Data-driven methodology illustrating mechanisms underlying word list recall: applications to clinical research.

The California Verbal Learning Task (CVLT) is a widely used neuropsychological tool for evaluating verbal memory strategies (Delis et al., 1987). A list of 16 words comprising four semantic categories - spices, tools, fruits and clothes, each containing four words - is presented orally then freely recalled; this occurs five consecutive times per administration. The performance metrics include the number of words recalled during the first recall, words recalled during the fifth (final) trial, the improvement between the first and fifth trial, and overall recall across all five trials. The mnemonic strategies employed are assayed by semantic and serial “clustering scores,” with semantic clustering being operationalized as recall of categorically similar words one after another, and serial clustering defined as the sequential recall of words according to the presentation order. In general, people who recall the most words employ a semantic clustering technique, whereas those who display poor recall tend to rely on serial techniques (Delis, Freeland, Kramer, & Kaplan, 1988). Indeed, among healthy individuals, the recall strategy employed predicts the number of words successfully recalled in the final trial on the CVLT, more so than performance on the first trial (Paulsen et al., 1995). An underlying assumption is that the semantic strategy during recall reflects to some extent the underlying semantic organization in memory, and indeed the CVLT was designed based upon the theory that semantic strategy is most likely to lead to encoding in long-term memory (Delis et al., 1987). That semantic recall techniques lead to better recall fits well with notions that semantic information is “deeply” encoded through stronger, longer-lasting bonds because of associations with pre-established information in long-term memory, while serial information is “shallowly” encoded in short-term memory because it is only related to the current task (Craik & Tulving, 1975). While studies have emphasized the superiority of semantic mnemonic strategies, little has been said about the interaction of semantic and serial strategies (Delis et al., 1987). Moreover, opposing serial and semantic clustering patterns (one increasing when the other decreases) have been considered to reflect “the incompatibility of serial learning and semantic organizations strategies” (p.381; Brebion, David, Jones, & Pilowsky, 2004) which perpetuates ideas that verbal memory strategies compete rather than interact and support each other. In fact, classic studies of word list learning show that participants recall the most words when the order of the presented list of words is constant rather than varied for each trial, which suggests that the temporal order of words is an underlying aid in free recall (Jung & Skeebo, 1967). While an increasingly semantically-based strategy can reduce reliance on serial strategy, careful examination of the two approaches reveals that they can operate in concert. In a longitudinal study, healthy participants employed a less serially-based recall strategy over time while increasing semantically-based strategy, but patients with schizophrenia increasingly (though not significantly) relied on both serial and semantic recall strategies (Roofeh et al., 2006). In order to better understand mechanisms of the strategies during free list recall, it is useful to examine verbal memory in a population for whom impairments are a hallmark feature, such as patients with schizophrenia who display deficits on a wide range of episodic verbal memory tasks (Paulsen et al., 1995). A recent study comparing verbal and visual episodic memory - using the Wechsler Memory Scale-Revised Logical Memory (story) and Visual Reproduction tasks (Wechsler, 1987) - found that patients with schizophrenia performed poorly on measures of verbal and visual learning, but their unaffected siblings performed poorly only on measures of verbal learning, therefore suggesting that verbal processing deficits, rather than memory deficits per se, represent a cognitive phenotype. (Skelley, Goldberg, Egan, Weinberger, & Gold, 2008). Attempts to characterize the nature of verbal memory impairment that employ the CVLT report that strategy predicts performance for patients with schizophrenia. As with healthy participants, recall strategy predicted the number of words successfully recalled in the final trial, more so than performance on the first trial (Iddon, McKenna, Sahakian, & Robbins, 1998). However, while both patients and healthy control participants recall an increasing number of words across multiple trials and maintain their respective performance levels in delayed recall (Paulsen et al., 1995), patients employ a less semantically-based strategy, thus recalling fewer words overall (Delis et al., 1987; Hazlett et al., 2000; Hill, Beers, Kmiec, Keshavan, & Sweeney, 2004; Kareken, Moberg, & Gur, 1996; Roofeh et al., 2006). However, the distinction has not been made between whether all patients rely less on semantically-based strategy or there are fewer patients than controls who choose to employ semantically-based strategy. The former assumption fits well with notions that semantic deficits accompany schizophrenia, such as findings of large variance in semantic priming (Minzenberg, Ober, & Vinogradov, 2002; Pomarol-Clotet, Oh, Laws, & McKenna, 2008) or even “widened” category boundaries (Chen, Wilkins, & McKenna, 1994). However, other studies do not provide unequivocal support for the notion of semantic anomalies per se in schizophrenia (Elvevag, Heit, Storms, & Goldberg, 2005; Elvevag & Storms, 2003; Prescott, Newton, Mir, Woodruff, & Parks, 2006), and indeed suggest that - at the very least - some semantic knowledge is represented by patients as it is by healthy control participants (Cohen, Elvevag, & Goldberg, 2005). A study that parsed patients with schizophrenia into high-achievers, learners, and non-learners based on their performance on the first trial of the CVLT and improvement between the first and last trial scores (i.e., the learning slope) found that patients not only relied heavily on semantic clustering in recall, but that no matter their performance level, they simultaneously employed some degree of serial strategy supporting the idea that semantic and serial strategies interact (Vaskinn et al., 2008). Examination of our own CVLT data - a large data set from the CBDB/ NIMH Schizophrenia Sibling study (Egan et al., 2000) - revealed that high performers, regardless of their diagnostic group (patient or control), seemed to employ both serial and semantic strategies. In addition, strategies appeared to change as a function of learning trial. However, this detail was not captured by the current CVLT scoring method (we describe this in detail below), which prompted us to develop a different approach to analyzing recall that considered recall strategies simultaneously and that would relate these strategies to the changes in performance as a function of learning. Such an approach promises to provide a framework with which to re-examine both the underlying cognitive mechanisms of poor verbal recall in general, but also, crucially, the neurobiology as determined by both functional brain networks and genetic functional polymorphisms. Clearly such a tool would be of enormous utility for understanding individual differences in modulations of the verbal recall process by both illness and genes. Thus, we sought to examine CVLT recall and learning strategies in high and low performing healthy people, as well as in a group for which problems in the verbal memory domain are a hallmark feature, namely patients with schizophrenia.