<h2>Excitatory/Inhibitory (E/I) balances</h2>
<p>The Max Planc Florida Institute (MPFI) for Neuroscience <a href="https://mpfi.org/balancing-act-in-the-brain-excitatory-and-inhibitory-activity/" rel="nofollow noreferrer">describes this balancing act within the brain</a>.</p>
<blockquote>
<p>Neurons communicate through electrical currents called action potentials, which are either excitatory or inhibitory. Excitatory currents are those that prompt one neuron to share information with the next through an action potential, while inhibitory currents reduce the probability that such a transfer will take place. It typically takes more than one excitatory connection to generate an action potential, but as you might expect, hundreds of electrical signals are constantly converging on any given neuron.</p>
<p>The measured effect of all excitatory and inhibitory currents received by one cell is known as global excitatory/inhibitory (E/I) balance. Although there are many more excitatory neurons in the cortex, inhibitory neurons are a diverse and influential group that regulate the activity of their excitatory counterparts. They are considered balanced when the ratio between E/I activity remains approximately constant, even under a wide range of conditions. Neuroscientists are interested in E/I balance because it is essential for stable brain function—in particular, our brain’s ability to faithfully capture information about the world and integrate it with our existing knowledge.</p>
</blockquote>
<h2>Are autism spectrum disorders included in the group of psychiatric disorders where an imbalance in E/I ratio is thought to occur?</h2>
<p>The short answer is yes.</p>
<p><a href="https://doi.org/10.1038/s41598-020-65500-4" rel="nofollow noreferrer">Bruining, et al. (2020)</a> points out that</p>
<blockquote>
<p>In clinical terms, disruption of E/I balance has become a dominant theory on the pathogenesis of various neurodevelopmental disorders, and perhaps most explicitly in autism spectrum disorder (ASD)<sup>3,4,5,6&lt;</sup></p>
<ol start="3">
<li><p>Dickinson, A., Jones, M., &amp; Milne, E. (2016). Measuring neural excitation and inhibition in autism: different approaches, different findings and different interpretations. <em>Brain Research, 1648</em>, 277-289. <a href="https://doi.org/10.1016/j.brainres.2016.07.011" rel="nofollow noreferrer">https://doi.org/10.1016/j.brainres.2016.07.011</a></p>
</li>
<li><p>Nelson, S. B., &amp; Valakh, V. (2015). Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. <em>Neuron, 87</em>(4), 684-698. <a href="https://doi.org/10.1016/j.neuron.2015.07.033" rel="nofollow noreferrer">https://doi.org/10.1016/j.neuron.2015.07.033</a></p>
</li>
<li><p>Rubenstein, J. L. R., &amp; Merzenich, M. M. (2003). Model of autism: increased ratio of excitation/inhibition in key neural systems. <em>Genes, Brain and Behavior, 2</em>(5), 255-267. <a href="https://doi.org/10.1034/j.1601-183X.2003.00037.x" rel="nofollow noreferrer">https://doi.org/10.1034/j.1601-183X.2003.00037.x</a></p>
</li>
<li><p>Uzunova, G., Pallanti, S., &amp; Hollander, E. (2016). Excitatory/inhibitory imbalance in autism spectrum disorders: implications for interventions and therapeutics. <em>The World Journal of Biological Psychiatry, 17</em>(3), 174-186. <a href="https://doi.org/10.3109/15622975.2015.1085597" rel="nofollow noreferrer">https://doi.org/10.3109/15622975.2015.1085597</a></p>
</li>
</ol>
</blockquote>
<p>However, Bruining et al points out that methods to measure E/I ratios in human brain networks are lacking, so they developed a method to quantify a functional E/I ratio (fE/I) from neuronal oscillations, and validate it against children with ASD and children without ASD.</p>
<blockquote>
<p>ASD is characterized by alterations in critical brain dynamics
To test the hypothesis that E/I imbalances characterize ASD <sup>4,41</sup>, we applied the algorithm to eyes-closed rest EEG recordings in non-medicated children with ASD (ASD<sub>all</sub>; <em>n</em> = 100, 7–15 years) and age-matched typically developing children (TDC; <em>n</em> = 29) (Table 1 and Supplementary Table S1). The children with ASD had lower total IQ (<em>p</em> &lt; 0.001) than TDC (Table 1). As with the CROS-model activity, we analyzed relative power (RP), LRTC, and <em>fE/I</em> in the alpha band of the EEGs. The topography of RP showed the characteristic occipito-parietal distribution of eyes-closed rest recordings both in TDC and ASD without between-group differences in mean or variance of whole-brain averages (Fig. 4a; Wilcoxon rank-sum test, mean ± SEM; <em>RP</em><sub>ASDall</sub> = 26.8 ± 1.1% and <em>RP</em><sub>TDC</sub> = 27.2 ± 2.1% <em>p</em> = 0.84; Levene’s test of variance: <em>p</em> = 0.82). The scalp distribution of LRTC quantified by DFA was also similar between TDC and ASD, but whole-brain average and variability were both larger in ASD (Fig. 4b; β<sub>ASDall</sub> = 0.70 ± .01, and β<sub>TDC</sub> = 0.65 ± 0.01 <em>p</em> = 0.01; Levene’s test: <em>p</em> = 0.001). The scalp topography of <em>fE/I</em> of alpha oscillations showed similar distributions in ASD<sub>all</sub> and TDC. A pronounced variability of <em>fE/I</em> was evident in ASD<sub>all</sub> (Fig. 4c; Levene’s test: <em>p</em> = 0.04), characterized by more extreme values of <em>fE/I</em> in both directions away from the balance point although between-group differences of whole-brain average <em>fE/I</em> were not significant (Fig. 4c; <em>fE/I</em><sub>ASDall</sub> = 1.03 ± 0.02 and <em>fE/I</em><sub>TDC</sub> = 1.01 ± 0.02, <em>p</em> = 0.65).</p>
<p><a href="https://i.sstatic.net/HuoRS.jpg" rel="nofollow noreferrer"><img src="https://i.sstatic.net/HuoRS.jpg" alt="Figure 4
From: Measurement of excitation-inhibition ratio in autism spectrum disorder using critical brain dynamics" /></a>
<sup><strong>Figure 4</strong><br>
Alpha oscillations in ASD are characterized by strong LRTC and large variability in <em>fE/I</em>. Grand-average topographies for the EEG biomarkers are shown for TDC (first column), ASD (second column), and for ASD-minus-TDC (third column). (<strong>a</strong>) Relative power (RP) showed the characteristic occipito-parietal distribution both in TDC and ASD. (<strong>b</strong>) Whole-brain average and variability of LRTC quantified by the DFA exponent were both larger in ASD compared to TDC. (<strong>c</strong>) A pronounced variability of whole-brain <em>fE/I</em> was evident in ASD. White circles on the topographies represent significant channels (i.e., <em>p</em>-value &lt; 0.05, using Wilcoxon rank-sum test and FDR correction). The fourth column shows individual-subject values, boxplots, and mean and SEM for TDC (<em>blue circles</em>) and ASD (<em>red squares</em>). Comparisons represented in boxplots were based on the average value of the EEG biomarkers across all 64 electrodes, each data point represents one subject (whole-head average; <em>p</em>-values are from Wilcoxon rank-sum test (mean)/Levene’s test (variability).</sup></p>
<ol start="41">
<li>Rubenstein, J. L. (2010). Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. <em>Current opinion in neurology, 23</em>(2), 118-123. <a href="https://doi.org/10.1097/WCO.0b013e328336eb13" rel="nofollow noreferrer">https://doi.org/10.1097/WCO.0b013e328336eb13</a></li>
</ol>
</blockquote>
<p><strong>Please Note: While Bruining et al mentioned that children with ASD in their study had lower total IQ than typical developing children, IQ is not a covariate in cognitive studies of neurodevelopmental disorders</strong> – see <a href="https://doi.org/10.1017/s1355617709090481" rel="nofollow noreferrer">Dennis, M., et al. (2009)</a>.</p>
<h2>References</h2>
<p>Bruining, H., Hardstone, R., Juarez-Martinez, E. L., Sprengers, J., Avramiea, A. E., Simpraga, S., ... &amp; Linkenkaer-Hansen, K. (2020). Measurement of excitation-inhibition ratio in autism spectrum disorder using critical brain dynamics. <em>Scientific reports, 10</em>(1), 1-15. <a href="https://doi.org/10.1038/s41598-020-65500-4" rel="nofollow noreferrer">https://doi.org/10.1038/s41598-020-65500-4</a></p>
<p>Dennis, M., Francis, D. J., Cirino, P. T., Schachar, R., Barnes, M. A., &amp; Fletcher, J. M. (2009). Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders. <em>Journal of the International Neuropsychological Society, 15</em>(3), 331-343. <a href="https://doi.org/10.1017/s1355617709090481" rel="nofollow noreferrer">https://doi.org/10.1017/s1355617709090481</a></p>

CC BY-SA 4.0
2022-12-06T07:45:47.833Z
2022-12-06T07:45:47.833Z
Chris Rogers
<p>Further to <a href="https://psychology.stackexchange.com/q/28966/7604">Are all synapses &quot;gappy&quot;, and what exactly is in the gap?</a>, I found an open access article (<a href="https://doi.org/10.1371/journal.pone.0003542" rel="nofollow noreferrer">Biswas et al. 2008</a>) pointing out that</p>
<blockquote>
<p>Vertebrate studies show neuroligins and neurexins are binding partners in a trans-synaptic cell adhesion complex, implicated in human autism and mental retardation disorders.</p>
</blockquote>
<p>First of all, I looked more into what neuroligins and neurexins are in the abstract of <a href="https://doi.org/10.1016/B978-0-12-823672-7.00008-9" rel="nofollow noreferrer">https://doi.org/10.1016/B978-0-12-823672-7.00008-9</a> then skimming through the introduction of Biswas et al, the article points out that research implicates</p>
<blockquote>
<p>human neuroligins and neurexins in neuro-developmental psychiatric disorders where an imbalance in E/I ratio [excitatory/inhibitory ratio] is thought to occur. Numerous studies have localised mutations to <em>neuroligin 3</em> and <em>4</em> in families affected by autism, Aspergers syndrome and X-linked mental retardation [39]–[42]. The disease mutations in <em>neuroligin 3</em> and <em>4</em> lead to loss of neurexin binding, loss of synaptogenic capability and retention in the endoplasmic reticulum [43], [44]. Recent studies have also identified a high frequency of neurexin structural variants in families affected with autism and schizophrenia [45], [46].</p>
</blockquote>
<p>First of all, I'd like to be pointed in the direction of literature (where available) which indicates what neuro-developmental psychiatric disorders there are where an imbalance in E/I ratio is thought to occur.</p>
<p>Are <a href="https://www.cdc.gov/ncbddd/autism/facts.html" rel="nofollow noreferrer">autism spectrum disorders</a> part of them?</p>
<p>I am happy to separate the 2 following interrelated queries from this question if it would make the answer too long, but I also wonder, does the E/I imbalance cause the neuro-developmental psychiatric disorders or do the neuro-developmental psychiatric disorders cause the E/I imbalance? If E/I imbalances are involved in autism, is the imbalance towards excitory or inhibitory, and does the imbalance get worse?</p>
<h2>Reference</h2>
<p>Biswas, S., Russell, R. J., Jackson, C. J., Vidovic, M., Ganeshina, O., Oakeshott, J. G., &amp; Claudianos, C. (2008). Bridging the synaptic gap: neuroligins and neurexin I in Apis mellifera. <em>Plos one, 3</em>(10), e3542. <a href="https://doi.org/10.1371/journal.pone.0003542" rel="nofollow noreferrer">https://doi.org/10.1371/journal.pone.0003542</a></p>

<neuroscience><cognitive-neuroscience><autism>
Neuroligins, neurexins and synaptic gaps
Chris Rogers
# Neuroligins, neurexins and synaptic gaps

(Asked by: username_0 on 2022-11-20)

Further to [Are all synapses "gappy", and what exactly is in the gap?](https://psychology.stackexchange.com/q/28966/7604), I found an open access article ([Biswas et al. 2008](https://doi.org/10.1371/journal.pone.0003542)) pointing out that

> Vertebrate studies show neuroligins and neurexins are binding partners in a trans-synaptic cell adhesion complex, implicated in human autism and mental retardation disorders.

First of all, I looked more into what neuroligins and neurexins are in the abstract of <https://doi.org/10.1016/B978-0-12-823672-7.00008-9> then skimming through the introduction of Biswas et al, the article points out that research implicates

> human neuroligins and neurexins in neuro-developmental psychiatric disorders where an imbalance in E/I ratio [excitatory/inhibitory ratio] is thought to occur. Numerous studies have localised mutations to *neuroligin 3* and *4* in families affected by autism, Aspergers syndrome and X-linked mental retardation [39]–[42]. The disease mutations in *neuroligin 3* and *4* lead to loss of neurexin binding, loss of synaptogenic capability and retention in the endoplasmic reticulum [43], [44]. Recent studies have also identified a high frequency of neurexin structural variants in families affected with autism and schizophrenia [45], [46].

First of all, I'd like to be pointed in the direction of literature (where available) which indicates what neuro-developmental psychiatric disorders there are where an imbalance in E/I ratio is thought to occur.

Are [autism spectrum disorders](https://www.cdc.gov/ncbddd/autism/facts.html) part of them?

I am happy to separate the 2 following interrelated queries from this question if it would make the answer too long, but I also wonder, does the E/I imbalance cause the neuro-developmental psychiatric disorders or do the neuro-developmental psychiatric disorders cause the E/I imbalance? If E/I imbalances are involved in autism, is the imbalance towards excitory or inhibitory, and does the imbalance get worse?

## Reference

Biswas, S., Russell, R. J., Jackson, C. J., Vidovic, M., Ganeshina, O., Oakeshott, J. G., & Claudianos, C. (2008). Bridging the synaptic gap: neuroligins and neurexin I in Apis mellifera. *Plos one, 3*(10), e3542. <https://doi.org/10.1371/journal.pone.0003542>

**Tags:** neuroscience, cognitive-neuroscience, autism


---

## 1 answers

### Answer by username_0 on 2022-12-06. Score: 1

## Excitatory/Inhibitory (E/I) balances

The Max Planc Florida Institute (MPFI) for Neuroscience [describes this balancing act within the brain](https://mpfi.org/balancing-act-in-the-brain-excitatory-and-inhibitory-activity/).

> Neurons communicate through electrical currents called action potentials, which are either excitatory or inhibitory. Excitatory currents are those that prompt one neuron to share information with the next through an action potential, while inhibitory currents reduce the probability that such a transfer will take place. It typically takes more than one excitatory connection to generate an action potential, but as you might expect, hundreds of electrical signals are constantly converging on any given neuron.
>
> The measured effect of all excitatory and inhibitory currents received by one cell is known as global excitatory/inhibitory (E/I) balance. Although there are many more excitatory neurons in the cortex, inhibitory neurons are a diverse and influential group that regulate the activity of their excitatory counterparts. They are considered balanced when the ratio between E/I activity remains approximately constant, even under a wide range of conditions. Neuroscientists are interested in E/I balance because it is essential for stable brain function—in particular, our brain’s ability to faithfully capture information about the world and integrate it with our existing knowledge.

## Are autism spectrum disorders included in the group of psychiatric disorders where an imbalance in E/I ratio is thought to occur?

The short answer is yes.

[Bruining, et al. (2020)](https://doi.org/10.1038/s41598-020-65500-4) points out that

> In clinical terms, disruption of E/I balance has become a dominant theory on the pathogenesis of various neurodevelopmental disorders, and perhaps most explicitly in autism spectrum disorder (ASD)3,4,5,6<
>
> 3. Dickinson, A., Jones, M., & Milne, E. (2016). Measuring neural excitation and inhibition in autism: different approaches, different findings and different interpretations. *Brain Research, 1648*, 277-289. <https://doi.org/10.1016/j.brainres.2016.07.011>
> 4. Nelson, S. B., & Valakh, V. (2015). Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. *Neuron, 87*(4), 684-698. <https://doi.org/10.1016/j.neuron.2015.07.033>
> 5. Rubenstein, J. L. R., & Merzenich, M. M. (2003). Model of autism: increased ratio of excitation/inhibition in key neural systems. *Genes, Brain and Behavior, 2*(5), 255-267. <https://doi.org/10.1034/j.1601-183X.2003.00037.x>
> 6. Uzunova, G., Pallanti, S., & Hollander, E. (2016). Excitatory/inhibitory imbalance in autism spectrum disorders: implications for interventions and therapeutics. *The World Journal of Biological Psychiatry, 17*(3), 174-186. <https://doi.org/10.3109/15622975.2015.1085597>

However, Bruining et al points out that methods to measure E/I ratios in human brain networks are lacking, so they developed a method to quantify a functional E/I ratio (fE/I) from neuronal oscillations, and validate it against children with ASD and children without ASD.

> ASD is characterized by alterations in critical brain dynamics
> To test the hypothesis that E/I imbalances characterize ASD 4,41, we applied the algorithm to eyes-closed rest EEG recordings in non-medicated children with ASD (ASDall; *n* = 100, 7–15 years) and age-matched typically developing children (TDC; *n* = 29) (Table 1 and Supplementary Table S1). The children with ASD had lower total IQ (*p* < 0.001) than TDC (Table 1). As with the CROS-model activity, we analyzed relative power (RP), LRTC, and *fE/I* in the alpha band of the EEGs. The topography of RP showed the characteristic occipito-parietal distribution of eyes-closed rest recordings both in TDC and ASD without between-group differences in mean or variance of whole-brain averages (Fig. 4a; Wilcoxon rank-sum test, mean ± SEM; *RP*ASDall = 26.8 ± 1.1% and *RP*TDC = 27.2 ± 2.1% *p* = 0.84; Levene’s test of variance: *p* = 0.82). The scalp distribution of LRTC quantified by DFA was also similar between TDC and ASD, but whole-brain average and variability were both larger in ASD (Fig. 4b; βASDall = 0.70 ± .01, and βTDC = 0.65 ± 0.01 *p* = 0.01; Levene’s test: *p* = 0.001). The scalp topography of *fE/I* of alpha oscillations showed similar distributions in ASDall and TDC. A pronounced variability of *fE/I* was evident in ASDall (Fig. 4c; Levene’s test: *p* = 0.04), characterized by more extreme values of *fE/I* in both directions away from the balance point although between-group differences of whole-brain average *fE/I* were not significant (Fig. 4c; *fE/I*ASDall = 1.03 ± 0.02 and *fE/I*TDC = 1.01 ± 0.02, *p* = 0.65).
>
> [![Figure 4
> From: Measurement of excitation-inhibition ratio in autism spectrum disorder using critical brain dynamics](https://i.sstatic.net/HuoRS.jpg)](https://i.sstatic.net/HuoRS.jpg)
> **Figure 4**  
> Alpha oscillations in ASD are characterized by strong LRTC and large variability in *fE/I*. Grand-average topographies for the EEG biomarkers are shown for TDC (first column), ASD (second column), and for ASD-minus-TDC (third column). (**a**) Relative power (RP) showed the characteristic occipito-parietal distribution both in TDC and ASD. (**b**) Whole-brain average and variability of LRTC quantified by the DFA exponent were both larger in ASD compared to TDC. (**c**) A pronounced variability of whole-brain *fE/I* was evident in ASD. White circles on the topographies represent significant channels (i.e., *p*-value < 0.05, using Wilcoxon rank-sum test and FDR correction). The fourth column shows individual-subject values, boxplots, and mean and SEM for TDC (*blue circles*) and ASD (*red squares*). Comparisons represented in boxplots were based on the average value of the EEG biomarkers across all 64 electrodes, each data point represents one subject (whole-head average; *p*-values are from Wilcoxon rank-sum test (mean)/Levene’s test (variability).
>
> 41. Rubenstein, J. L. (2010). Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder. *Current opinion in neurology, 23*(2), 118-123. <https://doi.org/10.1097/WCO.0b013e328336eb13>

**Please Note: While Bruining et al mentioned that children with ASD in their study had lower total IQ than typical developing children, IQ is not a covariate in cognitive studies of neurodevelopmental disorders** – see [Dennis, M., et al. (2009)](https://doi.org/10.1017/s1355617709090481).

## References

Bruining, H., Hardstone, R., Juarez-Martinez, E. L., Sprengers, J., Avramiea, A. E., Simpraga, S., ... & Linkenkaer-Hansen, K. (2020). Measurement of excitation-inhibition ratio in autism spectrum disorder using critical brain dynamics. *Scientific reports, 10*(1), 1-15. <https://doi.org/10.1038/s41598-020-65500-4>

Dennis, M., Francis, D. J., Cirino, P. T., Schachar, R., Barnes, M. A., & Fletcher, J. M. (2009). Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders. *Journal of the International Neuropsychological Society, 15*(3), 331-343. <https://doi.org/10.1017/s1355617709090481>


---

