Today’s post was prompted by Tyler highlighting a very recent paper from MIT and Harvard, with some interesting research on GABA in autism. It also provides the occasion to include an interesting epilepsy therapy, which I encountered a while back. This fits with my suggestion that the onset of much epilepsy in autism could be prevented.
In the MIT/Harvard study, they were looking into the excitatory/ inhibitory (E/I) imbalance found in ASD and schizophrenia. They used a non-invasive optical method to measure E/I imbalance and this did get some media coverage. However, I am not sure this could be a diagnostic tool in very young children with classic autism, as was suggested; most such children would not cooperate. It is not just a problem of being non-verbal, as was suggested in the media.
Indeed, due to the nature of the experiment, the researchers involved older subjects, with milder autism and none had MR/ID (IQ<70). Being a trial done in the US, of the 20 autistic subjects, 11 were being treated with psychiatric medications: antidepressants (n = 8), antipsychotics (n = 2), antiepileptics (n = 4), and anxiolytics (n = 2).
Indeed, due to the nature of the experiment, the researchers involved older subjects, with milder autism and none had MR/ID (IQ<70). Being a trial done in the US, of the 20 autistic subjects, 11 were being treated with psychiatric medications: antidepressants (n = 8), antipsychotics (n = 2), antiepileptics (n = 4), and anxiolytics (n = 2).
The easy to read version is from the MIT website:-
Study finds altered brain chemistry in people with autism
The full version is here:-
They used something called Binocular Rivalry as a proxy for E/I imbalance.
During binocular rivalry, two images, one presented to each eye, vie for perceptual dominance as neuronal populations that are selective for each eye’s input suppress each other in alternation [16, 17]. The strength of perceptual suppression during rivalry is thought to depend on the balance of inhibitory and excitatory cortical dynamics [12–15] and may serve as a non-invasive perceptual marker of the putative perturbation in inhibitory signaling thought to characterize the autistic brain.
We therefore measured the dynamics of binocular rivalry in individuals with and without a diagnosis of autism (41 individuals, 20 with autism). As predicted, individuals with autism demonstrated a slower rate of binocular rivalry (switches per trial: controls = 8.68, autism = 4.19; F(1,37) = 16.52, hp 2 = 0.311, p = 0.001; Figure 1A), which was marked by reduced periods of perceptual suppression (proportion of each trial spent viewing a dominant percept, (dominant percept durations)/(dominant + mixed percept durations): controls = 0.69; autism = 0.55; F(1,36) = 7.27, hp 2 = 0.172, p = 0.011; Figure 1B). The strength of perceptual suppression inversely predicted clinical measures of autistic symptomatology (Autism Diagnostic Observation Schedule [ADOS]: Rs = 0.39, p = 0.027; Figure 1) and showed high test-retest reliability in a control experiment (R = 0.94, p < 0.001; see Supplemental Experimental Procedures and also [18]). These results replicate our previous findings in an independent sample of autistic individuals [11] and confirm rivalry disruptions as a robust behavioral marker of autism.
To test whether altered binocular rivalry dynamics in autism are linked to the reduced action of inhibitory (g-aminobutyric acid [GABA]) or excitatory (glutamate [Glx]) neurotransmitters in the brain, we measured the concentration of these neurotransmitters in visual cortex using magnetic resonance spectroscopy (MRS).
GABA and glutamate are predicted to contribute to different aspects of binocular rivalry dynamics: mutual inhibition between (GABA) and recurrent excitation within (glutamate) populations of neurons coding for the two oscillating percepts [14].
. Critically, reducing either mutual inhibition or recurrent excitation is predicted to reduce the strength of perceptual suppression during rivalry in one implementation of this model [14], mirroring the dynamics we observed in autism. We therefore considered each neurotransmitter separately to test whether inhibitory or excitatory signaling was selectively disrupted in the autistic brain.
As predicted by models of binocular rivalry, GABA concentrations in visual cortex strongly predicted rivalry dynamics in controls, where more GABA corresponded to longer periods of perceptual suppression (Rs = 0.62, p = 0.002; Figure 2B). However, this relationship was strikingly absent in individuals with autism (Rs = 0.02, p = 0.473; Figure 2B). The difference between the two correlations was significant (hp 2 = 0.167, p = 0.013; Figure 2C), indicating a reduced impact of GABA on perceptual suppression in the autistic brain.
GABA was working backwards
Importantly, this finding was specific to GABA: glutamate strongly predicted the dynamics of binocular rivalry in autism (Rs = 0.60, p = 0.004; Figure 2B), to the same degree as that found in controls.
Glumate is working just fine.
These findings suggest that alterations in the GABAergic signaling pathway may characterize autistic neurobiology. Consistent with prior evidence from animal and post-mortem studies, such dysfunction may arise from perturbations in key components of the GABAergic pathway beyond GABA levels, such as receptors [3–9] and inhibitory neuronal density
Together with the pivotal roles of GABA in canonical cortical computations [39] and neurodevelopment [40], these findings point to the GABAergic signaling pathway as a prime suspect in the neurobiology of this pervasive developmental disorder [41]
This study reconfirms what regular readers of this blog already knew.
Epilepsy
I thought it was positive that the MIT researchers suggested that the high level of epilepsy in autism and this E/I imbalance really must be connected.
I have been suggesting for some time that by correcting this E/I imbalance in children with autism, it is likely that the onset of epilepsy could be avoided (in some cases).
I did suggest this to one well known researcher who thought the idea of preventing the onset of epilepsy was not something that the medical community would accept as a concept.
I also raised the novel epilepsy therapy, below, to the same researcher who thought it also would never be considered.
The therapy was to use both bumetanide and potassium bromide to switch GABA back to inhibitory and then give a little boost using a GABA agonist.
There are many types of epilepsy and some do not respond well to current treatments. It would seem plausible that the autism-associated type of epilepsy might constitute a specific sub-type.
Potassium Bromide was the original epilepsy therapy over a hundred years ago. It is still used in Germany as a therapy. Reports from a century ago suggest it has the same effect in autism as Bumetanide. (we saw this in my post on autism history).
As you can see on Wikipedia there is a wide range of GABA agonists, but the only ones that would help in epilepsy and autism would be the ones that can cross the blood brain barrier.
GABAA receptor Agonists
In an earlier post, we looked at the possible use of small doses of AEDs (anti-epileptic drugs). One reader found that tiny dose of Valproate (known to raise GABA) had a positive effect when combines with Bumetanide.
In a recent comment one reader showed the same result by combing picamilon with bumetanide.
Both Picamilon and Valproate are having the effect proposed by the epilepsy researchers.
Potassium Bromide does have known side effects, but the idea of further boosting the effect of Bumetanide is interesting. I have suggested before that this should also be possible using Diamox (Acetazolamide). Diamox does not affect NKCC1 or EGABA, it affects the Cl-/
I did suggest this a long time ago in my posts on the GABAa receptor. I am not the only one to realize this.
NKCC1 and AE3 Appear to Accumulate Chloride in Embryonic Motoneurons
I did suggest this a long time ago in my posts on the GABAa receptor. I am not the only one to realize this.
NKCC1 and AE3 Appear to Accumulate Chloride in Embryonic Motoneurons
Picamilon is well researched Russian drug, sold in other countries as a supplement. It is a modified version of GABA that includes niacin; together it can cross the blood brain barrier (BBB).
So I think a better version of what the epilepsy researchers suggest might be:-
Bumetanide + Diamox + a touch of Picamilon
What would be the effect in autism?