Monday, May 21, 2018

What counts as "memory" and who gets to define it?

Do Plants Have “Memory”?

A new paper by Bédécarrats et al. (2018) is the latest entry into the iconoclastic hullabaloo claiming a non-synaptic basis for learning and memory. In short, “RNA extracted from the central nervous system of Aplysia given long-term sensitization training induced sensitization when injected into untrained animals...” The results support the minority view that long-term memory is not encoded by synaptic strength, according to the authors, but instead by molecules inside cells (à la Randy Gallistel).

Adam Calhoun has a nice summary of the paper at Neuroecology:
...there is a particular reflex 1 (memory) that changes when they [Aplysia] have experienced a lot of shocks. How memory is encoded is a bit debated but one strongly-supported mechanism (especially in these snails) is that there are changes in the amount of particular proteins that are expressed in some neurons. These proteins might make more of one channel or receptor that makes it more or less likely to respond to signals from other neurons. So for instance, when a snail receives its first shock a neuron responds and it withdraws its gills. Over time, each shock builds up more proteins that make the neuron respond more and more. These proteins are built up by the amount of RNA (the “blueprint” for the proteins, if you will) that are located in the vicinity of the neuron that can receive this information.  ...

This new paper shows that in these snails, you can just dump the RNA on these neurons from someone else and the RNA has already encoded something about the type of protein it will produce.

Neuroskeptic has a more contentious take on the study, casting doubt on the notion that sensitization of a simple reflex to any noxious stimulus (a form of non-associative “learning”) produces “memories” as we typically think of them. But senior author Dr. David Glanzman tolerated none of this, and expressed strong disagreement in the comments:
“I’m afraid you have a fundamental misconception of what memory is. We claim that our experiments demonstrate transfer of the memory—or essential components of the memory—for sensitization. Now, although sensitization may not comport with the common notion of memory—it’s not like the memory of my Midwestern grandmother’s superb blueberry pies, for example—it nevertheless has unambiguous status as memory.  ...  [didactic lesson continues] ...  We do not claim in our paper that declarative memories—such as my memory of my grandmother’s blueberry pies—or even simpler forms of associative memories like those induced during classical conditioning—can be transferred by RNA. That remains to be seen.”

OK, so Glanzman gets to define what memory is. But later on he's caught in a trap and has to admit:
“Of course, there are many phenomena that can be loosely regarded as memory—the crease in folded paper, for example, can be said to represent the memory of a physical action.”

That was in response to who said:
“So a transfer of RNA that activates a cellular mechanism associated with touch isn't memory, but rather just exogenously turning on a cellular pathway. By that logic, gene therapy to treat sickle cell anemia changes blood "memory".” 2

However, my favorite comment was from Smut Clyde:
“Kandel set the precedent that reflexes in Aplysia are "memories", and now we're stuck with it.”

This reminded me of Dr. Kandel's bold [outlandish?] attempt to link psychoanalysis, Aplysia withdrawal reflexes, and human anxiety (Kandel, 1983). I was a bit flabbergasted that gill withdrawal in a sea slug was considered “mentation” (thought) and could support Freudian views.3
In the past, ascribing a particular behavioral feature to an unobservable mental process essentially excluded the problem from direct biological study because the complexity of the brain posed a barrier to any complementary biological analysis. But the nervous systems of invertebrates are quite accessible to a cellular analysis of behavior, including certain internal representations of environmental experiences that can now be explored in detail; This encourages the belief that elements of cognitive mentation relevant to humans and related to psychoanalytic theory can be explored directly [in Aplysia] and need no longer be merely inferred.

- click on image for a larger view -

So anticipatory anxiety in humans is isomorphic to invertebrate responses in a classical aversive conditioning paradigm, and chronic anxiety is recreated by long-term sensitization paradigms. Perhaps I missed the translational advances here, and any application to Psychoanalytic and Neuropsychoanalytic practice that has been fully realized.

If we want to accept a flexible definition of learning and memory in animals, why not consider associative learning experiments in pea plants, where a neutral cue predicting the location of a light source had a greater effect on the direction of plant growth than innate phototropism (Gagliano et al., 2016)? Or review the literature on associative and non-associative learning in Mimosa? (Abramson & Chicas-Mosier, 2016). Or evaluate the field of ‘plant neurobiology’ and even the ‘Philosophy of Plant Neurobiology’ (Calvo, 2016). Or are the possibilities of chloroplast-based consciousness and “mentation” without neurons too threatening (or too fringe)?

But in the end, we know we've reached peak plant cognition when a predictive coding model appears — Predicting green: really radical (plant) predictive processing (Calvo & Friston, 2017).

Further Reading

The Big Ideas in Cognitive Neuroscience, Explained (especially the sections on Gallistel and Ryan)

What are the Big Ideas in Cognitive Neuroscience? (you can watch the videos of their 2017 CNS talks)


1 edited to indicate my emphasis on reflex more specifically, the gill withdrawal reflex in Aplysia which can only go so far as a model of other forms of memory, in my view.

Another skeptic (but for different reasons) is Dr. Tomás Ryan, who was paraphrased in Scientific American:
But [Ryan] doesn’t think the behavior of the snails, or the cells, proves that RNA is transferring memories. He said he doesn’t understand how RNA, which works on a time scale of minutes to hours, could be causing memory recall that is almost instantaneous, or how RNA could connect numerous parts of the brain, like the auditory and visual systems, that are involved in more complex memories.

3 But I haven't won the Nobel Prize, so what do I know?


Abramson CI, Chicas-Mosier AM. (2016). Learning in plants: lessons from Mimosa pudica. Frontiers in psychology Mar 31;7:417.

Bédécarrats A, Chen S, Pearce K, Cai D, Glanzman DL. (2018). RNA from Trained Aplysia Can Induce an Epigenetic Engram for Long-Term Sensitization in Untrained Aplysia. eNeuro. May 14:ENEURO-0038.

Calvo P. (2016). The philosophy of plant neurobiology: a manifesto. Synthese 193(5):1323-43.

Calvo P, Friston K. Predicting green: really radical (plant) predictive processing. Journal of The Royal Society Interface. 14(131):20170096.

Gagliano M, Vyazovskiy VV, Borbély AA, Grimonprez M, Depczynski M. (2016). Learning by association in plants. Scientific Reports Dec 2;6:38427.

Kandel ER. (1983). From metapsychology to molecular biology: explorations into the nature of anxiety. Am J Psychiatry 140(10):1277-93.

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Sunday, May 13, 2018

“My family say they grieve for the old me” – profound personality changes after deep brain stimulation

Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease (PD) has been highly successful in controlling the motor symptoms of this disorder, which include tremor, slowed movement (akinesia), and muscle stiffness or rigidity. The figure above shows the electrode implantation procedure for PD, where a stimulating electrode is placed in either the subthalamic nucleus, (STN), a tiny collection of neurons within the basal ganglia circuit, or in the internal segment of the globus pallidus, another structure in the basal ganglia (Okun, 2012). DBS of the STN is more common, and more often a source of disturbing non-motor side effects.

In brief, DBS of the STN alters neural activity patterns in complex cortico-basal-ganglia-thalamo-cortical networks (McIntyre & Hahn, 2010).

DBS surgery may be recommended for some patients in whom dopamine (DA) replacement therapy has become ineffective, usually after a few years. DA medications include the classic DA precursor L-DOPA, followed by DA agonists such as pramipexole, ropinirole, and bromocriptine. But unfortunately, impulse control disorders (ICDs, e.g., compulsive shopping, excessive gambling, binge eating, and compulsive sexual behavior) occur in about 17% of PD patients on DA agonists (Voon et al., 2017).

There are many first-person accounts from PD patients who describe uncharacteristic and embarrassing behavior after taking DA agonists, like this grandpa who started seeing prostitutes for the first time in his life:
'I have become an embarrassment'

For most of his life John Smithers was a respected family man who ran a successful business. Then he started paying for sex. Now, in his 70s, he explains how his behaviour has left him broke, alone and tormented

I am 70 years old and used to be respectable. I was a magistrate for 25 years, and worked hard to feed my children and build up the family business. I was not the most faithful of husbands, but I tried to be discreet about my affairs.1 Now I seem to be a liability. Over the last two decades I have spent a fortune on prostitutes and lost two wives. I have made irrational business decisions that took me to the point of bankruptcy. I have become an embarrassment to my nearest and dearest.

Also reports like: Drug 'led patients to gamble'.

New-onset ICDs can also occur in patients receiving STN DBS, but the effects are mixed across the entire population: ICD symptoms can also improve or remain unchanged. Why this is the case is a vexing problem that includes premorbid personality, genetics, family history, past and present addictions, and demographic factors (Weintraub & Claassen).

- click on image for a larger view -

Neuroethicists are weighing in on the potential side effects of DBS that may alter a patient's perception of identity and self. A recent paper included a first-person account of altered personality and a sense of self-estrangement in a 46 year old woman undergoing STN DBS for PD (Gilbert & Viaña, 2018):
The patient reported a persistent state of self-perceived changes following implantation. More than one year after surgery, her narratives explicitly refer to a persistent perception of strangeness and alteration of her concept of self. For instance, she reported:
"can't be the real me anymore—I can't pretend . . . I think that I felt that the person that I have been [since the intervention] was somehow observing somebody else, but it wasn't me. . . . I feel like I am who I am now. But it's not the me that went into the surgery that time. . . . My family say they grieve for the old [me]. . . ."

Many of her quotes are striking in their similarity to behaviors that occur in the manic phase of bipolar disorder {loss of control, grandiosity}:
The patient also reported developing severe postoperative impulsivity: "I cannot control the impulse to go off if I'm angry." In parallel, while describing a sense of loss of control over some impulsions, she has also recognized that DBS gave her increased feelings of strength: "I never had felt this lack of power or this giving of power—until I had deep brain stimulation."

{also uncharacteristic sexual urges and hypersexuality; excessively energetic; compulsive shopping}:
...she experienced radically enhanced capacities, in the form of increased uncontrollable sexual urges:
"I know this is a bit embarrassing. But I had 35 staples in my head, and we made love in the hospital bathroom and that wasn't just me. It was just I had felt more sexual with the surgery than without."
And greater physical energy:
"I remember about a week after the surgery, I still had the 35 staples in my head and I was just starting to enter the cooler months of winter but my kids had got me winter clothes so I had nothing to wear to the follow up appointment and when I went back there of the morning, I thought "I can walk into the doctor's" even though it was 5 kilometers into town. It's like the psychologist said: "For a woman who had a very invasive brain surgery 9 days ago and you've just almost walked 10 kilometers." And on the way, I stopped and bought a very uncharacteristic dress, backless—completely different to what I usually do."

Examining the DSM-5 criteria for bipolar mania, it seems clear (to me, at least) that the patient is indeed having a prolonged manic episode induced by STN DBS.
In order for a manic episode to be diagnosed, three (3) or more of the following symptoms must be present:
  • Inflated self-esteem or grandiosity
  • Decreased need for sleep (e.g., one feels rested after only 3 hours of sleep)
  • More talkative than usual or pressure to keep talking
  • Flight of ideas or subjective experience that thoughts are racing
  • Attention is easily drawn to unimportant or irrelevant items
  • Increase in goal-directed activity (either socially, at work or school; or sexually) or psychomotor agitation
  • Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

It's also notable that she divorced her husband, moved to another state, ruptured the therapeutic relationship with her neurologist and surgical team, and made a suicide attempt. She also took up painting and perceived the world in a more vibrant, colorful way {which resembles narratives of persons experiencing manic episodes}:
"I don't know, all the senses came alive. I wanted to listen to Paul Kelly and all of my favorite music really loud in the toilet. And you know, also everything was colourful. . . . Well, since brain surgery I can. I didn't bother before. I can see the light . . . the light that is underlying every masterpiece in photography. . . . I've seen it like I've never seen it before . . . I am a totally different person. I like it that I love photography and music and colourful clothes, but where is the old me now?"

However, she appears to display more insight into her altered behavior than {most} people in the midst of bipolar mania. Perhaps her reality monitoring abilities are more intact? Or it's because her symptoms wax and wane.2 But like in many manic individuals, she did not want this feeling to stop:
"I went to the psychiatrist, and he said, 'Right, well, this is bordering on mania [NOTE: that is an understatement], you need to turn the settings right down to manage it.' I said to him, 'Please don't, this is not over the top—this is just joy.' "

I think this line of research studying individuals with Parkinson's who have impulse control disorders due to DA replacement or DBS   can provide insight into bipolar mania. Certainly, drugs that act as antagonists at multiple DA receptor subtypes (typical and atypical antipsychotics) are used in the management of bipolar disorder.

Patient narratives are also informative in this regard, and provide critical information for individuals considering various types of therapies for PD. In this paper, the patient was not informed by the medical team that there could be undesirable psychiatric side effects. She has taken legal action against the lead neurosurgeon, and the proceedings were ongoing when the article was written.

ADDENDUM (May 14 2018): The study was conducted in accordance with Human Research Ethics Committee regulations. The patient provided consent to have her narratives included in publications on neuropsychiatric side effects of DBS for PD.


1 One might wonder whether Mr. Smithers' premorbid propensity for affairs made him more vulnerable for compulsive sexual activity after DA agonists. And that is one consideration displayed in the box and circle diagram above.

2 She did experience bouts of depression as well as mania, perhaps related to the stimulation parameters and precise location. And bipolar individuals also gain insight once the manic episode subsides.


Gilbert F, Viaña JN. (2018). A Personal Narrative on Living and Dealing with Psychiatric Symptoms after DBS Surgery. Narrat Inq Bioeth. 8(1):67-77.

McIntyre CC, Hahn PJ. (2010). Network perspectives on the mechanisms of deep brain stimulation. Neurobiol Dis. 38(3):329-37.

Voon V, Napier TC, Frank MJ, Sgambato-Faure V, Grace AA, Rodriguez-Oroz M, Obeso J, Bezard E, Fernagut PO. (2017). Impulse control disorders and levodopa-induceddyskinesias in Parkinson's disease: an updateLancet Neurol. 16(3):238-250.

Weintraub D, Claassen DO. (2017). Impulse Control and Related Disorders in Parkinson's Disease. Int Rev Neurobiol. 133:679-717.

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