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Cited by 397Schizophrenia research and treatmentGenetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology Research

Developmental timing and critical windows for the treatment of psychiatric disorders

Open access
Marín, Oscar·2016·Nature Medicine
DOI 10.1038/nm.4225
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Abstract

There is a growing understanding that pathological genetic variation and environmental insults during sensitive periods in brain development have long-term consequences on brain function, which range from learning disabilities to complex psychiatric disorders such as schizophrenia. Furthermore, recent experiments in animal models suggest that therapeutic interventions during sensitive periods, typically before the onset of clear neurological and behavioral symptoms, might prevent or ameliorate the development of specific pathologies. These studies suggest that understanding the dynamic nature of the pathophysiological mechanisms underlying psychiatric disorders is crucial for the development of effective therapies. In this Perspective, I explore the emerging concept of developmental windows in psychiatric disorders, their relevance for understanding disease progression and their potential for the design of new therapies. The limitations and caveats of early interventions in psychiatric disorders are also discussed in this context.

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Written from the paper’s full text.

TL;DR

This Perspective argues that psychiatric disorders arise from altered developmental trajectories and that therapeutic interventions may be most effective during sensitive developmental windows before symptom onset. It reviews animal and clinical evidence for early, disease-modifying strategies in schizophrenia, Fragile X syndrome, and Rett syndrome, while outlining practical and ethical caveats.

Key findings

  • Psychiatric disorders are increasingly linked to altered neurodevelopment: risk genes are highly expressed during development, environmental risks such as hypoxia and maternal infection are early-life events, and current treatments are symptomatic rather than disease-modifying with low response rates.
  • In schizophrenia, which affects approximately 1% of the population worldwide, about 30% of individuals at ultra-high risk develop a psychotic disorder within three years; early interventions in animal models—such as benzodiazepines in juvenile MAM-treated rats, Gsk3β inhibition in juvenile Df(16)A+/− mice, and N-acetylcysteine in adolescent NVHL rats—prevent adult phenotypes.
  • In Fragile X syndrome, which affects approximately 1 in 4,000 males, mGluR5 inhibitor trials in adolescents and adults showed no measurable benefits, whereas bumetanide improved facial emotional labeling and communication in ASD children aged 3–11 years, suggesting an early-childhood treatment window.
  • In Rett syndrome, Mecp2 mutants show precocious PV+ interneuron development and precocious onset/closure of critical period plasticity; ketamine normalizes cortical activity and extends lifespan in mice, but whether early and late treatments achieve similar functional restoration remains untested.

Methods

  • Perspective/review article; no primary data, sample, or formal analysis reported.
  • Synthesizes human clinical observations and rodent/nonhuman primate model studies across schizophrenia, Fragile X syndrome, and Rett syndrome.
  • Main analysis is conceptual: uses developmental milestones and critical windows to interpret disease progression and the timing of therapeutic interventions.

Limitations

  • The paper states that assessing early treatment benefits is difficult in non-syndromic conditions, target groups should initially be those at highest relative risk, biomarkers are largely unavailable, early treatments may have cascading adverse effects, and drugs targeting interneurons can trigger widespread apoptotic death in developing rodent and primate brains.
  • The paper also states that at-risk populations are clinically heterogeneous, rodent-to-human translation is limited by species-specific gene expression and behavioral divergence, and ethical/regulatory concerns complicate testing in children.
  • Evident from the text: conclusions rely heavily on animal models and small-scale or failed clinical trials, with no systematic review or meta-analysis.

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

Integrity signals

Registry

Crossref · 10.1038/nm.4225

Cites

157 of 157 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 179 cited sources checked · 0 supported · 0 flagged

  • Findingcitation
    § Developmental milestones in the assembly of neural circuits

    Fast-spiking interneurons expressing the calcium binding protein parvalbumin (PV+) are the main modulators of critical period plasticity.

    “Fast-spiking interneurons expressing the calcium binding protein parvalbumin (PV+) are the main modulators of critical period plasticity (Figure 4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Hu, H., Gan, J. & Jonas, P. Interneurons. Fast-spiking, parvalbumin+ GABAergic interneurons: from cellular design to microcircuit function. Science 345, 1255263 (2014). source

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  • Findingcitation
    § Developmental milestones in the assembly of neural circuits

    During embryonic and early postnatal development GABA depolarizes - excites - because the intracellular concentration of chloride in the postsynaptic targets is higher than in the extracellular space.

    “Studies in rodents and non-human primates have shown during embryonic and early postnatal development GABA depolarizes -excites- because the intracellular concentration of chloride in the postsynaptic targets is higher than in the extracellular space 25 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Ben-Ari, Y. Excitatory actions of gaba during development: the nature of the nurture. Nat. Rev. Neurosci. 3, 728–739 (2002). source

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  • Findingcitation
    § Developmental milestones in the assembly of neural circuits

    The maturation of PV+ interneurons is crucial for the development of oscillatory activity across the neocortex and hippocampus.

    “In addition, the maturation of PV+ interneurons is crucial for the development of oscillatory activity across the neocortex and hippocampus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Sigurdsson, T. & Duvarci, S. Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease. Front. Syst. Neurosci. 9, 190 (2016). source

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  • Findingcitation
    § Developmental milestones in the assembly of neural circuits

    Early synchronous events are thought to play a fundamental role in the maturation of neuronal circuits.

    “Early synchronous events are thought to play a fundamental role in the maturation of neuronal circuits 27,28 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Kirkby, L.A., Sack, G.S., Firl, A. & Feller, M.B. A role for correlated spontaneous activity in the assembly of neural circuits. Neuron 80, 1129–1144 (2013). source

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    • cites [28] Uhlhaas, P.J., Roux, F., Rodriguez, E., Rotarska-Jagiela, A. & Singer, W. Neural synchrony and the development of cortical networks. Trends Cogn. Sci. 14, 72–80 (2010). source

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  • Findingcitation
    § Developmental timing and critical windows for the treatment of psychiatric disorders

    The brain seems to be particularly vulnerable to insults (genetic and environmental) around specific sensitive periods in which changes in brain structure have long-lasting impact over the lifespan.

    “Although development is a continuous process, the brain seems to be particularly vulnerable to insults (genetic and environmental) around specific sensitive periods in which changes in brain structure have long-lasting impact over the lifespan 11 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Hübener, M. & Bonhoeffer, T. Neuronal plasticity: beyond the critical period. Cell 159, 727–737 (2014). source

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    Findingcitation
    § Developmental milestones in the assembly of neural circuits

    Abnormal visual experience during a relatively narrow time window in early development dramatically changes cortical circuits processing vision and has a major impact on visual ability, whereas transient blindness in adulthood has much less severe functional consequences.

    “For example, abnormal visual experience during a relatively narrow time window in early development dramatically changes cortical circuits processing vision and has a major impact on visual ability 16 , whereas transient blindness in adulthood has much less severe functional consequences.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Wiesel, T.N. & Hubel, D.H. Extent of recovery from the effects of visual deprivation in kittens. J. Neurophysiol. 28, 1060–1072 (1965). source

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    Findingcitation
    § Developmental milestones in the assembly of neural circuits

    In mice, genetic loss of GABAergic function and sensory deprivation delays plasticity, whereas GABA A receptor agonists such as benzodiazepines can trigger precocious onset of the critical period.

    “In mice, genetic loss of GABAergic function and sensory deprivation delays plasticity, whereas GABA A receptor agonists such as benzodiazepines can trigger precocious onset of the critical period 37 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Hensch, T.K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005). source

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    Findingcitation
    § Developmental milestones in the assembly of neural circuits

    Delivery is associated with high risks to the fetal brain and preterm babies have a much higher incidence of neurological and cognitive impairments.

    “Delivery is associated with high risks to the fetal brain and preterm babies have a much higher incidence of neurological and cognitive impairments 30 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Mwaniki, M.K., Atieno, M., Lawn, J.E. & Newton, C.R. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet 379, 445–452 (2012). source

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    Findingcitation
    § Developmental timing and critical windows for the treatment of psychiatric disorders

    Psychiatric disorders are a major socio-economic burden, mostly because of the indirect costs derived from social support and unemployment.

    “Psychiatric disorders are a major socio-economic burden, mostly because of the indirect costs derived from social support and unemployment 1,2 .”
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    • cites [1] Gore, F.M. et al. Global burden of disease in young people aged 10–24 years: a systematic analysis. Lancet 377, 2093–2102 (2011). source

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    • cites [2] Lee, F.S. et al. Mental health. Adolescent mental health–opportunity and obligation. Science 346, 547–549 (2014). source

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    Findingcitation
    § Developmental milestones in the assembly of neural circuits

    During this period, GABA-induced currents are the main source of depolarization and are critical for the generation of synchronized patterns of activity that characterize developing networks.

    “During this period, GABAinduced currents are the main source of depolarization and are critical for the generation of synchronized patterns of activity that characterize developing networks 26 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Ben-Ari, Y., Gaiarsa, J.L., Tyzio, R. & Khazipov, R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol. Rev. 87, 1215–1284 (2007). source

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    Findingcitation
    § Developmental timing and critical windows for the treatment of psychiatric disorders

    Current treatments for schizophrenia only ameliorate psychotic symptoms in some patients and generally fail to improve cognition and other behavioral abnormalities.

    “For example, current treatments for schizophrenia only ameliorate psychotic symptoms in some patients and generally fail to improve cognition and other behavioral abnormalities 3 ,”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] van Os, J. & Kapur, S. Schizophrenia. Lancet 374, 635–645 (2009). source

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    Findingcitation
    § Developmental milestones in the assembly of neural circuits

    Fast-spiking PV+ interneurons synchronize local assemblies of pyramidal cells in the gamma frequency, which contributes to the emergence of functional interactions between the hippocampus and the prefrontal cortex.

    “Fast-spiking PV+ interneurons synchronize local assemblies of pyramidal cells in the gamma frequency, which contributes to the emergence of functional interactions between the hippocampus and the prefrontal cortex 39 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Sigurdsson, T. & Duvarci, S. Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease. Front. Syst. Neurosci. 9, 190 (2016). source

      Not checked in the free run.

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

    Findingcitation
    § Developmental milestones in the assembly of neural circuits

    These sensitive windows are known as critical periods, and constitute another major milestone in the development of brain circuits.

    “These sensitive windows are known as critical periods 35 , and constitute another major milestone in the development of brain circuits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Hubel, D.H. & Wiesel, T.N. The period of susceptibility to the physiological effects of unilateral eye closure in kittens. J. Physiol. (Lond.) 206, 419–436 (1970). source

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    Findingcitation
    § Developmental milestones in the assembly of neural circuits

    PV+ interneurons provide very strong inhibition to pyramidal cells, and their maturation rapidly restricts the influence of sensory experience in pyramidal cells and leads to the closure of critical period plasticity.

    “These cells provide very strong inhibition to pyramidal cells 38 , and so their maturation rapidly restricts the influence of sensory experience in pyramidal cells and leads to the closure of critical period plasticity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Hu, H., Gan, J. & Jonas, P. Interneurons. Fast-spiking, parvalbumin+ GABAergic interneurons: from cellular design to microcircuit function. Science 345, 1255263 (2014). source

      Not checked in the free run.

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    Findingcitation
    § Developmental timing and critical windows for the treatment of psychiatric disorders

    In some cases, knowledge of the underlying pathophysiology seems sufficient for the development of novel therapies, yet results are disappointing when new drugs are tested in adult patients.

    “In some cases, however, our knowledge of the underlying pathophysiology seems sufficient for the development of novel therapies, yet results are disappointing when new drugs are tested in adult patients 4 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Jeste, S.S. & Geschwind, D.H. Clinical trials for neurodevelopmental disorders: At a therapeutic frontier. Sci. Transl. Med. 8, 321fs1 (2016). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    The levels of GAD67 are consistently lower in the cortex of subjects with schizophrenia, and these defects are more prominent in PV+ interneurons.

    “For instance, the levels of one of the enzymes that contributes to the synthesis of GABA, GAD67, are consistently lower in the cortex of subjects with schizophrenia, and these defects are more prominent in PV+ interneurons 49 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Lewis, D.A., Curley, A.A., Glausier, J.R. & Volk, D.W. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 35, 57–67 (2012). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Reducing stress sensitivity in juvenile MAM-treated rats with benzodiazepines prevents the abnormal increase in the activity of dopaminergic neurons and reduces hyperlocomotion in adult rats.

    “Consistent with this view, reducing stress sensitivity in juvenile MAM-treated rats with benzodiazepines prevents the abnormal increase in the activity of dopaminergic neurons and reduces hyperlocomotion in adult rats 71 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Du, Y. & Grace, A.A. Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia. Neuropsychopharmacology 38, 1881–1888 (2013). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Current treatments with antipsychotics are relatively effective in the management of psychotic symptoms, but they have modest impact upon negative symptoms.

    “Current treatments with antipsychotics are relatively effective in the management of psychotic symptoms (delusions, hallucinations, bizarre thoughts, paranoia), but they have modest impact upon negative symptoms (decreased expression, avolition) 40 ,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Leucht, S. et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 31–41 (2009). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Antipsychotics fail to improve cognitive deficits, which are directly linked to poor real-world function.

    “and fail to improve cognitive deficits, which are directly linked to poor real-world function 41 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Green, M.F. What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry 153, 321–330 (1996). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Schizophrenia pathology worsens over time, as supported by studies suggesting that long-term morbidity increases in the absence of any treatment.

    “The notion that schizophrenia pathology worsen over time is supported by studies that suggest that long-term morbidity increases in the absence of any treatment 45,46 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [45] Wyatt, R.J. Neuroleptics and the natural course of schizophrenia. Schizophr. Bull. 17, 325–351 (1991). source

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    • cites [46] Robinson, D. et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch. Gen. Psychiatry 56, 241–247 (1999). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Stem cell-based models are beginning to be used for characterizing cellular defects linked to pathological gene variation.

    “and stem cell-based models are beginning to be used for characterizing cellular defects linked to pathological gene variation 58-60 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [58] Yoon, K.J. et al. Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15, 79–91 (2014). source

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    • cites [59] Shcheglovitov, A. et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503, 267–271 (2013). source

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    • cites [60] Brennand, K.J. et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 473, 221–225 (2011). source

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    Findingcitation
    § Fragile X syndrome

    The disorder is primarily caused by expansion of a CGG triplet repeat in the 5′ untranslated region of the FMR1 gene that cause a reduction of the FMR1 protein, although several other mutations in FMR1 have been described.

    “The disorder is primarily caused by expansion of a CGG triplet repeat in the 5 ′ untranslated region of the fragile X mental retardation 1 ( FMR1 ) gene that cause a reduction of the FMR1 protein, although several other mutations in FMR1 have been described 90 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Penagarikano, O., Mulle, J.G. & Warren, S.T. The pathophysiology of fragile X syndrome. Annu. Rev. Genomics Hum. Genet. 8, 109–129 (2007). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Df(16)A +/- mice are a model of DiGeorge syndrome, caused by a microdeletion (22q11.2) that accounts for a small percentage of schizophrenia cases.

    “For example, Df(16)A +/-mice are a model of DiGeorge syndrome, caused by a microdeletion (22q11.2) that accounts for a small percentage of schizophrenia cases 74 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl. Acad. Sci. USA 92, 7612–7616 (1995). source

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    Findingcitation
    § Fragile X syndrome

    In the absence of FMR1, uncontrolled mGluR signaling leads to exacerbated LTD and deceleration of synapse maturation, thereby contributing to the cognitive impairment associated with FXS.

    “In the absence of FMR1, uncontrolled mGluR signaling leads to exacerbated LTD and deceleration of synapse maturation, thereby contributing to the cognitive impairment associated with FXS 92 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Bear, M.F., Huber, K.M. & Warren, S.T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Inhibition of Gsk3β signaling in juvenile Df(16)A +/- mice rescues the functional connectivity between the hippocampus and prefrontal cortex and improves working memory in these mice.

    “Consistent with this hypothesis, inhibition of Gsk3 β signaling in juvenile Df(16)A +/-mice rescues the functional connectivity between the hippocampus and prefrontal cortex and improves working memory in these mice 79 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Tamura, M., Mukai, J., Gordon, J.A. & Gogos, J.A. Developmental inhibition of Gsk3 rescues behavioral and neurophysiological deficits in a mouse model of schizophrenia predisposition. Neuron 89, 1100–1109 (2016). source

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    Findingcitation
    § Fragile X syndrome

    Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder associated with autism, learning disabilities, abnormal attention, hyperactive and impulsive behaviors, and epilepsy, affecting approximately 1 in 4,000 males.

    “Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder associated with autism, learning disabilities, abnormal attention, hyperactive and impulsive behaviors, and epilepsy, affecting approximately 1 in 4,000 males 89 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Hagerman, R.J. et al. Advances in the treatment of fragile X syndrome. Pediatrics 123, 378–390 (2009). source

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    Findingcitation
    § Fragile X syndrome

    Hypersynchrony is due to a higher than normal proportion of active pyramidal cells, which are intrinsically more excitable and have increased firing rates.

    “Hypersynchrony is due to a higher than normal proportion of active pyramidal cells, which are intrinsically more excitable and have increased firing rates 104,105 .”
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    • cites [104] Gonçalves, J.T., Anstey, J.E., Golshani, P. & Portera-Cailliau, C. Circuit level defects in the developing neocortex of Fragile X mice. Nat. Neurosci. 16, 903–909 (2013). source

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    • cites [105] Gibson, J.R., Bartley, A.F., Hays, S.A. & Huber, K.M. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J. Neurophysiol. 100, 2615–2626 (2008). source

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    Findingcitation
    § Fragile X syndrome

    Fmr1 mutant mice have a significant delay in the stabilization of dendritic spines and in the maturation of thalamocortical and corticocortical synapses, defects associated with a temporal shift in the critical period for sensory-induced plasticity across different cortical areas.

    “Fmr1 mutant mice have a significant delay in the stabilization of dendritic spines and in the maturation of thalamocortical and corticocortical synapses 94-98 , defects associated with a temporal shift in the critical period for sensory-induced plasticity across different cortical areas 94,97,99-101 .”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [94] Bureau, I., Shepherd, G.M. & Svoboda, K. Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice. J. Neurosci. 28, 5178–5188 (2008). source

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    • cites [95] Cruz-Martín, A., Crespo, M. & Portera-Cailliau, C. Delayed stabilization of dendritic spines in fragile X mice. J. Neurosci. 30, 7793–7803 (2010). source

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    • cites [96] Galvez, R. & Greenough, W.T. Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndrome. Am. J. Med. Genet. A. 135, 155–160 (2005). source

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    • cites [97] Harlow, E.G. et al. Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout mice. Neuron 65, 385–398 (2010). source

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    • cites [98] Nimchinsky, E.A., Oberlander, A.M. & Svoboda, K. Abnormal development of dendritic spines in FMR1 knock-out mice. J. Neurosci. 21, 5139–5146 (2001). source

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    • cites [99] Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007). source

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    • cites [100] Kim, H., Gibboni, R., Kirkhart, C. & Bao, S. Impaired critical period plasticity in primary auditory cortex of fragile X model mice. J. Neurosci. 33, 15686–15692 (2013). source

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    • cites [101] Till, S.M. et al. Altered maturation of the primary somatosensory cortex in a mouse model of fragile X syndrome. Hum. Mol. Genet. 21, 2143–2156 (2012). source

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    Findingcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Df(16)A +/- mice have prominent working memory deficits that are likely caused by impaired functional connectivity between the hippocampus and the prefrontal cortex.

    “Df(16)A +/-mice have prominent working memory deficits that are likely caused by impaired functional connectivity between the hippocampus and the prefrontal cortex 77”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Sigurdsson, T., Stark, K.L., Karayiorgou, M., Gogos, J.A. & Gordon, J.A. Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010). source

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    Findingcitation
    § Fragile X syndrome

    Treatment with GABAA and GABAB receptor modulators seems to control hyperexcitability in Fmr1 mutant mice, but similar approaches in human patients have failed to yield positive outcomes.

    “Similarly, treatment with GABAA and GABAB receptor modulators seems to control hyperexcitability in Fmr1 mutant mice, but similar approaches in human patients have failed to yield positive outcomes 107,116 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [107] Braat, S. & Kooy, R.F. The GABAA receptor as a therapeutic target for neurodevelopmental disorders. Neuron 86, 1119–1130 (2015). source

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    • cites [116] Berry-Kravis, E.M. et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci. Transl. Med. 4, 152ra127 (2012). source

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    Findingcitation
    § Fragile X syndrome

    Fmr1 mutant mice are highly susceptible to seizures and exhibit abnormally high cortical network synchrony during juvenile stages.

    “Consistently, Fmr1 mutant mice are highly susceptible to seizures 103 and exhibit abnormally high cortical network synchrony during juvenile stages 104 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] Musumeci, S.A. et al. Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome. Epilepsia 41, 19–23 (2000). source

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    • cites [104] Gonçalves, J.T., Anstey, J.E., Golshani, P. & Portera-Cailliau, C. Circuit level defects in the developing neocortex of Fragile X mice. Nat. Neurosci. 16, 903–909 (2013). source

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    Findingcitation
    § Fragile X syndrome

    FMR1 is an RNA-binding protein that regulates neuronal protein synthesis.

    “FMR1 is an RNA-binding protein that regulates neuronal protein synthesis 91 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Santoro, M.R., Bray, S.M. & Warren, S.T. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu. Rev. Pathol. 7, 219–245 (2012). source

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    Findingcitation
    § Rett syndrome

    Mecp2 mutants have a precocious onset and closure of critical period plasticity.

    “Mecp2 mutants have a precocious onset and closure of critical period plasticity 125,126 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [125] Durand, S. et al. NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 76, 1078–1090 (2012). source

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    • cites [126] Krishnan, K. et al. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc. Natl. Acad. Sci. USA 112, E4782–E4791 (2015). source

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    Findingcitation
    § Rett syndrome

    Most affected individuals with Rett Syndrome are female heterozygotes who are somatic mosaics for normal and mutant MECP2.

    “Most affected individuals are female heterozygotes who are somatic mosaics for normal and mutant MECP2 120 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Chahrour, M. & Zoghbi, H.Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Findingcitation
    § Rett syndrome

    The abnormal activity of cortical circuits might be caused by the precocious development of GABAergic interneurons.

    “Recent studies suggest that the abnormal activity of cortical circuits might be caused by the precocious development of GABAergic interneurons, a hypothesis that has been primarily tested in the visual cortex.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [125] Durand, S. et al. NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 76, 1078–1090 (2012). source

      Not checked in the free run.

    • cites [126] Krishnan, K. et al. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc. Natl. Acad. Sci. USA 112, E4782–E4791 (2015). source

      Not checked in the free run.

    • cites [127] Mierau, S.B., Patrizi, A., Hensch, T.K. & Fagiolini, M. Cell-specific regulation of N-methyl-D-aspartate receptor maturation by Mecp2 in cortical circuits. Biol. Psychiatry 79, 746–754 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Findingcitation
    § Rett syndrome

    These conclusions seem at odds with work suggesting that behavioral deficits in mouse models of FXS and RTT can be reverted in adulthood.

    “It should be noted that these conclusions seem at odd with work suggesting that behavioral deficits in mouse models FXS and RTT can be reverted in adulthood 133 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Ehninger, D., Li, W., Fox, K., Stryker, M.P. & Silva, A.J. Reversing neurodevelopmental disorders in adults. Neuron 60, 950–960 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    The precocious window of critical period plasticity observed in Mecp2 mutant mice can be rescued by reducing sensory inputs (dark-rearing), decreasing the activation of PV+ interneurons by pyramidal cells (NMDA receptor disruption) or reducing GABAergic neurotransmission (Gad67 reduction).

    “The precocious window of critical period plasticity observed in Mecp2 mutant mice (which reduces the influence of visual experience on the developing cortex) can be rescued by reducing sensory inputs (dark-rearing), decreasing the activation of PV+ interneurons by pyramidal cells (NMDA receptor disruption) or reducing GABAergic neurotransmission (Gad67 reduction) 125-127 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [125] Durand, S. et al. NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 76, 1078–1090 (2012). source

      Not checked in the free run.

    • cites [126] Krishnan, K. et al. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc. Natl. Acad. Sci. USA 112, E4782–E4791 (2015). source

      Not checked in the free run.

    • cites [127] Mierau, S.B., Patrizi, A., Hensch, T.K. & Fagiolini, M. Cell-specific regulation of N-methyl-D-aspartate receptor maturation by Mecp2 in cortical circuits. Biol. Psychiatry 79, 746–754 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    The consequences of MeCP2 dysfunction on neuronal networks have been extensively explored in mice lacking MeCP2 and those with a conditional hemizygous deletion, but the results vary considerably possibly due to differences in the age of the mice in the analysis and the specific characteristics of each cortical area.

    “The consequences of MeCP2 dysfunction on neuronal networks have been extensively explored in mice lacking MeCP2 and those with a conditional hemizygous deletion, but the results vary considerably possibly due to differences in the age of the mice in the analysis (juvenile, young adults and adults) and the specific characteristics of each cortical area 123,124 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [123] Katz, D.M. et al. Rett syndrome: crossing the threshold to clinical translation. Trends Neurosci. 39, 100–113 (2016). source

      Not checked in the free run.

    • cites [124] Lombardi, L.M., Baker, S.A. & Zoghbi, H.Y. MECP2 disorders: from the clinic to mice and back. J. Clin. Invest. 125, 2914–2923 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    MECP2 is a global transcriptional modulator and multifunctional mediator of protein interactions that is strongly expressed in the CNS at a time that correlates with neuronal maturation and synaptogenesis.

    “MECP2 is global transcriptional modulator and multifunctional mediator of protein interactions that is strongly expressed in the CNS at a time that correlates with neuronal maturation and synaptogenesis 122 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Ausió, J., Martínez de Paz, A. & Esteller, M. MeCP2: the long trip from a chromatin protein to neurological disorders. Trends Mol. Med. 20, 487–498 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Fragile X syndrome

    A recent clinical trial with bumetanide has shown improved accuracy in facial emotional labeling and enhanced communication in a group of ASD children between the ages of 3 and 11 years.

    “In that context, a recent clinical trial with bumetanide, a drug that inhibits NKCC1, has shown improved accuracy in facial emotional labeling and enhanced communication in a group of ASD children between the ages of 3 and 11 years 117,118 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Lemonnier, E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl. Psychiatry 2, e202 (2012). source

      Not checked in the free run.

    • cites [118] Hadjikhani, N. et al. Improving emotional face perception in autism with diuretic bumetanide: a proof-of-concept behavioral and functional brain imaging pilot study. Autism 19, 149–157 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    Rett Syndrome is characterized by seemingly normal postnatal development followed by a sudden deceleration in growth associated with progressive loss of acquired motor and language skills, stereotypic hand movements, muscle hypotonia, autonomic dysfunctions and severe cognitive impairment.

    “The disease is characterized by seemingly normal postnatal development followed by a sudden deceleration in growth associated with progressive loss of acquired motor and language skills, stereotypic hand movements, muscle hypotonia, autonomic dysfunctions and severe cognitive impairment 121 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Hagberg, B. Clinical manifestations and stages of Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 8, 61–65 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    Inhibitory function seems to normalize in young adult mice, perhaps due to homeostatic compensations following long-term reduction of activity levels, but the early alterations in neural networks cause long-term functional deficits.

    “Inhibitory function seems to normalize in young adult mice 129 , perhaps due to homeostatic compensations following long-term reduction of activity levels 126 , but the early alterations in neural networks cause long-term functional deficits 125 .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [129] Dani, V.S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. USA 102, 12560–12565 (2005). source

      Not checked in the free run.

    • cites [126] Krishnan, K. et al. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc. Natl. Acad. Sci. USA 112, E4782–E4791 (2015). source

      Not checked in the free run.

    • cites [125] Durand, S. et al. NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 76, 1078–1090 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    Disinhibition of pyramidal cells through low (subanesthetic) doses of ketamine normalizes inhibitory connectivity, prevents the silencing of cortical circuits, and extends the lifespan of Mecp2 mutants.

    “Preclinical studies have shown that disinhibition of pyramidal cells through low (subanesthetic) doses of ketamine, an NMDAR antagonist that acts preferentially on PV+ interneurons reducing the excitatory drive onto these cells 130 , normalizes inhibitory connectivity, prevents the silencing of cortical circuits, and extends the lifespan of Mecp2 mutants 131 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [130] Moghaddam, B. & Krystal, J.H. Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr. Bull. 38, 942–949 (2012). source

      Not checked in the free run.

    • cites [131] Patrizi, A. et al. Chronic administration of the N-methyl-D-aspartate receptor antagonist ketamine improves Rett syndrome phenotype. Biol. Psychiatry 79, 755–764 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    Ketamine treatment normalizes cortical activity in both young adults and adult mice.

    “Ketamine treatment normalizes cortical activity in both young adults and adult mice 131,132 ,”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [131] Patrizi, A. et al. Chronic administration of the N-methyl-D-aspartate receptor antagonist ketamine improves Rett syndrome phenotype. Biol. Psychiatry 79, 755–764 (2016). source

      Not checked in the free run.

    • cites [132] Kron, M. et al. Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. J. Neurosci. 32, 13860–13872 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § Rett syndrome

    Vision acuity initially develops normally in Mecp2 mutants but regresses in young adult mice.

    “In a pattern that resembles the relapse of RTT patients, vision acuity initially develops normally in Mecp2 mutants but regresses in young adult mice 125 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Durand, S. et al. NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 76, 1078–1090 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Developmental timing and critical windows for the treatment of psychiatric disorders

    Therapeutical intervention may impact brain function differently depending on the stage of the disorder, and treatment in the adult brain might be less effective than at earlier stages.

    “Given the importance of developmental trajectories in mental illness, an emerging idea is that therapeutical intervention may impact brain function differently depending on the stage of the disorder, and that treatment in the adult brain might be less effective than at earlier stages 13,14 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Millan, M.J. et al. Altering the course of schizophrenia: progress and perspectives. Nat. Rev. Drug Discov. 15, 485–515 (2016). source

      Not checked in the free run.

    • cites [14] Veenstra-VanderWeele, J. & Warren, Z. Intervention in the context of development: pathways toward new treatments. Neuropsychopharmacology 40, 225–237 (2015). source

      Not checked in the free run.

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

    Interpretationnone given
    § Developmental milestones in the assembly of neural circuits

    Many unique features of neural computations are similarly established during critical periods across different brain areas and are important for disease.

    “It is conceivable that many unique features of neural computations are similarly established during critical periods across different brain areas and are important for disease.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given
    § Developmental timing and critical windows for the treatment of psychiatric disorders

    Many factors contribute to the absence of effective treatments for psychiatric disorders, not least the lack of a clear understanding of their neurobiological substrates.

    “Many factors contribute to the absence of effective treatments for psychiatric disorders, not least the lack of a clear understanding of their neurobiological substrates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Developmental milestones in the assembly of neural circuits

    The desynchronization of spontaneous network activity is an emerging property of mature cortices, in which information is massively distributed across neurons and only small sets of neurons respond to any given stimulus.

    “This is an emerging property of mature cortices, in which information is massively distributed across neurons and only small sets of neurons respond to any given stimulus.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning
    § Developmental timing and critical windows for the treatment of psychiatric disorders

    Understanding the dynamic nature of the pathophysiological mechanisms underlying psychiatric disorders is critical for the development of effective therapies.

    “These studies suggest that understanding the dynamic nature of the pathophysiological mechanisms underlying psychiatric disorders is critical for the development of effective therapies.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Psychosis is not the onset of schizophrenia, but rather a prominent consequence of a developmental path toward schizophrenia that can be perhaps prevented through early intervention.

    “According to this view, psychosis is not the onset of the disorder, but rather a prominent consequence of a developmental path toward schizophrenia that can be perhaps prevented through early intervention 44 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Insel, T.R. Rethinking schizophrenia. Nature 468, 187–193 (2010). source

      Not checked in the free run.

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

    Interpretationreasoning
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Early interventions are needed before pathological defects cascade into an irreversible state.

    “This observation strongly reinforces the need for early interventions before pathological defects cascade into an irreversible state.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Striatal dopamine changes are secondary to other defects and preventive treatments should aim for an earlier developmental window for course alteration.

    “Indeed, since dopamine is already elevated in some patients when they first seek help 52 , it is conceivable that striatal dopamine changes are secondary to other defects and preventive treatments should aim for an earlier developmental window for course alteration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Howes, O. et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol. Psychiatry 16, 885–886 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    By the time presynaptic dopamine function is abnormally increased, several other changes have occurred that limit prevention.

    “One possible explanation for this failure could be that by the time presynaptic dopamine function is abnormally increased, several other changes have occurred that limit prevention.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given
    § Developmental milestones in the assembly of neural circuits

    The development of neural circuits in the cerebral cortex and associated subcortical structures is characterized by a number of developmental milestones that have long-lasting effect in brain function.

    “In sum, the development of neural circuits in the cerebral cortex and associated subcortical structures is characterized by a number of developmental milestones that have long-lasting effect in the brain function.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Different pathophysiological mechanisms may operate in different groups of patients with schizophrenia, even if the final behavioral and functional deficits are relatively conserved.

    “Considering the clinical heterogeneity of schizophrenia, it seems likely that different pathophysiological mechanisms may operate in different groups of patients, even if the final behavioral and functional deficits are relatively conserved.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § Neurodevelopment and disease-modifying strategies in schizophrenia

    Redox dysregulation contributes to aberrant developmental trajectories in schizophrenia and early correction of this imbalance may have therapeutic potential.

    “these studies seem to support the idea that redox dysregulation contributes to aberrant developmental trajectories in schizophrenia and that early correction of this imbalance may have therapeutic potential 86 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Do, K.Q., Cabungcal, J.H., Frank, A., Steullet, P. & Cuenod, M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr. Opin. Neurobiol. 19, 220–230 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Rett syndrome

    Behavioral phenotypes are likely caused by both developmental and adult pathophysiology, and early interventions stand a better chance to restore the original deficits.

    “Consequently, behavioral phenotypes are likely caused by both developmental and adult pathophysiology, and early interventions stand a better chance to restore the original deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Practical considerations and caveats of early intervention

    Individuals carrying 22q11 deletions may develop ASD, schizophrenia, depression or anxiety disorders, among other conditions.

    “Individuals carrying 22q11 deletions may develop ASD, schizophrenia, depression or anxiety disorders, among other conditions 151”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Schneider, M. et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am. J. Psychiatry 171, 627–639 (2014). source

      Not checked in the free run.

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

    Interpretationreasoning
    § Conclusions and outlook

    Our ability to develop disease-modifying interventions that are time-matched to the specific state of neural networks at any given stage of development may prove indispensable for the treatment of many psychiatric disorders.

    “Looking forward, our ability to develop disease-modifying interventions that are time-matched to the specific state of neural networks at any given stage of development may prove indispensable for the treatment of many psychiatric disorders.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given
    § Practical considerations and caveats of early intervention

    From the perspective of developmental trajectories, a four-week treatment in newborn mice would be equivalent to over a decade of life in children.

    “From the perspective of developmental trajectories, a four-week treatment in newborn mice would be equivalent to over a decade of life in children.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The vital cycle of rodents is very different from humans.

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

    Interpretationreasoning
    § Practical considerations and caveats of early intervention

    A four-week treatment may indeed have similar effects in rodents and humans from a pharmacological point of view.

    “However, receptor sensitization might have similar dynamics in both species, and so a four-week treatment may indeed have similar effects in rodents and humans from a pharmacological point of view.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Receptor sensitization might have similar dynamics in both species.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Conclusions and outlook

    Neural network dynamics are extremely complex and change dramatically with disease progression, as shown in animal model studies exploring the function of specific neural circuits at different stages.

    “Neural network dynamics are extremely complex and change dramatically with disease progression, as shown in animal model studies exploring the function of specific neural circuits at different stages.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning
    § Conclusions and outlook

    In the case of psychiatric disorders that are diagnose relatively late in life such as schizophrenia, a better understanding of the longitudinal time course of initial symptoms will be necessary for the successful implementation of early therapies.

    “In the case of psychiatric disorders that are diagnose relatively late in life such as schizophrenia, a better understanding of the longitudinal time course of initial symptoms will be necessary for the successful implementation of early therapies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Conclusions and outlook

    Studies in animal models are also shifting from the analysis of behavioral deficits to the interrogation of neural circuit abnormalities, which is proving more powerful for the identification of pathophysiological mechanisms.

    “Studies in animal models are also shifting from the analysis of behavioral deficits to the interrogation of neural circuit abnormalities 61 , which is proving more powerful for the identification of pathophysiological mechanisms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Kaiser, T. & Feng, G. Modeling psychiatric disorders for developing effective treatments. Nat. Med. 21, 979–988 (2015). source

      Not checked in the free run.

60 of 60

  • The paper relies on this without support.

    Current treatments for psychiatric disorders are based on symptoms, are not disease modifying, and have low response rates.

    “Current treatments are based on symptoms, are not disease modifying, and have low response rates.”

  • The paper relies on this without support.

    There are no effective pharmacological therapies for autism spectrum disorders (ASD) and related intellectual disabilities.

    “and there are no effective pharmacological therapies for autism spectrum disorders (ASD) and related intellectual disabilities.”

  • The paper relies on this without support.

    GABA may be an inhibitory or excitatory neurotransmitter depending on the intracellular concentration of chloride ions present in the receiving cell.

    “GABA may be an inhibitory or excitatory neurotransmitter depending on the intracellular concentration of chloride ions present in the receiving cell.”

  • The paper relies on this without support.

    Some GABAergic deficits are already present in individuals at ultra-high risk for psychosis.

    “Interestingly, some of these deficits are already present -albeit in a less pronounced manner- in individuals at ultra-high risk for psychosis.”

  • The paper relies on this without support.

    Schizophrenia lacks clear monogenic syndromes that can be modeled in animals.

    “One important limiting factor for this approach is that schizophrenia lacks clear monogenic syndromes that can be modeled in animals.”

  • The paper relies on this without support.

    There is a link between oxidative stress and schizophrenia.

    “Another indication of the potential of early intervention therapies for schizophrenia is the link between oxidative stress and schizophrenia.”

  • The paper relies on this without support.

    Non-pharmacological interventions may increase their therapeutic value when applied early.

    “Several lines of evidence suggest that non-pharmacological interventions may increase their therapeutical value when applied early.”

  • The paper relies on this without support.

    Many syndromic neurodevelopmental disorders follow divergent trajectories that suggest that treatments should be tailored accordingly.

    “While frequently grouped under the large umbrella of ASD and related intellectual disabilities, many of these disorders follow divergent trajectories that suggest that treatments should be tailored accordingly.”

  • The paper relies on this without support.

    Differences in disease progression correlate with distinct temporal dynamics in the experience-dependent maturation of neural circuits.

    “The differences in disease progression, which correlate with distinct temporal dynamics in the experience-dependent maturation of neural circuits, are very prominent in two of the best-characterized syndromic neurodevelopmental disorders, Fragile X syndrome and Rett syndrome.”

  • The paper relies on this without support.

    Rett Syndrome is an X-linked neurodevelopmental disorder that is primarily caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2).

    “Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder that is primarily caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2).”

  • The paper relies on this without support.

    Most risk factors to which at risk individuals are potentially exposed in early development only contribute minimally to non-syndromic neurodevelopmental disorders.

    “most risk factors to which at risk individuals are potentially exposed in early development only contribute minimally to non-syndromic neurodevelopmental disorders”

  • The paper relies on this without support.

    A universal genetic biomarker of the risk of transition to schizophrenia is not currently available.

    “A universal genetic biomarker of the risk of transition to schizophrenia is not currently available”

  • The paper relies on this without support.

    The behavior of humans and rodents is highly divergent.

    “In addition, since the behavior of humans and rodents is highly divergent”

  • The paper relies on this without support.

    The vital cycle of rodents is very different from humans.

    “Most notably, the vital cycle of rodents is very different from humans.”

  • The paper relies on this without support.

    Receptor sensitization might have similar dynamics in both species.

    “However, receptor sensitization might have similar dynamics in both species”

  • The paper relies on this without support.

    We are currently unable to reliably predict pathological trajectories in 'at risk' populations.

    “since we are currently unable to reliably predict pathological trajectories in 'at risk' populations”

  • The paper relies on this without support.

    Not everyone from 'at risk' groups will go on to develop a psychiatric condition.

    “and not everyone from these groups will go on to develop a psychiatric condition”

  • The paper relies on this without support.

    Early intervention may prevent subsequent symptoms caused by the dynamic reorganization of developing circuits.

    “while early intervention may prevent subsequent symptoms caused by the dynamic reorganization of developing circuits”

  • The paper relies on this without support.

    Many therapeutic interventions in ASD and schizophrenia aim to target inhibitory interneurons, and these treatments have minor secondary effects in healthy adults.

    “As described above, many therapeutical interventions in ASD and schizophrenia aim to target inhibitory interneurons, and these treatments have minor secondary effects in healthy adults.”

  • The paper relies on this without support.

    It is unlikely that the affected proteins play very different roles in rodents and humans.

    “Although it is unlikely that the affected proteins play very different roles in rodents and humans”

  • The paper relies on this without support.

    Treatment in children and adolescents may trigger unexpected side effects that are unique to these patient populations.

    “Secondly, treatment in children and adolescents may trigger unexpected side effects that are unique to these patient populations.”

  • The paper relies on this without support.

    Testing new pharmacological treatments in children may have unwanted consequences.

    “On the other hand, testing new pharmacological treatments in children may have unwanted consequences.”
22 of 22

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Authors
Marín, O.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-10-26
Volume
22
Issue
11
Pages
1229-1238
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.4225
OpenAlex
W2545275594
Cited by
374
References
158
Citations by year
2026: 30 · 2025: 40 · 2024: 38 · 2023: 45 · 2022: 38 · 2021: 50 · 2020: 40 · 2019: 34 · 2018: 32 · 2017: 26 · 2016: 1
FWCI
27.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
Funders
  • Wellcome Trust (103714/Z/14/Z, 103714MA)
  • Simons Foundation Autism Research Initiative
  • Medical Research Council (MR/N026063/1)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
developmental timing, critical window, sensitive period, mental illness, early intervention, schizophrenia, brain development, environmental insults, genetic variation, learning disabilities, animal models, disease prevention, pathophysiology
MeSH terms
Autism Spectrum Disorder, Mental Disorders, Brain, Critical Period, Psychological, Humans, Nerve Net, Neuronal Plasticity, Psychotic Disorders, Schizophrenia, Age of Onset, Disease Progression, Gene Expression Regulation, Developmental, Neurogenesis, Early Medical Intervention

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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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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