex.

    “This type of confusion explains why Blinkov and Glezer (1968) listed Shariff’s numbers incorrectly for only one hemisphere, while Haug (1986) correctly listed those numbers for total cortex.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Revisions of numbers reported by the group of B. Pakkenberg are not surprising, given the large biological variability among human brains and the difficulties of working with human tissues.

    “this is not surprising, given the large biological variability among human brains and the difficulties of working with human tissues”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The notion that counting only 100-200 neurons is sufficient is controversial.

    “the controversial notion that counting only 100–200 neurons is sufficient”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gundersen, 1986

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    • cites Andersen et al., 1992

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    • cites Coggeshall and Lekan, 1996

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  • The quote only partly states this claim.

    Interpretationcitation

    An apparent decrease of less than 10% may be functionally insignificant.

    “and furthermore may be functionally insignificant”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Peters et al., 1998

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Across primary sources, in different brain regions including neocortical grey matter, oligodendrocytes are the most frequent at 45-75% of glial cells, followed by astrocytes (19-40%), while microglia contribute 10% or less.

    “There is also considerable, but not unanimous agreement across primary sources that in different brain regions, including neocortical grey matter, oligodendrocytes are the most frequent at 45–75% of glial cells, followed by astrocytes (19–40%), while microglia contribute 10% or less”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    All three methods (histology, DNA extraction, and the isotropic fractionator) support numbers of about 10-20 billion neurons and at most a 2-fold larger number of glial cells (20-40 billion) in human cerebral cortical grey matter, supporting an average GNR of approximately 1.5.

    “In conclusion, all three methods: histology, DNA extraction, and the IF method support numbers of about 10–20 billion neurons and at most a 2-fold larger number of glial cells (20–40 billion) in the human cerebral cortical grey matter, thus supporting an average GNR of approximately 1.5.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Endothelial cells in white matter comprise 10-20% of non-neuronal cells, lower than about 30% in cerebral cortex grey matter and other parts of the CNS.

    “endothelial cells in white matter appear to comprise a somewhat lower percentage (10–20% of non-neuronal cells, Bahney and von Bartheld, 2014) than they do in cerebral cortex grey matter and other parts of the CNS (about 30%, see below)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bahney and von Bartheld, 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In Azevedo et al. (2009), excluding endothelial cells leaves 70% glial cells and reduces the non-neuronal to neuron ratio from 1.48 to a true GNR of 1.04.

    “leaving 70% glial cells, and reducing the non-neuronal to neuron ratio (nNNR) from 1.48 to a true GNR of 1.04 in Azevedo et al. (2009)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Azevedo et al. (2009)

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The GNR of the human cerebellum implied by Andersen et al.'s data is about 0.03.

    “This implied that the GNR of the human cerebellum had to be extremely low, about 0.03.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Andersen et al., 1992

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies using the isotropic fractionator estimated the average number of cells in the cerebellum to be between 55 and 70 billion, with granule cells constituting the overwhelming majority.

    “Studies using the IF have estimated the average number of cells in the cerebellum to be between 55 and 70 billion (Azevedo et al. (2009); Andrade-Moraes et al., 2013), with granule cells (granule neurons) constituting the overwhelming majority (Azevedo et al. (2009)).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Azevedo et al. (2009)

      Not checked in the free run.

    • cites Andrade-Moraes et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Andersen and colleagues' counts of 30,000-40,000 glial cells per mm3 appear plausible, resulting in a total of about 3 billion glial cells in the cerebellum.

    “Andersen and colleagues’ counts of 30,000–40,000 glial cells per mm3 appear plausible, resulting in a total of about 3 billion glial cells in the cerebellum.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Andersen et al., 1992

      Not checked in the free run.

    • cites Bahney and von Bartheld, 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Andersen et al. estimated that among a total of 105 billion cells in the human cerebellum, there were 101 billion granule cells, with most of the remainder, about 3 billion, being glial cells.

    “Andersen et al. estimated that among a total of 105 billion cells in the human cerebellum, there were 101 billion granule cells, with most of the remainder, about 3 billion, being glial cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Andersen et al., 1992

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The isotropic fractionator yields an upper estimate of around 16 billion non-neuronal cells in the cerebellum, amounting to a maximal GNR of 0.23.

    “The same method yields an upper estimate of around 16 billion glial cells; this counts all non-neuronal cells which comprise the combined total of glial and endothelial cells in the cerebellum, and therefore amounts to a maximal GNR of 0.23”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Azevedo et al. (2009)

      Not checked in the free run.

    • cites Andrade-Moraes et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The human cerebellum is not an outlier in its GNR or glial cell composition; its low GNR is because of the very large density of neurons in this structure.

    “However, the human cerebellum is not an outlier in its GNR or glial cell composition; if the GNR appears abnormally low, it is because of the very large density of neurons in this structure (Herculano-Houzel, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Herculano-Houzel, 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    With 80-100 billion neurons in the cerebral cortex and cerebellum together, a 10:1 GNR implying 1 trillion or more glial cells is impossible.

    “When the number of neurons in these two structures together was determined to be between about 80–100 billion, it should have become apparent that a 10:1 GNR, with the implied 1 trillion or more glial cells, was impossible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The unusual cellular composition of the cerebellum was a key factor in failed attempts to calculate the true GNR for the total human brain, and a major reason for the persistence of the notion of one trillion glial cells.

    “The unusual cellular composition of the cerebellum was a key factor in failed attempts to calculate the true GNR for the total human brain, and a major reason for the persistence of the notion of one trillion glial cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The brainstem, diencephalon and striatum contain only about 700 million neurons and about 6.6-7.7 billion non-neuronal cells, with a GNR of maximal 10:1.

    “this part of the brain contains only about 700 million neurons and about 6.6–7.7 billion non-neuronal cells, with a GNR of maximal 10:1, as determined by the isotropic fractionator”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Azevedo et al. (2009)

      Not checked in the free run.

    • cites Andrade-Moraes et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Current estimates of non-neuronal cells in the entire human brain, as revealed by the isotropic fractionator, place total glial numbers well below 85 billion, closer to Haug's 40-50 billion than Blinkov and Glezer's 100-130 billion.

    “The current estimates of numbers of non-neuronal cells in the entire human brain, as revealed by the IF, place the total glial numbers well below 85 billion (since these 85 billion include approximately 20–25 billion endothelial cells), and therefore are closer to the estimates of Haug (40–50 billion glial cells) rather than those of Blinkov and Glezer (100–130 billion glial cells) (Fig. 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Azevedo et al. (2009)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blinkov and Glezer estimated 100-130 billion glial cells in the entire human brain, while Haug estimated 40-50 billion.

    “Blinkov and Glezer (1968) estimated the number of glial cells in the entire human brain to be 100–130 billion, while Haug, using his own densities and volume measurements, estimated 40–50 billion glial cells for the entire human brain (Haug, 1986).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Blinkov and Glezer (1968)

      Not checked in the free run.

    • cites Haug, 1986

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mühlmann established that the approximate GNR of the grey matter of the human cerebral cortex is about 1.5, a value that has since been widely confirmed.

    “Mühlmann established that the approximate GNR (“Prozentgehalt der Nerven und der Gliazellen”) of the grey matter of the human cerebral cortex is about 1.5, a value that since has been widely confirmed (Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mühlmann, 1936

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The GNR is age-specific and glia-neuron relations change as the brain matures.

    “This showed that the GNR is age-specific and that glia-neuron relations change as the brain matures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The GNR does not increase universally with brain mass or cortical mass, but rather with decreasing neuronal density.

    “The GNR was shown not to increase universally with brain mass or cortical mass, but rather with decreasing neuronal density, which may or may not coincide with increasing brain mass (Herculano-Houzel, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Herculano-Houzel, 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The GNR largely reflects differences in neuronal density, but not, or only to a very minor extent, differences in glial density.

    “Accordingly, the GNR largely reflects differences in neuronal density, but not, or only to a very minor extent, differences in glial density (Blinkov and Glezer, 1968).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Blinkov and Glezer, 1968

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The vasculature represents a constant (and small, 1-5%) fraction of brain tissue, so values of nN-NR likely translate into GNR by the same proportion across species.

    “Given that the vasculature represents a constant (and small, 1–5%) fraction of brain tissue (and cerebral cortex in particular; Buchweitz and Weiss, 1986; Lawers et al., 2008; Tsai et al., 2009; Karbowski, 2011), values of nN-NR likely translate into GNR by the same proportion across species.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Buchweitz and Weiss, 1986

      Not checked in the free run.

    • cites Lawers et al., 2008

      Not checked in the free run.

    • cites Tsai et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The ratio obtained with the isotropic fractionator is not a GNR, but a non-neuronal cells/neurons ratio (nN-NR), which serves as a useful upper limit to the GNR.

    “The ratio obtained with the IF is therefore not a GNR, but a “nN-NR” ratio (non-neuronal cells/neurons ratio) – which, however, serves as a useful upper limit to the GNR.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Based on studies in the 1950s to 1980s, it was reported and generally believed that the normal aging brain loses large numbers of neurons each day after 30 years of age.

    “Based on studies in the 1950s to 1980s, it was reported and generally believed that the normal aging brain loses large numbers of neurons each day after 30 years of age (Brody, 1955; Devaney and Johnson, 1980), so that “a 60-year span of adulthood would mean loss of half the cerebral neurons” (Hanley, 1974; see also Curcio et al., 1982; Kausler et al., 2007).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The refutation of the notion of one trillion glial cells is an example where the isotropic fractionator initiated a paradigm shift, but subsequent scrutiny showed the new paradigm had been supported all along by traditional histological techniques.

    “The refutation of the notion of one trillion glial cells is also an example where a new (or substantially improved) technique, the IF, initiated a paradigm shift, but subsequent scrutiny showed – surprisingly – that the new paradigm had been supported all along, for decades, by traditional (histological) techniques.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Once a myth has found its way into textbooks, curricula and common knowledge, it becomes difficult to rectify.

    “As revealed in our review, once a myth has found its way into textbooks, curricula and common knowledge, it becomes difficult to rectify.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Throughout much of the 20th century the notion prevailed that the cellular composition of the human brain was exceptional among species and likely responsible for superior cognitive abilities of humans.

    “Throughout much of the 20th century the notion prevailed that the cellular composition of the human brain was exceptional among species and likely responsible for the superior cognitive abilities of humans (Gazzaniga, 2008).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The shrinkage of brains after fixation depends on the person's age, and reference volumes of brains from older people differ from those of younger brains.

    “The shrinkage of brains after fixation depends on the person’s age, and accordingly the reference volumes of brains from older people differ from those of younger brains.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Classical studies documented loss of neurons in degenerative diseases, correlating extent of neuron loss with disease severity.

    “There are numerous examples of how cell counting has informed and impacted progress in the field, with classical studies documenting the loss of neurons in degenerative diseases, for example correlating the extent of neuron loss with disease severity (Damier et al., 1999; Stark and Pakkenberg, 2004; Kordower et al., 2013).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    The lack of citations for the notion of a 10:1 GNR over a 50 year period is an example of a major failure in the scientific process that is supposed to self-correct invalid claims or reports.

    “The lack of citations for the notion of a 10:1 GNR over a 50 year period is an example of a major failure in the scientific process that is supposed to self-correct invalid claims or reports (Committee on the Conduct of Science, 1989; Neville, 2007; Firestein, 2012; Ioannidis, 2012), as explained in more detail below.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The problem appears to have been disregard of conflicting primary data and a failure to recognize the lack of supporting data for the prevailing consensus.

    “The problem appears to have been disregard of conflicting primary data and a failure to recognize the lack of supporting data for the prevailing consensus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The human brain and its neocortex have "hardware" and cellular contents that are expected for its body size and are not extraordinary in their cellular composition.

    “Thus, the new studies comparing GNRs of different primate brains have shown that the human brain and its neocortex have “hardware” and cellular contents that are expected for its body size and are not extraordinary in their cellular composition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The GNR can vary substantially among different brainstem nuclei, and the assumption that the distribution in one small nucleus was representative for the whole brain likely contributed to the widely overstated GNR in reviews and textbooks.

    “As revealed by the work of Blinkov and Glezer (1968) as well as Thörner and colleagues (1975), the GNR can vary substantially among different brainstem nuclei – thus, the assumption that the distribution in one small nucleus of the brain was representative for the whole brain likely contributed to the widely overstated GNR in reviews and textbooks (Table 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The development of the isotropic fractionator made it possible to re-examine GNRs and survey a much larger number of species in more detail.

    “The development of a more efficient cell counting method, the IF, made it possible to re-examine GNRs and to survey a much larger number of species, and in more detail (Azevedo et al. (2009); Herculano-Houzel, 2009; Herculano-Houzel, 2011; Herculano-Houzel, 2012; Herculano-Houzel, 2014).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The human ratio of non-neuronal to neuronal cells of 1 is similar to that of other primates, firmly establishing humans as non-outliers.

    “Most importantly, a GNR of 10 would indeed have made the human brain extraordinary – but that is not the case: The human ratio of non-neuronal to neuronal cells of 1 is similar to that of other primates, firmly establishing humans as non-outliers (Herculano-Houzel, 2012).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The neurons (retinal ganglion cells) communicated signals either to glial cell precursors to proliferate or to existing glia to allow more of the already produced glial cells to survive, so that a constant ratio between neurons or axons and supporting glial cells was maintained in the mice with increased neuron numbers.

    “These results implied that the neurons (retinal ganglion cells) communicated signals either to glial cell precursors to proliferate or to existing glia to allow more of the already produced glial cells to survive, so that a constant (presumably optimal) ratio between neurons or axons and supporting glial cells was maintained in the mice with increased neuron numbers (Burne et al., 1996).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous work suggested that the human brain and in particular the human neocortex showed an abnormally high GNR compared with other mammals with lesser cognitive abilities.

    “Previous work had suggested that the human brain and in particular the human neocortex showed an abnormally high GNR when compared with other mammals with lesser cognitive abilities (Friede, 1954; Jerison, 1973; Araque et al., 2001; Fields, 2009; Koob, 2009; Verkhratsky and Butt, 2013).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Notions have been controversial whether destruction of nuclei may affect primarily the larger, neuronal nuclei or the smaller, glial cell nuclei.

    “In fact, notions have been controversial whether destruction of nuclei may affect primarily the larger, neuronal nuclei (Lovtrup-Rein and McEwen, 1966; Clarke and Oppenheim, 1995) or the smaller, glial cell nuclei (Hadjiolov et al., 1965; Kato and Kurokawa, 1967).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    This time, the significance of the findings was realized, and the authors drew attention to the discrepancies and made considerable efforts to locate the source of the prevailing erroneous estimates.

    “This time, the significance of the findings was realized, and the authors drew attention to the discrepancies and made considerable efforts to locate the source of the prevailing erroneous estimates (Herculano-Houzel, 2009; Hilgetag and Barbas, 2009; Firestein, 2012; Yuhas and Jabr, 2012) (Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The perpetuation of the claim was to a large part due to errors in Kandel's textbook editions, which helped glia biologists to advance their arguments of glial neglect, yet at the same time, Kandel was criticized for promoting the "neural dogma" and ignoring the importance of glial cells.

    “There is a certain irony in that the perpetuation of the claim was to a large part due to errors in Kandel’s textbook editions (Table 6), which helped glia biologists to advance their arguments of glial neglect (e.g., Fields, 2009; Koob, 2009), yet at the same time, Kandel was criticized for promoting the “neural dogma” and ignoring the importance of glial cells (Merrill, 2009).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The third challenge was based on data obtained by the isotropic fractionator which showed that the cellular composition of the human brain comprised an average of 86 billion neurons, 85 billion non-neuronal cells, and thus rendered a GNR of less than 1:1 (Azevedo et al. (2009)).

    “The third challenge was based on data obtained by the isotropic fractionator which showed that the cellular composition of the human brain comprised an average of 86 billion neurons, 85 billion non-neuronal cells, and thus rendered a GNR of less than 1:1 (Azevedo et al. (2009)).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Most influential for the propagation of those numbers appear to have been the textbooks of prominent neuroscientists such as Kuffler and Nicholls and the textbook by Nobel laureate Kandel and his colleagues.

    “Most influential for the propagation of those numbers appear to have been the textbooks of prominent neuroscientists such as Kuffler and Nicholls and the textbook by Nobel laureate Kandel and his colleagues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The second challenge came with Haug's estimate of less than 50 billion glial cells and a GNR of less than 1 (Haug, 1986).

    “The second challenge came with Haug’s estimate of less than 50 billion glial cells and a GNR of less than 1 (Haug, 1986).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The notion of a 10:1 GNR appears to have originated as an inadvertent mistake, with no evidence of deliberate manipulation.

    “The notion appears to have originated as an inadvertent mistake, with no evidence of deliberate manipulation, as in other instances of mis-information in science (Proctor and Schiebinger, 2008).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some gliabiologists and neuroscientists disagreed: the IF had not yet been validated against the current standard in the field, stereology.

    “Some gliabiologists and neuroscientists, however, disagreed: the IF had not yet been validated against the current standard in the field, stereology (Yuhas and Jabr, 2012; Carlo and Stevens, 2013; Verkhratsky and Butt, 2013; Charvet et al., 2015), although the estimates obtained with the IF for the human brain were very close to those in the literature, where they existed (Azevedo et al. (2009)).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Haug (1986) had calculated the numbers of glia and neurons to be equally low, with a low GNR - with a remarkable accuracy, as revealed in hindsight.

    “Haug (1986) had calculated the numbers of glia and neurons to be equally low, with a low GNR – with a remarkable accuracy, as revealed in hindsight.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Maximally 130 billion glia with a 10:1 GNR could not be true, because that would cap the total number of neurons at 13 billion, but there were 10-16 billion neurons in cerebral cortex alone, plus at least 10 billion neurons in cerebellar cortex, and possibly up to a total of 100 billion neurons in cerebellar cortex.

    “Maximally 130 billion glia with a 10:1 GNR could not be true, because that would cap the total number of neurons at 13 billion, but there were 10–16 billion neurons in cerebral cortex alone, plus at least 10 billion neurons in cerebellar cortex (granule neurons alone), and possibly up to a total of 100 billion neurons in cerebellar cortex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Once the notion of an overabundance of glia relative to neurons had formed and been incorporated into early influential textbooks, the notion was treated as a fact, and the abundance itself was rarely questioned; rather, it became largely reduced to the question of by exactly how much glia outnumbered neurons.

    “Once the notion of an overabundance of glia relative to neurons had formed and had been incorporated into early influential textbooks (Hyden, 1960; Kuffler and Nicholls, 1976; Kandel and Schwartz, 1981), the notion was treated as a fact, and the abundance itself was rarely questioned; rather, it became largely reduced to the question of by exactly how much glia outnumbered neurons, whether it was”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Recent calibration studies have dispelled these concerns and validated the IF against other counting methods, including stereology.

    “Recent calibration studies have dispelled these concerns and validated the IF against other counting methods, including stereology (Bahney and von Bartheld, 2014; Miller et al., 2014).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The GNR could not exceed 6.5:1 (130:20 = 6.5), and probably was much lower, possibly as low as a GNR of 100:116 which equals 0.86:1.

    “This should have been a warning signal – that the GNR could not exceed 6.5:1 (130:20 = 6.5), and probably was much lower, possibly as low as a GNR of 100:116 which equals 0.86:1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Meta-analyses have become common to explore the status and validity of previously published quantitative studies.

    “Therefore, meta-analyses have become common to explore the status and validity of previously published quantitative studies”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Harrison, 1999

      Not checked in the free run.

    • cites Rajkowska, 2000, 2002

      Not checked in the free run.

    • cites Hof et al., 2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approaches used were to examine adjacent samples of white matter to directly compare the methods of IF, histology/stereology, and DNA retrieval; and the two cerebral hemispheres of the same non-human primate were examined with IF and stereology, again showing equivalency between methods.

    “Approaches used were to examine adjacent samples of white matter to directly compare the methods of IF, histology/stereology, and DNA retrieval. In addition, the two cerebral hemispheres of the same non-human primate were examined with IF and stereology, again showing equivalency between methods (Miller et al., 2014).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Early research into glia abnormalities was much forgotten - so much so, that the significance of glial changes in psychiatric diseases had to be re-discovered in 2000.

    “Early research into glia abnormalities (as described above) was much forgotten – so much so, that the significance of glial changes in psychiatric diseases had to be re-discovered in 2000 (Coyle and Schwarcz, 2000).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    A precise balance of glia to neurons in human brain regions seems essential for normal function and this balance is disturbed in disease and trauma.

    “A precise balance of glia to neurons in human brain regions seems essential for normal function and this balance is disturbed in disease and trauma (see below).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Too often in the history of cell quantification have discrepancies between investigators, studies, and techniques remained hidden.

    “Too often in the history of cell quantification have discrepancies between investigators, studies, and techniques remained hidden.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Isotropic fractionator technology is a relatively fast and simple procedure.

    “Isotropic fractionator technology is a relatively fast and simple procedure”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bahney and von Bartheld, 2014

      Not checked in the free run.

94 of 94

  • The paper relies on this without support.

    The primary data from different counting methods and studies are sufficiently comparable to derive a consensus GNR.

    “Taken together, we conclude that based on all available primary data”

  • The paper relies on this without support.

    Numerical glia abnormalities have potential roles in neurological and psychiatric diseases.

    “defining the potential roles of numerical glia abnormalities in neurological and psychiatric diseases”
2 of 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 nonhuman primates and humans, glial cells seem to somewhat outnumber neurons in the PFC, with regional variation likely contributing to formation of secondary and tertiary gyri.

    “In nonhuman primates and human, glial cells seem to somewhat outnumber neurons in the PFC, albeit with regional variation which is likely to contribute to the formation of secondary and tertiary gyri [77–81].”

    From Development of prefrontal cortex (2022) · cites this paper as [81]

    The Cerebral cortex section (page unavailable) reports that glial cells modestly outnumber neurons on average in human cortical grey matter, with a glia-to-neuron ratio of approximately 1.5. The review does not establish that ratio specifically for the PFC in humans and nonhuman primates, or link regional variation to the formation of secondary and tertiary gyri. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The ratio of microglial cells to primary neurons inside the neurospheroids was tuned to be similar to the ratio in an in vivo brain (1:10).

    “To better mimic the in vivo conditions, we tuned the ratio of microglial cells to primary neurons inside our neurospheroids by tuning the ratio of cell suspension and finally set to be a similar ratio as in an in vivo brain (1:10).44”

    From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [44]

    The Cerebral cortex section says microglia make up 10% or less of glial cells in studied brain regions, while the Reports of the GNR section gives a whole-human-brain glia-to-neuron ratio of about 0.7:1–1:1. Together these make 1:10 a plausible approximation, but the paper does not establish that microglia-to-neuron ratio for the in vivo brain generally or for the primary neurons used in the neurospheroids. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • At least 40% of cells in the rodent and human brain are non-neuronal.

    “At least 40% of cells in the rodent [171] and human [172] brain are non-neuronal, but how non-neuronal cells interact with reward circuitry in MDD is unknown.”

    From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [172]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Two incompatible glial-cell estimates for the globus pallidus

    Major

    The text attributes both 63-82 million and 89-114 million glial cells in the globus pallidus to Thörner et al. (1975). The ranges do not overlap.

  • White-matter neuron density can exceed 1% of glial density

    Minor

    At the stated upper neuron density of 1,000 per mm3 and lower glial density of 20,000 per mm3, neurons are 5% as numerous as glia, not less than 1%.

    Reported 1 · recomputed 5

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 52

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  2. Barres BA, 2015, Glia. Cold Spring Harbor perspectives in biology
  3. Bayraktar OE, 2015, Glia, 1
  4. Bear MF, 2001, Exploring the brain
  5. Bear MF, 2007, Exploring the brain
  6. Blinkov SM, 1968, A quantitative handbook
  7. Brodal A, 1969, Neurological anatomy
  8. Bullock TH, 1967, The neurosciences: a study program, 347
  9. Curcio CA, 1982, The aging motor system. Advances in neurogerontology, 7
  10. Donaldson HH, 1895, The growth of the brain
  11. Ferrero C, 1947, [Le champ frontal granulaire magnocellulaire de l'ecorce cerebrale], Schweiz Arch Neurol Psychiatr, 59, 41
  12. Friede RL, 1953, Gliaindex und Hirnstoffwechsel, Wien Zeitschr Nervenh, 7, 143
  13. Ganong WF, 1977, The nervous system
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  15. Glees P, 1955, Morphology and function
  16. Hatton WJ, 1999, Analysis of cell death in the trochlear nucleus of the chick embryo: calibration of the optical disector counting method reveals systematic bias, J Comp Neurol 1999, 409, 169
  17. Haug H, 1984, Der Einfluss der sakularen Akzeleration auf das Hirngewicht des Menschen und dessen Anderung wahrend der Alterung, Gegenbaurs Morphol Jahrb, 130, 481
  18. Haug H, 1985, Gibt es Nervenzellverluste wahrend der biologischen Alterung in der menschlichen Hirnrinde? Ein morphometrischer Beitrag zu dieser Frage, Nervenheilkunde, 4, 103
  19. Howard CV, 1998, Three‐dimensional measurement in microscopy
  20. Hubel DH, 1979, The brain. A Scientific American Book, 2
  21. Hyden H, 1967, The neuron, 179
  22. Hyden H, 1967, The neurosciences: a study program, 248
  23. Kandel ER, 2013, Principles of neural xcience
  24. Kettenmann H, 1995, Neuroglia
  25. Kreuzfuchs S, 1902, Die Groesse der Oberflaeche des Kleinhirns, Arb Neur Inst Univ Wien, 9, 274
  26. Kryspin‐Exner W, 1952, Über die Architektonik der Glia im Zentralnervensystem des Menschen und der Säugetiere, Proc Ist Internat Congr Neuropath, Rome, 3, 504
  27. Kuffler SW, 1985, From neuron to brain
  28. Lojda Zd, 1955, Quantitative study of the Purkinje cells in the brain. [Czech.], Cs Morfol, 3, 66
  29. McMahan UJ, 1990, Steve: Remembrances of Stephen W. Kuffler
  30. Merril BC, 2009, The neural dogma. A Master's Thesis in Philosophy
  31. Meynert T, 1868, Der Bau der Grosshirnrinde und seine ortlichen Verschiedenheiten, nebst einem pathologisch‐anatomischen Corollarium, Vierteljahresschr Psych, 88
  32. Mouton PR, 2002, An introduction for bioscientists
  33. Mühlmann M, 1936, About the question of glia formation. Zur Neurogliabildungsfrage, Beitr Pathol Anat Allg Pathol, 96, 361
  34. Nauta WJH, 1979, The brain. A scientific american book, 41
  35. Nicholls JG, 1998, Biographical memoirs, 193
  36. Nicholls JG, 1985, From neuron to brain
  37. Nicholls JG, 1992, From neuron to brain
  38. Nicholls JG, 2012, From neuron to brain
  39. Nissl F, 1898, Nervenzellen und graue Substanz, Munch Med Wochenschr, 45, 988
  40. Noback CR, 1972, Introduction and review
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  42. Nurnberger JI, 1958, Biology of neuroglia, 193
  43. Pakkenberg B, 1989, Total number of neurons in human neocortex related to age and sex estimated by way of optical disectors, Acta Stereol, 8, 251
  44. Palay SL, 1958, Biology of neuroglia, 24
  45. Pope A, 1958, Biology of neuroglia, 211
  46. Purves D, 2010, How they work and what that tells us about who we are
  47. Scheff SW, 1996, Preparation and staining of tissue for counting neurons, Kopf Carrier, 45, 1
  48. Streit W, 2013, Neuroglia, 86
  49. Thomson W, 1889, Nature series. Popular lectures and addresses, 73
  50. Apathy S, 1897, Das leitende Element des Nervensystems und seine topographischen Beziehungen zu den Zellen, Erste Mitth Zool Stat Neapel, 12, 495
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Cited by

Sorted by citations

Related

Authors
von Bartheld, C. S., Bahney, J., & Herculano‐Houzel, S.
Affiliations
  • Department of Physiology and Cell Biology University of Nevada School of Medicine Reno Nevada USA
  • University of Nevada, Reno (US)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR)
ORCID
Herculano‐Houzel, Suzana
Venue
Journal of Comparative Neurology
Publisher
Wiley
Published
2016-06-16
Volume
524
Issue
18
Pages
3865-3895
ISSN
  • 0021-9967 (ISSN-L)
  • 1096-9861
DOI
10.1002/cne.24040
PMC
PMC5063692
OpenAlex
W2404695164
Semantic Scholar
c3181407c7ad6b7f6a268b017f22822695b26815
Cited by
1,063
References
339
Citations by year
2026: 73 · 2025: 109 · 2024: 131 · 2023: 152 · 2022: 145 · 2021: 148 · 2020: 147 · 2019: 78 · 2018: 47 · 2017: 26 · 2016: 7
FWCI
4.62
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Comparative Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (NIH) (NS079884, GM104944, GM103554)
  • CNPq, Faperj
  • James S. McDonnell Foundation (both to S.H.H.)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Anatomy › Medical and Biological Sciences
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
neuron number, human brain, cell counting methods
MeSH terms
Animals, Brain, Cell Count, Humans, Neuroglia, Neurons, History, 19th Century, History, 20th Century, History, 21st Century

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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