Práctica Pedagógica

Therapeutic treatment with corticosteroids is common practice for a number of medical conditions including asthma, multiple sclerosis and rheumatoid arthritis, and may cause deleterious side-effects. As early as the 1950s, prior to the identification of adrenal steroid receptors in the brain, it was observed that treatment with glucocorticoids for a variety of medical complaints resulted in “thinking disturbances” (Rome & Braceland, 1952) with both cognitive and psychiatric manifestations (Quarton, Clark, Cobb, & Bauer, 1955). More recently, impairment of explicit and declarative memory related to therapeutic use of GCs has been reported (Barnes & Pederson, 1993; Keenan, Jacobson, Soleymani, & Newcomer, 1995). Brown and colleagues (E. S. Brown et al., 2004) reported reduced hippocampal volume, lowered hippocampal N-acetyl aspartate (NAA), creatine (Cr) and choline (Cho) ratios (NAA/Cho and NAA/(Cr+Cho)) and poorer cognitive performance on tests of verbal learning and delayed recall (RAVLT) and response inhibition (Stroop Color-Word) in 17 patients undergoing long-term treatment with prednisolone (> 6 months; mean duration of treatment 7.6 years) due to various medical conditions such as asthma and arthritis. Participants with comparable medical histories who were not undergoing corticosteroid treatment did not show such effects.

Controlled exogenous administration of GCs has been used experimentally to demonstrate the adverse effects of high levels of corticosteroids in humans. Acute administration of cortisone (25mg) to young men and women one hour prior to a delayed retention test significantly impaired recall on a list of unrelated words (de Quervain, Roozendaal, Nitsch, McGaugh, & Hock, 2000; Roozendaal, Okuda, de Quervain, & McGaugh, 2006). Similar effects were seen in a study by Kuhlman, Kirschbaum and Wolf (2005), who reported that 30mg of hydrocortisone given to 16 healthy young women (mean age 26.56 years) four hours after initial learning impaired free recall of both neutral and negative emotionally-laden words, compared to placebo-treated controls, with a trend towards poorer recall of the negative words. Newcomer and colleagues (1999) reported significant reductions in participants’ memory performance (WMS-R Logical Memory) after four days of hydrocortisone administration,

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with a dose dependent effect on memory performance (lower memory performance with a higher dose). There were no differences between groups

(160 mg/day vs. 40 mg/day vs. placebo) at baseline or after only one day’s administration, suggesting a cumulative rather than an acute effect of GCs on memory performance. The effect was reversible, with memory performance rebounding to above baseline levels following a six-day washout. In contrast to studies reporting adverse affects on memory performance, Abercrombie and colleagues (2003) reported fewer commission errors in free recall of a word list after administration of 40mg of hydrocortisone, as well as fewer errors of commission in a picture recall task after 20mg, compared to placebo in a group of 90 healthy males.

The acute effect of exogenous GCs appears to be attenuated with repeated administration (E. S. Brown, Beard, Frol, & Rush, 2006). In a recent study with a placebo controlled cross-over design, Brown and colleagues showed that memory performance on the RAVLT decreased compared to baseline following three days exposure to 60mg prednisolone per day. Repeated administration of prednisolone following an 11-day washout period also resulted in reduced performance, however the effect was significantly smaller than that seen after the first administration. The authors suggested the development of tolerance or habituation to the effects of prednisolone with repeated exposures. However, this is inconsistent with the same group’s findings (outlined above) that prolonged exposure to exogenous GCs results in measurable effects on hippocampal volume, metabolism and declarative memory performance (E. S. Brown et al., 2004).

The effect of corticosteroids on memory performance is thought to be dependent upon the time of day of administration, and on the timing of administration in relation to memory task. Administration of exogenous GCs to coincide with the morning peak is more likely to impair declarative memory performance than when it is administered in the afternoon (Fehm-Wolfsdorf, Reutter, Zenz, Born, & Fehm, 1993; Lupien et al., 2002; Maheu et al., 2005). A recent meta-analysis of 16 studies examining the effect of cortisol on human memory showed that cortisol administered before learning had little to no effect

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on later information retrieval. If administered after learning and before retrieval, significant decreases in memory were likely (Het, Ramlow, & Wolf, 2005). Blockade of cortisol production during sleep (particularly during the early morning) by administration of metyrapone has also been shown to affect memory. Metyrapone given to 16 healthy males after a verbal learning task (consisting of neutral and emotionally-laden words) was shown to affect consolidation of the neutral material only. Memory for neutral material was assumed to be related to hippocampal memory processes. In contrast, memory for emotionally-laden words (thought to be dependent on an intact amygdala) was not affected (Wagner, Degirmenci, Drosopoulos, Perras, & Born, 2005). Animal studies have provided further evidence for the effects of GCs on memory functioning. Filipini, Gijsbers, Birmingham and Dubrovsky (1991) showed that administration of exogenous GCs to adrenalectomised rats resulted in impairment of long-term potentiation (LTP). LTP is an excitatory post- synaptic potential brought about by repeated stimulation, and is thought to mediate aspects of learning and memory. GCs have also been shown to affect performance on a spatial memory task (the Morris water maze) in adrenalectomised rats, restoring performance to pre-lesion levels (McCormick, McNamara, Kelsey, & Klecker, 1995). In intact rats, GCs have been demonstrated to exert a direct and deleterious effect on performance on spatial memory tasks (Catalani et al., 1993; Dachir, Kadar, Robinson, & Levy, 1993). McClay, Freeman and Zadina (1998) reported that corticosterone-treated rats were significantly impaired on their performance on the Morris water maze, the Barnes circular platform maze and the Radial Arm maze, making significantly more errors, taking longer and covering a greater distance (i.e. performing less economically) compared to control rats.

In summary, the administration of exogenous corticosteroids, either therapeutically or experimentally, is associated with reductions in memory performance. However, this effect may be attenuated with repeated administration. In humans, performance is modulated by the emotional salience of the material to be recalled, providing further evidence of the preferential effects of corticosteroids on the hippocampus.

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