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expert reaction to study looking at invasive brain stimulation and memory and recall in people with epilepsy

In a new study, published in Nature Communications, researchers report that stimulating a region of the brain known as the lateral temporal cortex can improve memory.

 

Prof. Thom Baguley, Professor of Experimental Psychology, Nottingham Trent University, said:

“This is an interesting study but I think there are major limitations and some concerns about the robustness of the conclusions to different analyses or modelling assumptions.

“The authors appear broadly to give a good overview of the topic, although I think one could argue that the link to therapeutic interventions is very premature and that the interpretation of the findings on a single study are somewhat optimistic.

“The work has a number of strengths including sample size (n =25) which is higher than many studies in the area, and attempting to control for multiple location and repeated measurements through generalised linear mixed effects models (GLMEs).  However, it is a single study and there are some aspects of the study that are puzzling.  Many of the crucial effects are just under the conventional statistical significance threshold (e.g., p < 0.04) and the GLME tests they report are approximations that may be a little liberal.  More importantly the experimental procedure has a potentially major problem because they only report stimulating trials where predicted probability of recall (using their classifier) was poor (below 50%).  Thus some or all of the effect could be regression to the mean.  As the classifier is imperfect the stimulated trials include many where the true probability of recall is above 50% and therefore some or all improvement could be explained purely by this.  It is possible the authors controlled for this – but this isn’t clear.  One check might be to add the predicted probability from the classifier as a covariate but ideally one would run the study with randomly selected trials.  Arguably the 15% improvement in recall is also a bit misleading.  First, the improvement depends on the probability of recall – so if I had a 50% chance of recall to start with an OR of 1.18 stimulation would give me 54% (a relative improvement of 54/50 = 8%), for 25% recall this would go to 28.2% (13% improvement) and for 10% recall would go to 11.6% (16% improvement).  Relative improvement makes small absolute improvements (around 2% here as the average probability seems to be a bit over 10%) seem bigger.  Second this small study doesn’t estimate the effect very precisely – given that the p value is around 0.05 the true effect could be close to zero or much large.  Overall there is weak evidence of an effect, albeit potentially quite an exciting one.

“It isn’t clear whether they have controlled for the predicted probability of recall – or how effective these controls are if they have.

“In terms of how this fits with existing evidence, based on the literature it would make sense that if you could improve encoding of an item it should improve recall, but there other mechanisms that could explain what is going on.

“To date there is, as I understand it, no substantial evidence that TMS stimulation can translate into useful clinical interventions (as opposed to being a useful laboratory tool or for diagnosis).  This makes me doubtful that this research – even if replicated independently – could translate into a useful therapeutic intervention, though the findings might inform other interventions.

“Any implications for Alzheimer’s are extremely speculative at this stage.  Aside from the difficulties of translating research from laboratory to clinical settings, TMS is rather an unpleasant, noisy thing to administer – so it would not be suitable for many (late stage) patients.”

 

Dr Doug Brown, Chief Policy and Research Officer, Alzheimer’s Society, said:

“This inventive study looked at using electrical stimulation to improve memory in volunteers who were receiving treatment for epilepsy.  As this study didn’t include people who have dementia we don’t know if this technique could overcome the damage caused by disease.  Due to brain cell loss in the memory centres of the brain in Alzheimer’s, it’s possible that there would not be enough healthy brain cells left to stimulate by the time the condition has been diagnosed.

“As the method involves a person’s skull being open during the treatment this would leave the brain vulnerable to damage and infection, suggesting that the risks of this method alone would be likely to limit any real world application.  If this invasive aspect of the technique cannot be refined then this would mean that it would be less useful in older people who are already prone to infection.  Lastly, as the study did not look at whether this method could improve memory in people with damage to their memory centres, caused by injury or disease, we cannot be certain that this treatment could overcome these issues.

“While this is a fascinating step in understanding how the memory centres of the brain work, future research would need to confirm the usefulness of this technique in people who have damage to the memory centres of their brain before it could be considered as a method of treating Alzheimer’s disease.”

 

Dr David Reynolds, Chief Scientific Officer, Alzheimer’s Research UK, said:

“While dementia involves a range of complex symptoms, memory problems are among the most common and can have a devastating impact on many people’s lives.  Brain function depends on electrical as well as chemical signals, and as technology advances, research is beginning to investigate whether direct electrical stimulation of certain areas brain could help improve aspects of memory and thinking.

“In this small study, brain stimulation allowed people with severe epilepsy to better remember and recall lists of words, however none of the participants had dementia.  As this research looks at how well the device works in people with epilepsy, it stimulates a different part of the brain than would typically be targeted in people with Alzheimer’s disease.  Although it’s promising to see tests of this innovative device, which can detect and be trained to recognise areas of brain that may benefit from further stimulation, we cannot yet say whether it will benefit people living with dementia.

“Ways to improve memory and thinking skills is a key goal in dementia research, but it has now been over 15 years since researchers developed a new drug that is able to do this.  It is crucial that we see continued investment in dementia research so that scientists are able to evaluate and realise the clinical potential of interesting new findings like this.”

 

Prof Dame Til Wykes, Professor of Clinical Psychology & Rehabilitation and Vice Dean of Psychology and Systems Sciences, Institute of Psychiatry Psychology & Neuroscience, King’s College London, said:

“Brain stimulation produced a slight improvement in recall of a word list in a relatively small group of people who had a diagnosis of drug resistant epilepsy.  Despite this small improvement its use as a potential treatment is limited, although it has shed light on potential brain memory mechanisms.  But people use all sorts of strategies to remember everyday activities – perhaps using smartphones and calendars are a better bet for those of us who have to balance our complex lives and get all the important things done.”

 

Prof. Roi Cohen Kadosh, Professor of Cognitive Neuroscience, University of Oxford, said:

“This is a well-designed study that provides convincing results about the potential to improve memory using invasive brain stimulation and a closed-loop approach.  The sample size is not very high, but that can be attributed to the relative difficulties in having participants who have the required condition to justify intracranial EEG and invasive brain stimulation.  The results, while exciting, do not at this stage have therapeutic implications and would need to be replicated in clinical populations such as Alzheimer’s disease.  Whether this could be found using non-invasive, rather than invasive, brain stimulation techniques is an open question that deserves further research.”

 

* ‘Closed-loop stimulation of temporal cortex rescues functional networks and improves memory’ by Youssef Ezzyat et al. will be published in Nature Communications on Tuesday 6 February 2018.

 

Declared interests

Prof. Thom Baguley: “I don’t work directly in this area so I’m not aware of any conflict from my other work or funding.”

Dr David Reynolds: “No conflicts of interest to declare.”

Prof Dame Til Wykes: “I have no competing interests.”

None others received.

 

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