The DOI matches its Crossref record; 217 of the 227 references it cites were found in a registry or an index; 6 of the 220 sources its claims cite were checked for support.
Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications
Open accessAbstract
Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift toward a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural, and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.
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In the paper
“We have shown that DG granule neuron number and DG volume were smaller in anterior and mid, but not posterior hippocampus in unmedicated MDD postmortem62.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source
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In the paper
“Additionally, we found more granule neurons and a larger DG in resilient subjects who were exposed to childhood adversity but had no lifetime psychiatric diagnosis and died from natural causes63.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [63] Boldrini M, Galfalvy H, Dwork AJ, Rosoklija GB, Trencevska-Ivanovska I, Pavlovski G, et al. Resilience is associated with larger dentate gyrus, while suicide decedents with major depressive disorder have fewer granule neurons. Biol Psychiatry. 2019;85:850–62. source
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In the paper
“However, our group and others have shown evidence of neurogenesis throughout adulthood using double immunofluorescence98-101, in situ hybridization102 and 14C decay-defined neuronal age103.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [98] Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25:554–60. source
- Not checked yetcites [99] Terreros-Roncal J, Moreno-Jiménez EP, Flor-García M, Rodríguez-Moreno CB, Trinchero MF, Cafini F, et al. Impact of neurodegenerative diseases on human adult hippocampal neurogenesis. Science. 2021;374:1106–13. source
- Not checked yetcites [100] Tobin MK, Musaraca K, Disouky A, Shetti A, Bheri A, Honer WG, et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell. 2019;24:974–82.e3. source
- Not checked yetcites [101] Tartt AN, Fulmore CA, Liu Y, Rosoklija GB, Dwork AJ, Arango V, et al. Considerations for assessing the extent of hippocampal neurogenesis in the adult and aging human brain. Cell Stem Cell. 2018;23:782–3. source
- Not checked yetcites [102] Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219–27. source
- Not checked yetcites [103] Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. Evidences for adult hippocampal neurogenesis in humans. J Neurosci. 2021;41:2541–53. source
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In the paper
“In postmortem human brain, we found fewer neural progenitor cells and mature granular neurons in unmedicated depressed subjects, selectively in anterior DG, compared with non-psychiatric sudden death controls, suggesting that neurogenesis may be blunted in MDD62, 63.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source
- Not checked yetcites [63] Boldrini M, Galfalvy H, Dwork AJ, Rosoklija GB, Trencevska-Ivanovska I, Pavlovski G, et al. Resilience is associated with larger dentate gyrus, while suicide decedents with major depressive disorder have fewer granule neurons. Biol Psychiatry. 2019;85:850–62. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that antidepressant treatment is associated with more neural progenitor cells and granule neurons in postmortem human DG in MDD compared with non-MDD sudden death controls.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Treatment Induced Neuroplasticity
What the sources say
- Not checked yetcites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source
- Not checked yetcites [121] Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001;25:836–44. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The hippocampus is of particular importance in understanding depression pathogenesis14-16.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Introduction
What the sources say
- Not checked yetcites [14] Liu B, Liu J, Wang M, Zhang Y, Li L. From serotonin to neuroplasticity: evolvement of theories for major depressive disorder. Front Cell Neurosci. 2017;11:305. source
- Not checked yetcites [15] Price RB, Duman R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry. 2020;25:530–43. source
- Not checked yetcites [16] Sanchez-Mendoza EH, Camblor-Perujo S, Martins Nascentes-Melo L, Dzyubenko E, Fleischer M, Silva de Carvalho T, et al. Compromised hippocampal neuroplasticity in the interferon-α and toll-like receptor-3 activation-induced mouse depression model. Mol Neurobiol. 2020;57:3171–82. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Within the same patient, there is no consistency of severity of individual symptoms, symptom components or factors across successive episodes of major depression32.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [32] Oquendo MA, Barrera A, Ellis SP, Li S, Burke AK, Grunebaum M, et al. Instability of symptoms in recurrent major depression: a prospective study. Am J Psychiatry. 2004;161:255–61. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Second, the hippocampus is one of the few brain regions thought to be capable of adult neurogenesis19, 20.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Introduction
What the sources say
- Not checked yetcites [19] Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–7. source
- Not checked yetcites [20] Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22:589–99.e5. source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Given its role in neuronal maturation and differentiation75 as well as its neuroprotective effects76, low brain levels of BDNF may affect neuronal viability in MDD.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [75] Waterhouse EG, An JJ, Orefice LL, Baydyuk M, Liao GY, Zheng K, et al. BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J Neurosci. 2012;32:14318–30. source
- Not checked yetcites [76] Li H, Lin LY, Zhang Y, Lim Y, Rahman M, Beck A, et al. Pro-BDNF knockout causes abnormal motor behaviours and early death in mice. Neuroscience. 2020;438:145–57. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Top-down dysregulation of limbic structures may mediate affective symptoms and altered decision-making seen in mood disorders44-46.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [44] Zetsche U, D’Avanzato C, Joormann J. Depression and rumination: relation to components of inhibition. Cogn Emot. 2012;26:758–67. source
- Not checked yetcites [45] Joormann J, Levens SM, Gotlib IH. Sticky thoughts: depression and rumination are associated with difficulties manipulating emotional material in working memory. Psychol Sci. 2011;22:979–83. source
- Not checked yetcites [46] Lewis EJ, Blanco I, Raila H, Joormann J. Does repetitive negative thinking affect attention? Differential effects of worry and rumination on attention to emotional stimuli. Emotion. 2019;19:1450–62. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 50
- Probably not a substantial claim. 10
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In the paper
“The pathogenesis of cognitive and affective deficits in untreated MDD is not fully elucidated but likely involves abnormalities across multiple brain regions33-35, and includes but is not limited to changes in functional and/or structural connectivity.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [33] Cao X, Liu Z, Xu C, Li J, Gao Q, Sun N, et al. Disrupted resting-state functional connectivity of the hippocampus in medication-naïve patients with major depressive disorder. J Affect Disord. 2012;141:194–203. source
- Partly supportedcites [34] de Kwaasteniet B, Ruhe E, Caan M, Rive M, Olabarriaga S, Groefsema M, et al. Relation between structural and functional connectivity in major depressive disorder. Biol Psychiatry. 2013;74:40–7. sourceExperimental — accuracy not yet measured
The introduction (p. 2) describes abnormalities across a frontolimbic network, and the results (p. 2) report altered structural and functional connectivity in MDD. However, the Patients section (p. 4) includes participants taking psychotropic medication, so the findings do not specifically establish this account for untreated MDD. The paper also does not establish the pathogenesis of cognitive deficits. (LLM, conf=0.88)
- Supportedcites [35] Hao ZY, Zhong Y, Ma ZJ, Xu HZ, Kong JY, Wu Z, et al. Abnormal resting-state functional connectivity of hippocampal subfields in patients with major depressive disorder. BMC Psychiatry. 2020;20:71. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“A few studies provide evidence that the absence of neurogenesis elicits depressive like symptoms in rodents123, 124, but most studies find that absent neurogenesis is not sufficient to induce a depressive phenotype125 although it is required in mice for the behavioral effects of antidepressants118, 126.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [123] Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza PV, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry. 2009;14:959–67. source
- Partly supportedcites [124] Petrik D, Lagace DC, Eisch AJ. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology. 2012;62:21–34. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [125] Hill AS, Sahay A, Hen R. Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. Neuropsychopharmacology. 2015;40:2368–78. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [118] David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [126] Anacker C, Luna VM, Stevens GS, Millette A, Shores R, Jimenez JC, et al. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature. 2018;559:98–102. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
plainconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, different study populations may have different proportions of certain mood or cognitive subgroups of depression, explaining conflicting findings and the wide range in incidence of cognitive deficits.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“it has been estimated that cognitive deficits affect 20-90% of MDD patients22-27.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [22] McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30:515–27. source
- Not checked yetcites [23] Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41:1165–74. source
- Not checked yetcites [24] Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 2006;145:39–48. source
- Not checked yetcites [25] Kaser M, Zaman R, Sahakian BJ. Cognition as a treatment target in depression. Psychol Med. 2017;47:987–9. source
- Not checked yetcites [26] Siddarth P, Funes CM, Laird KT, Ercoli L, Lavretsky H. Predictors of cognitive improvement following treatment for late-life depression. J Geriatr Psychiatry Neurol. 2021;34:162–8. source
- Not checked yetcites [27] McAllister-Williams RH, Bones K, Goodwin GM, Harrison J, Katona C, Rasmussen J, et al. Analysing UK clinicians’ understanding of cognitive symptoms in major depression: a survey of primary care physicians and psychiatrists. J Affect Disord. 2017;207:346–52. source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Allostatic load is elevated in depression, which is associated with prolonged stress response, including elevated levels of cortisol associated with melancholia5, 21.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Introduction
What the sources say
- Not checked yetcites [5] Dahmen B, Puetz VB, Scharke W, von Polier GG, Herpertz-Dahlmann B, Konrad K. Effects of early-life adversity on hippocampal structures and associated HPA axis functions. Dev Neurosci. 2018;40:13–22. source
- Not checked yetcites [21] Wang Q, Van Heerikhuize J, Aronica E, Kawata M, Seress L, Joels M, et al. Glucocorticoid receptor protein expression in human hippocampus; stability with age. Neurobiol Aging. 2013;34:1662–73. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“First, the hippocampus plays a critical role in mood regulation, in part, due to its connections with emotion-related brain regions such as amygdala and anterior cingulate cortex (ACC)17, 18 as well as its feedback role in regulating the hypothalamus-pituitary-adrenal (HPA) axis.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Introduction
What the sources say
- Not checked yetcites [17] Ruiz S, Buyukturkoglu K, Rana M, Birbaumer N, Sitaram R. Real-time fMRI brain computer interfaces: self-regulation of single brain regions to networks. Biol Psychol. 2014;95:4–20. source
- Not checked yetcites [18] Schumacher A, Villaruel FR, Ussling A, Riaz S, Lee ACH, Ito R. Ventral hippocampal CA1 and CA3 differentially mediate learned approach-avoidance conflict processing. Curr Biol. 2018;28:1318–24.e4. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, hippocampal neuroplasticity has been implicated in MDD etiology and antidepressant action.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Introduction
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: High concentrations of hippocampal glucocorticoid receptors make the hippocampus particularly vulnerable to allostatic load.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, deficits in memory, attention and executive functioning have been observed in the absence of a current depressive episode28-31 and even in individuals responding well to antidepressant treatment for affective symptoms23, suggesting that cognitive deficits are only partly a state-dependent phenotype in MDD.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [28] Pu S, Noda T, Setoyama S, Nakagome K. Empirical evidence for discrete neurocognitive subgroups in patients with non-psychotic major depressive disorder: clinical implications. Psychol Med. 2018;48:2717–29. source
- Not checked yetcites [29] Hammar A, Sørensen L, Ardal G, Oedegaard KJ, Kroken R, Roness A, et al. Enduring cognitive dysfunction in unipolar major depression: a test-retest study using the Stroop paradigm. Scand J Psychol. 2010;51:304–8.
- Not checked yetcites [30] Semkovska M, Quinlivan L, O’Grady T, Johnson R, Collins A, O’Connor J, et al. Cognitive function following a major depressive episode: a systematic review and meta-analysis. Lancet Psychiatry. 2019;6:851–61. source
- Not checked yetcites [31] Perini G, Cotta Ramusino M, Sinforiani E, Bernini S, Petrachi R, Costa A. Cognitive impairment in depression: recent advances and novel treatments. Neuropsychiatr Dis Treat. 2019;15:1249–58. source
- Not checked yetcites [23] Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41:1165–74. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consequently, there has been a paradigm shift from a synaptic effect derived from the monoamine hypothesis to a more complex delayed downstream neuroplasticity hypothesis of antidepressant action that involves correcting a deficiency in neurons, processes and synapses that comprise the pathogenesis of depression.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Antidepressant medications are pharmacologically active within hours, but their antidepressant effects are not apparent for weeks after starting treatment.
- Rests on an assumption: Even when antidepressants have meaningful pharmacologic effects, many patients do not improve.
- The authors state this as an assumption: The effects of antidepressants depend on downstream processes, such as increased neurogenesis, that take time to appear and are robust only in medication responders.
In the paper
“In healthy controls, when asked to downregulate emotional responses in the presence of an aversive stimuli, the PFC and ACC were hyperactivated and the amygdala was hypoactivated. When participants were asked to upregulate negative emotions in response to aversive stimuli, both the PFC and amygdala were activated47, suggesting a PFC-dependent cognitive component in emotional regulation in healthy”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [47] Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, et al. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23:483–99. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The association between DLPFC activity, memory and MDD has not been consistent, as others have reported DLPFC hypoactivity in conjunction with decreased working memory performance41, 42.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [41] Elliott R, Baker SC, Rogers RD, O’Leary DA, Paykel ES, Frith CD, et al. Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography. Psychol Med. 1997;27:931–42. source
- Not checked yetcites [42] Okada G, Okamoto Y, Morinobu S, Yamawaki S, Yokota N. Attenuated left prefrontal activation during a verbal fluency task in patients with depression. Neuropsychobiology. 2003;47:21–6. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Moreover, in MDD, the extent of hippocampal gray matter volume loss is related to time spent depressed58, 61 and smaller hippocampal volume is associated with worse depression scores.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [58] Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA. 1996;93:3908–13. source
- Not checked yetcites [61] Roddy DW, Farrell C, Doolin K, Roman E, Tozzi L, Frodl T, et al. The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression. Biol Psychiatry. 2019;85:487–97. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This is because BDNF can bind to tropomyosin kinase B (TrkB) receptor which activates the mechanistic target of rapamycin (mTOR) signaling pathway which promotes neuronal growth, proliferation and migration77.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [77] Takei N, Nawa H. mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci. 2014;7:28. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Neuroimaging studies have consistently reported DLPFC hypoactivity at rest in unmedicated MDDs37, 38 but DLPFC hyperactivity during working memory tasks39.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [37] Baxter LR, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry. 1989;46:243–50. source
- Not checked yetcites [38] Soares JC, Mann JJ. The functional neuroanatomy of mood disorders. J Psychiatr Res. 1997;31:393–432. source
- Not checked yetcites [39] Harvey PO, Fossati P, Pochon JB, Levy R, Lebastard G, Lehéricy S, et al. Cognitive control and brain resources in major depression: an fMRI study using the n-back task. Neuroimage. 2005;26:860–9. source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“One potential process involved in neuronal loss is decreased brain-derived neurotrophic factor (BDNF) via histone modifications to the promoter region associated with downregulation of BDNF transcripts73, 74.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [73] Lopez JP, Mamdani F, Labonte B, Beaulieu MM, Yang JP, Berlim MT, et al. Epigenetic regulation of BDNF expression according to antidepressant response. Mol Psychiatry. 2013;18:398–9. source
- Not checked yetcites [74] Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–25. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, focus on negative internal stimuli can result in more strongly encoding negative experiences and sustain negative thoughts and expectations, and underly a biased recall of negative relative to other memories in depressed patients.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Variations between hippocampal-amygdala connectivity during resting state and emotional and cognitive tasks suggests that this network is context-dependent and modulated by environmental stimuli and individual emotional state.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Most studies find that untreated depressed patients have smaller hippocampal volume58, 59, neuronal and glial number, and cell size60 compared with non-psychiatric controls.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [58] Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA. 1996;93:3908–13. source
- Not checked yetcites [59] Luo Y, Cao Z, Wang D, Wu L, Li Y, Sun W, et al. Dynamic study of the hippocampal volume by structural MRI in a rat model of depression. Neurol Sci. 2014;35:1777–83. source
- Not checked yetcites [60] Czéh B, Simon M, Schmelting B, Hiemke C, Fuchs E. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology. 2006;31:1616–26. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, in the absence of familial risk, early childhood trauma severity (operationalized via the Childhood Trauma Questionnaire) correlated with amygdala responsiveness and hippocampal volume loss in a group of healthy volunteers, and these associations were not influenced by recent life stress, depression or anxiety scores70.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [70] Dannlowski U, Stuhrmann A, Beutelmann V, Zwanzger P, Lenzen T, Grotegerd D, et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry. 2012;71:286–93. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This concept has been demonstrated in an MRI study of PTSD which showed how smaller hippocampal volume predicted risk of PTSD and did not result from the trauma that triggered PTSD71.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [71] Xie H, Claycomb Erwin M, Elhai JD, Wall JT, Tamburrino MB, Brickman KR, et al. Relationship of hippocampal volumes and posttraumatic stress disorder symptoms over early posttrauma periods. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:968–75.
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In the paper
“Interestingly, there is disagreement over which regions of the hippocampus are smaller in depression. Some find volumetric sparing of CA164 while others report CA1 volume loss61, 65, 66. Some report volume loss selectively in the hippocampal head and others observed volume loss in the hippocampal body67.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [64] Liu MN, Pantouw JG, Yang KC, Hu LY, Liou YJ, Lirng JF, et al. Sub-regional hippocampal volumes in first-episode drug-naïve major depression disorder. Neurosci Lett. 2021;763:136178. source
- Not checked yetcites [61] Roddy DW, Farrell C, Doolin K, Roman E, Tozzi L, Frodl T, et al. The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression. Biol Psychiatry. 2019;85:487–97. source
- Not checked yetcites [65] Frodl T, Carballedo A, Frey EM, O’Keane V, Skokauskas N, Morris D, et al. Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder. Dev Psychopathol. 2014;26:1209–17. source
- Not checked yetcites [66] Huang Y, Coupland NJ, Lebel RM, Carter R, Seres P, Wilman AH, et al. Structural changes in hippocampal subfields in major depressive disorder: a high-field magnetic resonance imaging study. Biol Psychiatry. 2013;74:62–8. source
- Not checked yetcites [67] Travis S, Coupland NJ, Silversone PH, Huang Y, Fujiwara E, Carter R, et al. Dentate gyrus volume and memory performance in major depressive disorder. J Affect Disord. 2015;172:159–64. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, unmedicated adolescents with MDD showed less resting state fMRI (rsfMRI) connectivity between hippocampus and amygdala compared with healthy controls52. This lack of connectivity between hippocampus and amygdala correlated with severity of depression52.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [52] Cullen KR, Westlund MK, Klimes-Dougan B, Mueller BA, Houri A, Eberly LE, et al. Abnormal amygdala resting-state functional connectivity in adolescent depression. JAMA Psychiatry. 2014;71:1138–47. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, in human and rodent studies, changes to hippocampal circuitry have been associated with early life adversity which suggests an epigenetic mechanism for these changes and MDD pathogenesis53, 54.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [53] Turecki G, Meaney MJ. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol Psychiatry. 2016;79:87–96. source
- Not checked yetcites [54] Smith KE, Pollak SD. Early life stress and development: potential mechanisms for adverse outcomes. J Neurodev Disord. 2020;12:34. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Currently, reported mechanisms potentially underlying cell loss include, but are not limited to, glutamate/glutamine cycling (see section on Molecular and Cellular Mechanisms of Neuroplasticity), blunted neurogenesis, decreased neurotrophic factor expression and upregulation of pro-apoptotic pathways72.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [72] Banasr M, Dwyer JM, Duman RS. Cell atrophy and loss in depression: reversal by antidepressant treatment. Curr Opin Cell Biol. 2011;23:730–7. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Smaller ACC, DLPFC, medial prefrontal cortex (MPFC) and hippocampus were shown in non-depressed individuals with a familial history of depression (first degree relative with MDD diagnosis) exposed to emotional neglect when compared to non-depressed individuals with no familial risk factors but who had been exposed to emotional neglect, suggesting a gene-environment interaction affecting cell”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [69] Carballedo A, Lisiecka D, Fagan A, Saleh K, Ferguson Y, Connolly G, et al. Early life adversity is associated with brain changes in subjects at family risk for depression. World J Biol Psychiatry. 2012;13:569–78. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Conversely, when patients with MDD were asked to ignore negative stimuli, they failed to recruit the DLPFC which was correlated with amygdala hyperactivity48.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [48] Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, et al. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. 2008;63:377–84. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“The dorsolateral prefrontal cortex (DLPFC) is responsible for attention, working memory and executive function and is positively correlated with working memory load in healthy controls36.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Learning, Memory, and Mood: Network Changes in Depression
What the sources say
- Not checked yetcites [36] Braver TS, Cohen JD, Nystrom LE, Jonides J, Smith EE, Noll DC. A parametric study of prefrontal cortex involvement in human working memory. Neuroimage. 1997;5:49–62. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“During embryonic development in rodents, primitive dentate progenitors from dentate neuroepithelium migrate along the dentate migratory stream to establish the primitive dentate gyrus89, 90. The majority of dentate granule neurons are generated during the first postnatal week90.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [89] Urbán N, Guillemot F. Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front Cell Neurosci. 2014;8:396. source
- Not checked yetcites [90] Bayer SA, Altman J. Hippocampal development in the rat: cytogenesis and morphogenesis examined with autoradiography and low-level X-irradiation. J Comp Neurol. 1974;158:55–79. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“While 14C decay-defined neuronal age estimates that the human brain adds up to 700 new neurons each day (approx. 0.004% of total DG neurons), resulting in a 1.7% cell turnover annually103”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [103] Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. Evidences for adult hippocampal neurogenesis in humans. J Neurosci. 2021;41:2541–53. source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Humans receiving chemotherapy, which kills proliferating cells (thus blunting neurogenesis), experience cognitive deficits and are more likely to develop depression than cancer patients treated with other therapies128-130.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [128] Wen S, Xiao H, Yang Y. The risk factors for depression in cancer patients undergoing chemotherapy: a systematic review. Support Care Cancer. 2019;27:57–67. source
- Not checked yetcites [129] Wigmore P. The effect of systemic chemotherapy on neurogenesis, plasticity and memory. Curr Top Behav Neurosci. 2013;15:211–40. source
- Not checked yetcites [130] Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res. 2012;18:1954–65. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although less is known about embryonic hippocampal neurogenesis in humans, some studies suggest overlap in developmental timing and molecular signatures between the rodent and human brain91. The switch between developmental neurogenesis and AHN is gradual, and some sequencing studies have demonstrated these two processes share highly similar transcriptional trajectories91.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [91] Hochgerner H, Zeisel A, Lönnerberg P, Linnarsson S. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing. Nat Neurosci. 2018;21:290–9. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Some groups have reported absent or minimal hippocampal neurogenesis in the mature brain using double immunofluorescence targeting markers expressed by neuronal cells at different maturational stages95, 96 and single nucleus transcriptomics97.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [95] Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555:377–81. source
- Not checked yetcites [96] Cipriani S, Ferrer I, Aronica E, Kovacs GG, Verney C, Nardelli J, et al. Hippocampal radial glial subtypes and their neurogenic potential in human fetuses and healthy and Alzheimer’s disease adults. Cereb Cortex. 2018;28:2458–78. source
- Not checked yetcites [97] Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron. 2021;110:452–69.e14. source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Others have argued that these stem cells originated in the ventral hippocampus and migrated dorsally94.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [94] Li G, Fang L, Fernández G, Pleasure SJ. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. Neuron. 2013;78:658–72. source
plain- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
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In the paper
“Some have demonstrated that neural stem cells in the adult hippocampal subgranular zone (SGZ) niche are remnants of dentate neuroepithelium92 and this same population of progenitors exclusively contributes to hippocampal neurogenesis throughout development and into adulthood, shifting out of quiescence at different time points93.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [92] Seki T, Sato T, Toda K, Osumi N, Imura T, Shioda S. Distinctive population of Gfap-expressing neural progenitors arising around the dentate notch migrate and form the granule cell layer in the developing hippocampus. J Comp Neurol. 2014;522:261–83. source
- Not checked yetcites [93] Berg DA, Su Y, Jimenez-Cyrus D, Patel A, Huang N, Morizet D, et al. A common embryonic origin of stem cells drives developmental and adult neurogenesis. Cell. 2019;177:654–68.e15. source
boosted- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Deficits in AHN may not only explain the learning and memory deficits in MDD, but also play a role in the selective engagement with negative valence memories, mood regulation and antidepressant response118-122.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [118] David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93. source
- Not checked yetcites [119] Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104–10. source
- Not checked yetcites [120] Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34:2376–89. source
- Not checked yetcites [121] Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001;25:836–44. source
- Not checked yetcites [122] Wang H, Warner-Schmidt J, Varela S, Enikolopov G, Greengard P, Flajolet M. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice. Proc Natl Acad Sci USA. 2015;112:9745–50. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“in rodents, it has been estimated that up to 30-70% of newborn neurons die in the first month and that 1300 neurons are eliminated daily from the rodent hippocampus111, 112.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
What the sources say
- Not checked yetcites [111] Dayer AG, Ford AA, Cleaver KM, Yassaee M, Cameron HA. Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol. 2003;460:563–72. source
- Not checked yetcites [112] Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002;12:578–84. source
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Additionally, BDNF expression was decreased in postmortem hippocampus in untreated MDDs but not in antidepressant-treated depressed individuals79.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A Balancing Act: Cell Death and Survival
What the sources say
- Not checked yetcites [79] Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry. 2001;50:260–5. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, proxy measurements such as paired associative stimulation (PAS) using a transcranial magnetic stimulation protocol have shown that PAS-induced increases in motor-evoked potential amplitudes were attenuated during major depressive episodes compared with healthy controls and normalized during remission151, 152.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [151] Player MJ, Taylor JL, Weickert CS, Alonzo A, Sachdev P, Martin D, et al. Neuroplasticity in depressed individuals compared with healthy controls. Neuropsychopharmacology. 2013;38:2101–8. source
- Not checked yetcites [152] Moghaddam B, Bolinao ML, Stein-Behrens B, Sapolsky R. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res. 1994;655:251–4. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Some have reported increased glutamate levels in the plasma of untreated MDD patients157, 158 in line with reports of high CSF glutamate concentrations in severely depressed, hospitalized MDD patients159 and in untreated elderly MDD patients when compared to healthy controls160.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [157] Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F. Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry. 1993;150:1731–3. source
- Not checked yetcites [158] Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW. Increased cerebrospinal fluid glutamine levels in depressed patients. Biol Psychiatry. 2000;47:586–93. source
- Not checked yetcites [159] Hashimoto K, Bruno D, Nierenberg J, Marmar CR, Zetterberg H, Blennow K, et al. Abnormality in glutamine-glutamate cycle in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder: a 3-year follow-up study. Transl Psychiatry. 2016;6:e744. source
- Not checked yetcites [160] Kantrowitz JT, Dong Z, Milak MS, Rashid R, Kegeles LS, Javitt DC, et al. Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder. Transl Psychiatry. 2021;11:419. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Synaptic strength moderates neural signaling between cells over an extended period175, 176, underlying circuit functionality.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [175] Ho VM, Lee JA, Martin KC. The cell biology of synaptic plasticity. Science. 2011;334:623–8. source
- Not checked yetcites [176] Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4:409–18. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In vivo proton magnetic resonance spectroscopy (1H MRS) detected elevated glutamate levels in ventromedial prefrontal cortex/anterior cingulate cortex in untreated MDD161 consistent with a recent meta-analysis of MRS imaging studies that found higher glutamate/glutamine concentrations in medial frontal cortex of unmedicated MDD but not in antidepressant-treated patients162.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [161] Moriguchi S, Takamiya A, Noda Y, Horita N, Wada M, Tsugawa S, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. 2019;24:952–64. source
- Not checked yetcites [162] Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron. 2012;73:962–77. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, it is possible that, like in rodents, the role of newborn neurons in humans is predominately for conferring resilience on the hippocampal circuitry, and possibly facilitating circuit rewiring for the antidepressant response.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > A role for adult hippocampal neurogenesis in depression pathology?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These studies have generally observed increases in DG LTP147 and reductions in LTP at Schaffer collaterals-CA1 synapses148, 149 in response to acute and chronic stress.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [147] Alfarez DN, Joëls M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17:1928–34. source
- Not checked yetcites [148] Chaouloff F, Hémar A, Manzoni O. Acute stress facilitates hippocampal CA1 metabotropic glutamate receptor-dependent long-term depression. J Neurosci. 2007;27:7130–5. source
- Not checked yetcites [149] Maggio N, Segal M. Striking variations in corticosteroid modulation of long-term potentiation along the septotemporal axis of the hippocampus. J Neurosci. 2007;27:5757–65. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The transcription of BDNF is dependent upon activation of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein which plays a critical role in LTP and synaptic plasticity142, 143.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [142] Won J, Silva AJ. Molecular and cellular mechanisms of memory allocation in neuronetworks. Neurobiol Learn Mem. 2008;89:285–92. source
- Not checked yetcites [143] Tejeda GS, Díaz-Guerra M. Integral Characterization of defective BDNF/TrkB signalling in neurological and psychiatric disorders leads the way to new therapies. Int J Mol Sci. 2017;18:1–24. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“BDNF+/− mice show less dendritic branching as well as dendritic retraction and simplification in CA381 and DG80 and dysregulation of BDNF/TrkB pathways has been reported in MDD and animal models of depression78, 169-171.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [81] Magariños AM, Li CJ, Gal Toth J, Bath KG, Jing D, Lee FS, et al. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus. 2011;21:253–64. source
- Not checked yetcites [80] Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–3. source
- Not checked yetcites [78] Strauss J, Barr CL, George CJ, Ryan CM, King N, Shaikh S, et al. BDNF and COMT polymorphisms: relation to memory phenotypes in young adults with childhood-onset mood disorder. Neuromolecular Med. 2004;5:181–92. source
- Not checked yetcites [169] Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008;33:73–83. source
- Not checked yetcites [170] Kim YK, Lee HP, Won SD, Park EY, Lee HY, Lee BH, et al. Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:78–85. source
- Not checked yetcites [171] Xu Y, Ku B, Tie L, Yao H, Jiang W, Ma X, et al. Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res. 2006;1122:56–64. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Normal stress responses involve glutamate release which downregulates AMPA and NMDA receptor expression, glutamate clearance by glia, and less dendritic spine and process complexity163, 164.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [163] Floriou-Servou A, von Ziegler L, Waag R, Schläppi C, Germain PL, Bohacek J. The acute stress response in the multiomic era. Biol Psychiatry. 2021;89:1116–26. source
- Not checked yetcites [164] Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, et al. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry. 2011;16:634–46. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, lower glutamate may be an antidepressant effect and not part of MDD pathogenesis.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This may upregulate LTP pathways, and downregulate LTD177, 178, having benefits on network activity and consequently cognition and behavior.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Treatment Induced Neuroplasticity
What the sources say
- Not checked yetcites [177] Kraus C, Castrén E, Kasper S, Lanzenberger R. Serotonin and neuroplasticity - Links between molecular, functional and structural pathophysiology in depression. Neurosci Biobehav Rev. 2017;77:317–26. source
- Not checked yetcites [178] Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ, et al. Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. J Affect Disord. 2009;112:206–11. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Dendritic retraction may be an adaptive way to protect neurons from high glutamate transmission, resulting in less LTP and cognitive decline.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Exposure to stress attenuates LTP in dorsal hippocampus but augments LTP in ventral hippocampus of rodents150, which may explain memory deficits in the presence of strong emotional responses.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Molecular and Cellular Mechanisms of Neuroplasticity
What the sources say
- Not checked yetcites [150] Kuhn M, Mainberger F, Feige B, Maier JG, Mall V, Jung NH, et al. State-dependent partial occlusion of cortical LTP-like plasticity in major depression. Neuropsychopharmacology. 2016;41:2794. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In fact, rodent studies have shown that infusion of ketamine onto hippocampal neurons caused dose-dependent apoptosis, which was rescued by incubation with rapamycin (an inhibitor of mTOR), suggesting context-dependent benefits of ketamine196.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Treatment Induced Neuroplasticity
What the sources say
- Not checked yetcites [196] Zorumski CF, Izumi Y, Mennerick S. Ketamine: NMDA receptors and beyond. J Neurosci. 2016;36:11158–64. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Psychedelic drugs likely work via 5-HT2A receptors but require more research to elucidate their antidepressant effects202.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Treatment Induced Neuroplasticity
What the sources say
- Not checked yetcites [202] Lenze EJ, Nicol GE, Barbour DL, Kannampallil T, Wong AWK, Piccirillo J, et al. Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders. J Psychiatry Neurosci. 2021;46:E97–110. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This suggests an increase in neurogenesis over normal levels that allows a catchup in mature granule neurons in MDD to regain levels seen in controls62, 121.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Treatment Induced Neuroplasticity
What the sources say
- Not checked yetcites [62] Boldrini M, Santiago AN, Hen R, Dwork AJ, Rosoklija GB, Tamir H, et al. Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology. 2013;38:1068–77. source
- Not checked yetcites [121] Duman RS, Nakagawa S, Malberg J. Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology. 2001;25:836–44. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Rodent models of depression show that ketamine administration increases dendritic spine density, length, arborization and morphology in CA1 pyramidal neurons201.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Treatment Induced Neuroplasticity
What the sources say
- Not checked yetcites [201] Artin H, Zisook S, Ramanathan D. How do serotonergic psychedelics treat depression: the potential role of neuroplasticity. World J Psychiatry. 2021;11:201–14. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent studies suggest that blood levels of sertraline, a common first-line antidepressant, can successfully be predicted through analysis of genes involved in sertraline metabolism and thus, giving an indication of drug effectiveness204-206.”
§ Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications > Treatment Induced Neuroplasticity
What the sources say
- Not checked yetcites [204] Islam F, Gorbovskaya I, Müller DJ. Pharmacogenetic/pharmacogenomic tests for treatment prediction in depression. Adv Exp Med Biol. 2021;1305:231–55. source
- Not checked yetcites [205] Claudio-Campos K, Padrón A, Jerkins G, Nainaparampil J, Nelson R, Martin A, et al. Acceptability, feasibility, and utility of integrating pharmacogenetic testing into a child psychiatry clinic. Clin Transl Sci. 2021;14:589–98. source
- Not checked yetcites [206] Barrenschee M, Lange C, Cossais F, Egberts JH, Becker T, Wedel T, et al. Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system. Front Cell Neurosci. 2015;9:360. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Antidepressant medications are pharmacologically active within hours, but their antidepressant effects are not apparent for weeks after starting treatment.
“First, although these medications are pharmacologically active within hours, their antidepressant effects are not apparent for weeks after starting treatment.”
The paper relies on this without support.
Even when antidepressants have meaningful pharmacologic effects, many patients do not improve.
“Second, even when the medications are having meaningful pharmacologic effects, many patients do not improve.”
The authors state this as an assumption.
The effects of antidepressants depend on downstream processes, such as increased neurogenesis, that take time to appear and are robust only in medication responders.
“The most widely accepted response to both questions is to assume that the effects of antidepressants are dependent on downstream processes, such as an increase in neurogenesis, that take time to appear and are only robust in medication responders.”
The paper relies on this without support.
High concentrations of hippocampal glucocorticoid receptors make the hippocampus particularly vulnerable to allostatic load.
“Third, given its role in HPA axis regulation, the high concentrations of hippocampal glucocorticoid receptors make it particularly vulnerable to allostatic load.”
The paper relies on this without support.
Hippocampal volume loss is not pathognomonic for depression and can occur in the presence of environmental stressors, other psychiatric conditions, and neurodegenerative diseases.
“Hippocampal volume loss is not pathognomonic for depression and can occur in the presence of environmental stressors, other psychiatric conditions, and neurodegenerative diseases.”
The paper relies on this without support.
Traditional antidepressants act on the monoaminergic system to increase synaptic monoamine neurotransmitter levels.
“As previously discussed, traditional antidepressants target the monoaminergic system to increase levels of monoaminergic neurotransmitters in the synapse.”
The paper relies on this without support.
To increase LTP, some NMDA receptors must remain available.
“The dosage and affinity are important because, to increase LTP, some NMDA receptors must be available.”
The paper relies on this without support.
Neuroplasticity is integral to healthy cognitive and affective functioning.
“Neuroplasticity is integral to healthy cognitive and affective functioning.”
The paper relies on this without support.
Major depressive disorder clinical heterogeneity remains poorly understood, particularly how it relates to pathogenesis and treatment choices.
“MDD clinical heterogeneity remains poorly understood, particularly in terms of how it relates to pathogenesis and implications for treatment choices.”
The paper relies on this without support.
The duration or presence of major depression correlates with declines in neuroplasticity.
“While duration or presence of major depression correlates with declines in neuroplasticity, administration of antidepressants may reverse some of the neurobiological changes observed in MDD (Figure 4).”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Within this framework, glutamate serves as the principal excitatory neurotransmitter and the primary molecular interface between acute cellular activation and longer-term synaptic remodeling [38,39].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [39]
Experimental — accuracy not yet measuredIn the citing paper
“The dentate gyrus is a unique source of ongoing neurogenesis in the adult brain, at least in nonhuman animals, and there is preclinical evidence that the birth and maturation of new granule cells may play a role in depression and antidepressant drug actions [89].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [89]
Citations
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“Although SSRIs and serotonin-norepinephrine reuptake inhibitor perform better than placebo at reducing symptoms of depression [187, 188], there are weeks-long lag time in attaining Untreated Depression Treated Depression”
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“Some find volumetric sparing of CA1 [64] while others report CA1 volume loss [61, 65, 66].”
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Metadata
- Authors
- Tartt, A. N., Mariani, M. B., Hen, R., Mann, J. J., & Boldrini, M.
- Affiliations
- Stanford Medicine (US)
- Columbia University (US)
- New York State Psychiatric Institute (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Boldrini, Maura
- Venue
- Molecular Psychiatry
- Published
- 2022-03-30
- Volume
- 27
- Issue
- 6
- Pages
- 2689-2699
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC9167750
- OpenAlex
- W4221105875
- Cited by
- 408
- References
- 227
- Citations by year
- 2026: 94 · 2025: 127 · 2024: 115 · 2023: 54 · 2022: 18
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R56AG063372, R01AG076949)
- National Institute of Mental Health (R01MH083862, R21MH094888)
- National Institute of Allergy and Infectious Diseases (R21AI164769)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, hippocampal plasticity, adult hippocampal neurogenesis, antidepressant mechanism, synaptic plasticity, depression pathogenesis, depression treatment
- MeSH terms
- Adult, Antidepressive Agents, Depression, Depressive Disorder, Major, Major Depressive Disorder, Hippocampus, Humans, Neuronal Plasticity
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.
A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-05 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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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