Saturday, December 23, 2017

Amygdala Stimulation in the Absence of Emotional Experience Enhances Memory for Neutral Objects

The amygdala is a small structure located within the medial temporal lobes (MTL), consisting of a discrete set of nuclei. It has a reputation as the “fear center” or “emotion center” of the brain, although it performs multiple functions. One well-known activity of the amygdala, via its connections with other MTL areas, involves an enhancement of memories that are emotional in nature (compared to neutral). Humans and rodents with damaged or inactivated amygdalae fail to show this emotion-related enhancement, although memory for neutral items is relatively preserved (Adolphs et al., 1997; Phelps & Anderson, 1997; McGaugh, 2013).

A new brain stimulation study (Inman et al., 2017) raises interesting questions about the necessity of subjective emotional experience in the memory enhancement effect. A group of 14 refractory epilepsy patients underwent surgery to implant electrodes in the left or right amygdala (and elsewhere) for the sole purpose of monitoring the source of their seizures. In a boon for affiliated research programs everywhere, patients are able to participate in experiments while waiting around for seizures to occur.

The stimulating electrodes were located in or near the basolateral complex of the amygdala (BLA), shown below. The stimulation protocol was developed from similar studies in rats, which demonstrated that direct electrical stimulation of BLA can improve memory for non-emotional events when tested on subsequent days (Bass et al., 2012; 2014; 2015).

Fig. 1A and B (modified from Inman et al., 2017). 
(A) A representative postoperative coronal MRI showing electrode contacts in the amygdala (white square). (B) Illustration of left amygdala with black circles indicating estimated centroids of bipolar stimulation in or near the BLA in all 14 patients. White borders denote right-sided stimulation.

The direct translation from animals to humans is a clear strength of the paper (Inman et al., 2017): activation of the BLA modulated neuronal activity and markers of synaptic plasticity in the hippocampus and perirhinal cortex, two structures important for declarative memory that are directly innervated by the BLA.  ... These and other studies [in animals] have led to the view that an emotional experience engages the amygdala, which in turn enhances memory for that experience through modulation of synaptic plasticity-related processes underlying memory consolidation in other brain regions. This model predicts that direct stimulation of the human amygdala could enhance memory in a manner analogous to emotion’s enhancing effects on long-term memory.

The experimental task was a test of object recognition memory. Pictures of 160 neutral objects were presented on Day 1 while the participants made “indoor” or “outdoor” decisions (which were quite ambiguous in many cases). The purpose of this task was to engage a deep level of semantic encoding of each object, which was presented for 3 seconds. Immediately after stimulus offset for half the items (n=80), a train of electrical stimulation pulses was presented for 1 second (each pulse = 500 μs biphasic square wave; pulse frequency = 50 Hz; train frequency = 8 Hz). For the other half (n=80), no stimulation was presented. Each trial was separated by a 5 second interval.

Fig. 1D (modified from Inman et al., 2017).

An immediate recognition memory test was presented after completion of the study phase. Yes/no decisions were made on 40 old objects with post-stimulation, 40 old objects with no stimulation, and 40 new objects (“foils”). Then 24 hours later, a similar yes/no recognition test was presented, but this time with the other set of items not tested previously, along with a new set of foils. The prediction was that electrical stimulation of the amygdala would act as an artificial “boost” of performance on the 24 hour test, after memory consolidation had occurred.

This prediction was (mostly) supported as shown below, with one caveat I'll explain shortly. In Panel A, a commonly used measure of discrimination performance (d′) is shown for the Immediate and One-Day tests, with red dots indicating stimulation and blue dots no stimulation (one dot per patient). Most participants performed better on stimulated items regardless of whether on the Immediate test or One-Day test, although variability was higher on the Immediate test. Panel B shows a summary of the performance difference for stimulation no stimulation trials. Paired-samples t-tests (two sided) were conducted for each recognition-memory interval. The result for One-Day was significant (p=.003), but the result for Immediate was not (p=.30). This would seem to be convincing evidence that amygdala stimulation during encoding enhanced delayed recognition memory selectively.

Fig. 2A and B (modified from Inman et al., 2017).

HOWEVER, from the statistics presented thus far, we don't know whether the memory enhancement effect was statistically larger for the One-Day test. My guess is not, because an ANOVA showed a main effect of test day (p< 0.001) and a main effect of stimulation (p= 0.03). But no interaction between these variables was reported.

Nonetheless, the study was fascinating because the patients were unable to say whether or not stimulation was delivered in a subsequent test of awareness (10 trials of each condition):
All 14 patients denied subjective awareness of the amygdala stimulation on every trial. In addition, no patient reported emotional responses associated with amygdala stimulation during the stimulation awareness test or during recognition-memory testing. Moreover, similar amygdala-stimulation parameters caused no detectable autonomic changes in patients (n = 7) undergoing stimulation parameter screening.

The take-home message is that subjective and objective indicators of emotion were not necessary for amygdala stimulation during encoding to enhance subsequent recognition of neutral material. “This memory enhancement was accompanied by neuronal oscillations during retrieval that reflected increased interactions between the amygdala, hippocampus, and perirhinal cortex”1 (as had been shown previously in animals).2

So it seems that subjective emotional experience may be an unnecessary epiphenomenon for the boosting effect of emotion in the formation of declarative memories. Or at least in this limited (albeit impressive) laboratory setting. And here I will step aside from being overly critical. Anyone who wants to slam the reproducibility of an n=14 rare patient sample size should be prepared to run the same study with 42 individuals with amygdala depth electrodes.


1 Inman et al., 2017:
For [n = 5 patients] with electrodes localized concurrently in the amygdala, hippocampus, and perirhinal cortex), local field potentials (LFPs) from each region were recorded simultaneously during the immediate and one-day recognition-memory tests... LFP oscillations were apparent in the theta (here 5–7 Hz) and gamma (30–55 Hz) ranges...  ...  Recognition during the one-day test but not during the immediate test exhibited increased power in perirhinal cortex in the gamma frequency range for remembered objects previously followed by stimulation compared with remembered objects without stimulation. Furthermore, LFPs during the one-day test, but not during the immediate test, revealed increased coherence of hippocampal–perirhinal oscillations in the theta frequency range for remembered objects previously followed by stimulation compared with remembered objects without stimulation.

2 If you think the 14 patients with epilepsy were variable, wait until you see the [overly honest] results from even smaller studies with rats.

Fig. S7 (Inman et al., 2017).

Conveniently, Professor Dorothy Bishop has a new blog post on Using simulations to understand the importance of sample size. So yes, sample size matters...


Adolphs R, Cahill L, Schul R, Babinsky R. (1997). Impaired declarative memory for emotional material following bilateral amygdala damage in humans. Learn Mem. 4(3):291-300.

Bass DI, Manns JR. (2015). Memory-enhancing amygdala stimulation elicits gamma synchrony in the hippocampus. Behav Neurosci. 129(3):244-56.

Bass DI, Nizam ZG, Partain KN, Wang A, Manns JR. (2014). Amygdala-mediated enhancement of memory for specific events depends on the hippocampus. Neurobiol Learn Mem. 107:37-41.

Bass DI, Partain KN, Manns JR. (2012). Event-specific enhancement of memory via brief electrical stimulation to the basolateral complex of the amygdala in rats. Behav Neurosci. 126(1):204-8.

Ikegaya Y, Saito H, Abe K. (1996). The basomedial and basolateral amygdaloid nuclei contribute to the induction of long-term potentiation in the dentate gyrus in vivo. Eur J Neurosci. 8(9):1833-9.

Inman CS, Manns JR, Bijanki KR, Bass DI, Hamann S, Drane DL, Fasano RE, Kovach CK, Gross RE, Willie JT. (2017). Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci.  Dec 18. [Epub ahead of print]

McGaugh JL.(2013). Making lasting memories: remembering the significant. Proc Natl Acad Sci 110 Suppl 2:10402-7.

Phelps EA, Anderson AK. (1997). Emotional memory: what does the amygdala do? Curr Biol. 7(5):R311-4.

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At December 23, 2017 4:51 PM, Blogger Unknown said...

Hi Neurocritic! Thank you very much for reviewing our work. I've been a fan of your blog for a long time! In our paper we did both a repeated measures ANOVA to determine whether there was an omnibus effect. Our main statistical test, as done in the previous rat studies, was a planned paired t-test between the stim and no stim conditions for each of test delays (immediate and one-day test). In your opinion, is the planned t-test between each condition during the one-day test sufficient to show this memory enhancement effect specifically for the one-day test? It's a very strong effect according to Cohen's D. Also since we have a relatively small N, we also ran the Non-parametric version of the paired t-test, the Wilcoxon Sign-Rank test with monte carlo simulation (10000 iterations). We didn't report this test in the paper to keep it simple since the paired t-test was sufficient, but it also showed a significant difference between stim and no stim on the one-day test (p<0.003). I'm happy to discuss this more and would appreciate your opinion. Thanks again for reviewing our work on your blog!

At December 23, 2017 6:52 PM, Blogger Unknown said...

Also, thank you for making the point that a sample of 14 is a lot for this rare patient population. I also work on the current DARPA Restoring Active Memory project and through that project we've produced some large sample sizes (>100 patients) and very interesting data, but that is certainly the exception rather than the rule given that that project combines data across 8 epilepsy centers and has cost around 30 million dollars over the past 4 years. Thanks again!

At December 23, 2017 7:05 PM, Blogger Unknown said...

Sorry for another comment, but one other point is that if we control for the baseline variation in memory capacity (as measured by the Rey Auditory Verbal Learning test or other standard neuropsyschological tests of memory capacity) in our repeated measures ANOVA, we do see an interaction of the Stimulation condition and the Test Delay, with stimulation showing enhanced memory relative to no stimulation on the one-day test. This interaction is obscured by the broad variation in baseline memory capacity across our sample, thus we have to covary out that variability.

At December 24, 2017 1:38 AM, Blogger The Neurocritic said...

Cory -- Thanks for your comments. The effect size for the one-day test was certainly large. For assessing the difference between the test delays, I was thinking about these papers: Erroneous analyses of interactions in neuroscience: a problem of significance and The Difference Between “Significant” and “Not Significant” is not Itself Statistically Significant.

The RAM project is definitely ambitious (as one would expect with DARPA). I haven't yet read the 2017 paper in Current Biology, so my year-old post (Bad news for DARPA's RAM program: Electrical Stimulation of Entorhinal Region Impairs Memory) is out of date now.

For the neuropsych data, I did notice the large variation in memory and especially IQ. I'll take a closer look at that.

At December 24, 2017 4:40 AM, Anonymous Paul W. said...


Been following your blog for quite a while too, and I've been waiting for you to take a look at the CurrBiol paper and then you leapfrog straight to Cory? So disappointed ;)


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