Can improving episodic memory make you a better writer?
Galantamine Can Help You
Write Your Story

And make retrieval of what has
made you who you are easier

By Will Block

Tell me a story, tell me a story
Tell me a story, remember what you said …

—  “Tell Me a Story,” Frankie Laine (1953)

E pisodic memory recounts the memory of autobiographical events, including sensory details such as emotions, sights, and sounds. It also takes time, place, and other contextual remembrances into consideration — who, what, when, where, and why knowledge — that can be explicitly stated. Episodic memory is the collection of past personal experiences that occurred at a particular time and place. This seems like a highly desirable experience — remembering key episodes of your life — doesn’t it?

Exercising Memory Is a Truly Great and Liberating Experience

Of course, episodic memory represents a unique personal memory of a specific event, dissociated from anyone else’s recall. Thus, it is important to distinguish episodic memory from something known as autobiographical memory, which takes a larger cast, part of which involves episodic memory. That larger embrace also takes semantic memory into consideration, which includes details without specific memories, e.g., knowing the city where you were born without the specific memories of being born. To paraphrase what has been said elsewhere, telling your story is a big relief. And, it should be added, a truly great and liberating experience!

My Hair Flying in the Wind and My Spirit Soaring

A few years ago, I recounted the story of a dear friend of mine, who used her knowledge of the past to write her autobiography, and because she knows me well, she was taking galantamine at the time. Her recall of ecstatic episodes of her life was self-confident and glistened with credibility. The finished product was magnificent (see “Improve Episodic Memory” in the July 2009 issue of Life Enhancement magazine; the above subhead is from Chapter I of her book).

Remember Before You Forget

Figure 1. A simplified diagram showing how galantamine’s biological effects lead to significant protection for neurons of the brain’s cholinergic system. Galantamine’s strong stimulation of nicotinic acetylcholine receptors — the α7 subunit in particular — sets it apart from other anti-Alzheimer’s agents and makes it effective in providing long-term treatment in mild to moderate cases of this disease.
LEM1502GMFig1_274.gif
(click on thumbnail for full sized image)

An early indicator of Alzheimer’s disease (AD) is the impairment of hippocampus-based episodic memory function. This weakening of memory may be thwarted, in part, through reversing the decline of cholinergic neurotransmission. Supporting this, a number of studies have found that activation of the α7 nicotinic receptor (nAChR) — a type of nicotinic acetylcholine receptor implicated in long-term memory — constitutes a beneficial therapy for the cognitive impairments associated with the initial appearance of AD. This is explained by the fact that nAChRs are expressed by basal forebrain cholinergic protection neurons, as well as by their targets in the hippocampus.1 Because galantamine is an activator of nAChRs, its use to preserve, recover, and enhance episodic memory is thought to follow (see Fig. 1). Here is the evidence.


At the end of the study,
significant reductions in reaction time
were seen in the test of episodic
memory for faces.


Galantamine Improves Episodic Memory

In a study published 10 years age, researchers investigated the effects of galantamine on the performance of patients with mild to moderate AD in a computerized neuropsychological test battery (CNTB).2 Twenty-nine patients with probable AD were treated with galantamine for three months and evaluated in a prospective, open-label, multi-center study. The CNTB and the ADAS-Cog* were administered at baseline and after 12 weeks. The CNTB includes reaction time tests to evaluate attention, and implicit and episodic memory for faces and words. Statistical comparisons were performed between the results in week 12 versus baseline.


* The Alzheimer’s Disease Assessment Scale-Cognitive Subscale test is one of the most frequently used tests to measure cognition in clinical trials. It’s more thorough than the Mini Mental State Exam, and it primarily measures language and memory. ADAS-Cog consists of 11 parts and takes approximately 30 minutes to administer.


The Faces of Episodic Memory

Each patient was treated with galantamine doses of either 24 mg  /  day (n=22) or 16 mg / day (n=7). At the end of the study, significant reductions in reaction time were seen in the test of episodic memory for faces and in the test of two-choice reaction time of the CNTB. Treatment with galantamine produced improvement in computerized tests of attention and episodic memory, leading to statistically significant reduction in the reaction times.

Galantamine Produces Episodic Brain Activation

Figure 2. Episodic face-encoding task: left prefrontal areas, the anterior cingulate gyrus, left occipital areas, and left posterior hippocampus. For working memory: right precuneus and right middle frontal gyrus.
LEM1502GMFig2_274.jpg
(click on thumbnail for full sized image)

The same year, a study examining the effects of galantamine on mild cognitive impairment (MCI) subjects was published.3 MCI represents a gradual incremental loss of cognitive function, along with an increased risk for developing Alzheimer’s disease. In both MCI and AD, distinctive cholinergic changes may occur. In this study, MCI patients (n=28; mean age 73.6+ /  – 7.5; mini mental state examination (MMSE) 27.0+ /  – 1.2) were scanned with functional magnetic resonance imaging (fMRI). This was done during task performance in a randomized trial using three different galantamine regimes: at baseline after no galantamine, after a single oral dose of galantamine and after prolonged exposure to galantamine. The memory tasks included an episodic face-encoding task and a working memory task. Significant increases in brain activation from galantamine were observed after prolonged exposure only. These involved left prefrontal areas, the anterior cingulate gyrus, left occipital areas, and left posterior hippocampus (see Fig. 2).


Enhancing the cholinergic system
with galantamine produces
episodic brain activation patterns in
elderly MCI patients.


For working memory, increased activation was found in the right precuneus and right middle frontal gyrus, coinciding with increased accuracy scores after galantamine treatment. Enhancing the cholinergic system with galantamine produces episodic brain activation patterns in elderly MCI patients.

Depression Suppresses Autobiographical Memory

Low-dose acute tryptophan depletion (LD-ATD), while having no effect on mood, has been shown to diminish autobiographical memory in patients who have recovered from a depressive episode. A recent study set out to determine more about this.1

Nineteen healthy young adults with at least one first-degree relative with a history of major depression were given LD-ATD drinks containing 1.15 g of tryptophan or no tryptophan on two separate occasions, in a double blind random order crossover design.

The Autobiographical Memory Test was given 5 hours after drink administration, and analysis revealed a significant difference in the effects of LD-ATD drinks on plasma free tryptophan with no mood change with either drink. Despite that, the results were similar to those following recovery from depression. LD-ATD can reduce autobiographical memory in the absence of lowered mood in healthy individuals with a strong family history of depression.

In another study,2 depressed patients performed poorly on tests of autobiographical memory specificity (AMS). This may have negative consequences for other important cognitive abilities, and delays recovery from mood episodes. Also, in recovered patients, these downturns may mediate vulnerability to future episodes.


Tryptophan depletion also reduced
autobiographical memory specificity
in response to negative cue words.


According to the researchers, while the cognitive mechanisms underlying AMS deficits are beginning to be understood, the neurobiological mechanisms remain unclear. Serotonin is implicated in both depression and long-term memory. Therefore, temporary lowering of brain serotonin function via acute tryptophan depletion offers a means of studying the role of serotonin in autobiographical memory specificity.

In this study, 24 previously depressed women underwent low-dose ATD or sham depletion and then completed tests of initial and delayed memory, recollection- and familiarity-based recognition, and AMS.

ATD did not differentially affect state mood, but compared with sham depletion, ATD impaired immediate recall on the Auditory Verbal Learning Test. Although ATD did not differentially impair recollection- and familiarity-based recognition, it did slow recognition of positive words. ATD also reduced autobiographical memory specificity in response to negative cue words.

The results confirm previous findings (see ref. #1) that low-dose ATD can reinstate depression biases in cognition without causing depressive mood in vulnerable populations. The ATD-induced reduction in memory specificity suggests that serotonergic dysfunction may mediate depressive deficits in autobiographical memory. Rather than looking at tryptophan depletion, we think a more positive approach would be reasonable repletion of serotonin via a 5-HTP or tryptophan supplement.

References

  1. Alhaj HA1, Selman M, Jervis V, Rodgers J, Barton S, McAllister-Williams R. Effect of low-dose acute tryptophan depletion on the specificity of autobiographical memory in healthy subjects with a family history of depression. Psychopharmacology (Berl). 2012 Jul;222(2):285 – 92.
  2. Haddad AD1, Williams JM, McTavish SF, Harmer CJ. Low-dose tryptophan depletion in recovered depressed women induces impairments in autobiographical memory specificity. Psychopharmacology (Berl). 2009 Dec;207(3):499 – 508. doi: 10.1007 / s00213 – 009 – 1693 – 2.

­Galantamine Enhances Late Episodic Learning and Delayed Recall

Two years later, another MCI study noted that the chief complaint and diagnostic criterion of such subjects is memory failure.4 The researchers hypothesized that cholinergic malfunction may underlie memory impairment in MCI and applied a low dosage of an acetylcholinesterase inhibitor and modulator of nicotinic acetylcholine receptors, galantamine (4 mg twice per day), for 7 days. Neuropsychological tests were used to investigate attention, cognitive flexibility, verbal and visual short-term and working memory, susceptibility to interference and episodic memory, and fMRI to assess spatial navigation both prior to and after treatment.


Late episodic learning and delayed
recall improved with galantamine as
did involvement of the hippocampal
region during spatial navigation.


Late episodic learning and delayed recall improved with galantamine as did involvement of the hippocampal region during spatial navigation. The research showed that an increase of cholinergic neurotransmission in subjects with MCI specifically improves hippocampal function and thus that a cholinergic deficit is functionally relevant in subjects with MCI. Malfunction of the cholinergic system may be tackled pharmacologically via the inhibition of acetylcholinesterase, such as with galantamine, even when the impairment is slight.

Late episodic learning and delayed recall improved on treatment with 4 mg of galantamine twice per day for seven days.

Galantamine Bolsters Episodic Memory

Episodic memory is impaired in several neuropsychiatric disorders. The object recognition task (ORT) is a method to measure a specific form of episodic memory in rats and mice.5 It is based on the spontaneous behavior of rodents and can be considered as a retention test completely free of reference memory components. Consequently, the ORT has been increasingly used as an experimental tool to assess drug effects on memory and to investigate the neural mechanisms underlying learning and memory.

In a study employing ORT,5 the principal goal was to evaluate the effects of galantamine in mice with scopolamine-induced memory deficits and with different retention intervals. At the 15 minutes retention interval, the mice had good object recognition memory. However, object discrimination had disappeared at the longer intervals (1 hour, 4 hours, and 24 hours).


Late episodic learning and delayed
recall improved with
4 mg of galantamine twice per day
for seven days.


Galantamine (10 mg / kg), administered 30 minutes prior to induced-memory deficits, partially reversed the effects of scopolamine and normalized performance to control levels. A lower dose of galantamine (0.63 mg / kg) was also investigated with two different retention intervals (15 minutes and 1 hour). Galantamine, even at the low dose, enabled the mice to attain significant object recognition memory performance. Galantamine was shown to possess memory-enhancing effects in two conditions that reduced object discrimination: scopolamine-induced deficits and when a longer retention interval was used. This measurement of a specific form of episodic memory showed that galantamine enhanced object recognition memory performance and thus imparted memory-enhancing effects in two conditions that involve loss of episodic memory.

Galantamine Benefits Episodic Memory in Bipolar Patients

There is increasing evidence that cognitive impairment is common in patients with bipolar disorder.6 The purpose of a study published in 2009 was to determine whether galantamine augmentation improved cognition in patients with euthymic bipolar disorder.

Using a randomized double-blind, placebo-controlled, parallel design, researchers examined the impact of galantamine on cognition and other clinical measures in 30 patients during the course of 3 months. Sixteen subjects who completed baseline and follow-up second neuropsychological testing were evaluable (10 with galantamine and 6 with placebo).

Episodic memory performance was improved in the galantamine treatment group but not in the placebo group. Galantamine may thus have specific benefits for episodic memory, but not processing speed, in patients with cognitive impairment as part of bipolar disorder.


Galantamine enhanced object
recognition memory performance and
thus imparted memory-enhancing
effects in two conditions that involve
loss of episodic memory.


Galantamine Reduces Episodic Memory Deficits

Several studies have shown that administration of amyloid-beta (Aβ) into the brain causes some of the pathological events observed in AD.7 However, the validity of these models has not been fully examined. Consequently, in a recent study7 researchers injected AD model mice with Aβ, which caused significant impaired memory acquisition, but not memory retrieval. This implies similarity to the episodic anterograde memory (a loss of the ability to create new memories) deficit observed in the early stage of AD.

Assessment showed that the Aβ burden significantly reduced hippocampal long-term potentiation. However, galantamine significantly improved cognitive dysfunction in the model used. Galantamine improved the type of memory dysfunction similar to the episodic memory deficit observed in the early stage of AD, the loss of the ability to create new memories.

Muscular Support for Writing

Muscle memory can be described as gradual adaptation of muscles over a period of time to perform a new movement or action. While its precise mechanism is unknown, what is now known is that when a motor skill is learned it leads to significant brain activity.1 Astrocytes are the most abundant glial cell types in the CNS and play an active role with neurons in learning and memory.

Astrocytes are interconnected to neurons via gap junctions forming astroglial network for fast communication and synchronization. Researchers hypothesized that astroglial cells play main roles in the formation of muscle memory, and they evaluated it by experimental evidence that indicates the mechanisms of astroglia on various cellular and molecular aspects of muscle memory. The basis of their hypothesis is that during training or motor learning periods, neuronal output data related to learning lead to certain specific patterns for stimulating target muscles over a period of time, and these data are stored in the astroglial network.

These stored data fine-tune glial parameters that affect synaptic space and neuronal output and are used to perform rapid motor actions. Scientists generated a computational model for a section of a neural pathway with an astroglial network. By using inhibitory and stimulatory neurotransmitters, they showed that the astroglial network can generate certain patterns and modulate and balance synaptic space across the neural pathway during the acquisition of muscle memory. In its earlier traditional uses, galantamine had been shown to operate as an anesthetic to reverse neuromuscular paralysis as a muscle relaxant.2 Also, see “Galantamine Preserves Muscles” in the July 2014 issue.

Taurine’s Neuroprotective Properties

Alzheimer’s disease (AD) is a lethal progressive neurological disorder affecting memory. Recently, US Food and Drug Administration lessened the standard for drug approval, allowing symptomatic drugs that only improve cognitive deficits to be allowed to accelerate on to clinical trials (this is uncharacteristic of that agency!).

In a new study,3 Korean researchers focused on taurine, an amino acid found in high concentrations in humans. Nevertheless, other research has demonstrated taurine’s neuroprotective properties against many forms of dementia. In this study, the cognitive-enhancing properties of taurine in a mouse model of AD were assessed.

After 6 weeks of administration, the taurine treated mice demonstrated rescued cognitive deficits in terms of Y-maze and passive avoidance tests. In the cortex of the mice, taurine slightly decreased insoluble fraction of Aβ. While the exact mechanism of taurine in AD has not yet been determined, the results suggest that taurine can aid cognitive impairment and may inhibit Aβ-related damages.

References

  1. Hassanpoor H1, Fallah A, Raza M. New role for astroglia in learning: formation of muscle memory. Med Hypotheses. 2012 Dec;79(6):770 – 3.
  2. 2. Harvey AL. The pharmacology of galanthamine and its analogues. Pharmacol Ther. 1995;68(1):113 – 28. Review.
  3. 3. Kim HY, Kim HV, Yoon JH, Kang BR, Cho SM, Lee S, Kim JY2, Kim JW, Cho Y, Woo J, Kim Y. Taurine in drinking water recovers learning and memory in the adult APP / PS1 mouse model of Alzheimer’s disease. Sci Rep. 2014 Dec 12;4:7467. doi: 10.1038 / srep07467.

Galantamine Promotes Verbal Episodic Memory

Many subjects with bipolar disorder experience significant cognitive dysfunction, even when euthymic — a normal non-depressed, reasonably positive mood. Yet, few studies assess biological correlates of or treatment strategies for cognitive dysfunction.8

Nineteen subjects with bipolar disorder in remission, who reported subjective cognitive deficits, were treated with open-label galantamine 8 – 24 mg / day for 4 months.8 The galantamine used was an extended release version. Ten healthy volunteers matched for age and gender were also assessed and mood and subjective cognitive questionnaires were administered monthly for both groups. Neuropsychological tests, including tests of attention and episodic memory were also employed.


Episodic memory performance
was improved in the galantamine
treatment group but not in
the placebo group.


Compared to healthy volunteers, bipolar subjects had higher baseline subjective cognitive deficits and lower scores on objective tests of attention and verbal episodic memory. But after galantamine, bipolar subjects were found to improve by all measures. Galantamine was associated with improved cognition and with increases in neuronal viability and normalization of lipid membrane metabolism in the left hippocampus. After treatment with galantamine, bipolar subjects experienced significant improvement of subjective cognitive scores and on objective tests of attention and verbal episodic memory. In the left hippocampus, a measure of neuronal viability increased.


Galantamine improved the type of
memory dysfunction similar to the
episodic memory deficit observed in
the early stage of AD, the loss of the
ability to create new memories.


Episodic Memory Paves the Way for Other Enhancements

A new analysis aimed to identify factors for predicting long-term outcome of galantamine treatment.9 Analyses were conducted with data from a 24 weeks randomized, double-blind, placebo controlled trial to evaluate the efficacy and the safety of galantamine in the treatment of 303 patients with mild to moderate AD.


After treatment with galantamine,
bipolar subjects experienced
significant improvement of
subjective cognitive scores and
on objective tests of attention and
verbal episodic memory.


Patients were divided into responders (as measured by a 4-point increase in ADAScog scores at 24 weeks of treatment) and non-responders. The scientists explored whether patients’ background (e.g. sex, age, and duration of disease) and scores of cognitive scales at early stage, are relevant to the long-term response to acetylcholinesterase inhibitors such as galantamine. The responder rate was 31.7%.

Changes in scores of ADAS-cog subscales between week 4 and baseline, especially word recognition, were found to be a good variable to predict subsequent response to galantamine, with approximately 75% of predictive performance.


Patients who show improvement of
episodic memory function during
the first 4 weeks of galantamine
administration may be
especially likely to benefit from
galantamine treatment.


But characteristics of patients — including demographic characteristics, severity of disease, and neuro­psychological features before treatment — were poorly predictive. These findings indicate that initial response to galantamine in patients with mild to moderate AD seems to be a reliable predictor of response to subsequent galantamine treatment.

Patients who show improvement of episodic memory function during the first 4 weeks of galantamine administration may be especially likely to benefit from galantamine treatment.

Write Your Story with Galantamine

What has been reviewed, especially the research pertaining to MCI, is good news for those who choose to write their stories, because if you can’t remember the past, your history is censured. But galantamine can make this retrieval of what has made you who you are easier, and you can revel in storing it into the memory banks of your computer and / or committing it to paper.

References

  1. Hernandez CM1, Dineley KT. a7 nicotinic acetylcholine receptors in Alzheimer’s disease: neuroprotective, neurotrophic or both? Curr Drug Targets. 2012 May;13(5):613 – 22.
  2. Caramelli P, Chaves ML, Engelhardt E, Machado JC, Schultz RR, Vale FA, Charchat-Fichman H; Brazilian Multi-Center Galantamine Study (GAL-BRA-01). Effects of galantamine on attention and memory in Alzheimer’s disease measured by computerized neuropsychological tests: results of the Brazilian Multi-Center Galantamine Study (GAL-BRA-01). Arq Neuropsiquiatr. 2004 Jun;62(2B):379 – 84.
  3. Goekoop R1, Rombouts SA, Jonker C, Hibbel A, Knol DL, Truyen L, Barkhof F, Scheltens P. Challenging the cholinergic system in mild cognitive impairment: a pharmacological fMRI study. Neuroimage. 2004 Dec;23(4):1450 – 9.
  4. Grön G1, Brandenburg I, Wunderlich AP, Riepe MW. Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis. Neurobiol Aging. 2006 Jan;27(1):78 – 87.
  5. de Bruin N1, Pouzet B.Beneficial effects of galantamine on performance in the object recognition task in Swiss mice: deficits induced by scopolamine and by prolonging the retention interval. Pharmacol Biochem Behav. 2006 Sep;85(1):253 – 60
  6. Ghaemi SN1, Gilmer WS, Dunn RT, Hanlon RE, Kemp DE, Bauer AD, Chriki L, Filkowski MM, Harvey PD. A double-blind, placebo-controlled pilot study of galantamine to improve cognitive dysfunction in minimally symptomatic bipolar disorder. J Clin Psychopharmacol. 2009 Jun;29(3):291 – 5.
  7. Takeda S1, Sato N, Niisato K, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Kano M, Morishita R. Validation of Abeta1-40 administration into mouse cerebroventricles as an animal model for Alzheimer disease. Brain Res. 2009 Jul 14;1280:137 – 47.
  8. Iosifescu DV1, Moore CM, Deckersbach T, Tilley CA, Ostacher MJ, Sachs GS, Nierenberg AA. Galantamine-ER for cognitive dysfunction in bipolar disorder and correlation with hippocampal neuronal viability: a proof-of-concept study. CNS Neurosci Ther. 2009 Winter;15(4):309 – 19.
  9. Ohnishi T, Sakiyama Y, Okuri Y, Kimura Y, Sugiyama N, Saito T, Takahashi M, Kobayashi T. The prediction of response to galantamine treatment in patients with mild to moderate Alzheimer’s disease. Curr Alzheimer Res. 2014 Feb;11(2):110 – 8.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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