The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain – A detailed case report

Abstract

We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting, evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy, in particular the subtype of Transient Epileptic Amnesia. The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia persisted. This exceptional case highlights the occurrence of 'non-standard' forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in 'epileptic amnesia'.Dear Professor Gilboa, Thank you for your comments on our paper, and for the reviews, which we found stimulating and helpful .We were glad that you found the paper 'of great value' overall.We have done as you suggested, resubmitting as a regular manuscript, as we found that dealing with the points raised by the reviewers required some additions to the main text of the paper and to the reference list.We decided to leave the description of the control experiment alluded to in the Results (section 3.3, final sentence) in the Supplementary data, as we felt that its inclusion in the main text of the paper was unnecessary. If you disagree, however, we would of course be happy to move it into the main text.We could supply a version of the paper with all changes 'tracked' if you wish.We hope that you now find the paper acceptable for publication. In these responses, for ease of navigation, we have left the reviewers' original remarks in plain text, have italicised our responses and have highlighted the resulting changes to the text:Reviewer #1: In this manuscript (MS) an interesting case of a 52 year old woman is described who showed a complex symptomatology of memory impairments which were attributed to her treatment with intrathecal baclofen for spasticity. While the paper is well-written in general, I have several concerns and comments, which I am going to outline below.The results are in my eyes not as straight-forward as the authors interpret them. I would therefore recommend that the authors devote some more room to discussing other possible interpretations.a) Although the control participants were matched to CS (the patient) with respect to "age, education and performance on standard psychometric tests" the question is whether baclofen (additionally) affected other functions than memory. In particular one would like to know if it impacted on attention and concentration, motivation (to be tested), mood (depression?), and executive functions. There were no significant differences between CS and control participants on standard measur...

External details revisited – A new taxonomy for coding ‘non‐episodic’ content during autobiographical memory retrieval

“…Instead, many studies default to reporting only the total external details metric without considering their constituent elements in more detail (e.g., Benjamin, Cifelli, Garrard, Caine, & Jones, 2015;Spreng et al, 2018), with others reporting only selective subcategories (e.g., Mair, Poirier, & Conway, 2017;Rensen et al, 2017), or failing to examine external details entirely (e.g., Baron & Bluck, 2009;Crete-Nishihata et al, 2012). In addition to the inconsistent reporting of external details, a common tendency to consider the aggregated external details category as uniformly 'semantic' pervades the literature (e.g., Ally, Hussey, & Donahue, 2013;Zeman et al, 2016). While no such claim was made in the original AI validation study (Levine et al, 2002), findings that elevated external details in healthy older adults are primarily driven by increased semantic information (e.g., Levine et al, 2002;St.…”

The evolution of accelerated long-term forgetting: Evidence from the TIME study

“…In our second study, we investigated the prognosis of ALF and ABM in a case of Baclofen-induced memory disturbance. A full description of the case history and original study can be found in Zeman et al (2016) . A summary is provided below.…”

“…By conducting a series of tailored memory experiments, we clearly documented the presence of ALF while CS was ON baclofen (in 2012) and the cessation of ALF after CS withdrew from Baclofen (i.e. OFF baclofen, in 2013) ( Zeman et al, 2016 ). Despite remission of her ALF, CS’s ability to retain recent autobiographical events remained impaired.…”

“…ALF has been shown to result from treatment with baclofen in a recently described case (patient CS) of a medication induced TEA-like syndrome ( Zeman et al, 2016 ), with resolution on drug withdrawal. Baclofen is a GABA B receptor agonist which modulates neural plasticity and memory in animals, but has, to date, received little investigation in humans.…”

“…While Zeman et al (2016) provide a first insight into the ALF caused by a GABA B receptor agonist, further investigation is needed to determine the longer-term outcome in such cases. Specifically, has CS remained free of ALF following cessation of baclofen, and if so, has a stable, ALF-free environment allowed for improvements in autobiographical memory for recent events?…”