Memory, the capacity to mentally encode, retain, and retrieve information, is a fundamental human cognition, shaping our daily activities and underpinning our sense of self (Zlotnik et al., 2019). In the mid-20^th century, Karl Lashley set out to understand the neural basis of memory in his famous search for ‘the engram’, the physical trace or neural representation of memory (Lashley, 1950). Using cortical lesioning on rats before and after learning tasks, Lashley observed that lesion-induced memory impairment was correlated, not with the lesion’s location, but with the quantity of cortical damage. From this, he concluded his ‘principle of mass action’ – the idea that memory is distributed throughout the cortex. This essay seeks to critically evaluate this principle. It will first discuss the methodological limitations of his experiments and subsequent conclusions. It will then explore how, in light of more recent and technologically advanced research into memory, his approach appears to neglect the multifaceted nature of memory, the involvement of sub-cortical structures, and the influence of the endocrine system. Nonetheless, this essay will also acknowledge the pioneering significance of Lashley’s experiments in understanding the dynamic nature of the neurobiological substrates of memory.

Lashley’s experiments involved training rats in maze tasks and then lesioning different parts of their cortices pre- and post-training to observe their task performance (Lashley, 1929). Remarkably, he found that memory impairment correlated with the extent of cortical damage rather than with specific lesion locations. Consequently, Lashley concluded that memory is distributed across all cortical tissue, challenging the contemporary notion of functional specialisation (Thomas et al., 1971).

Lashley’s experiments are subject to several criticisms. Foremost amongst these is the contention that the maze tasks chosen for the rats are overly complex (Tonegawa et al., 2015). Neuroimaging studies have shown that these tasks engage multiple cognitive functions and require coordination among various cortical and subcortical systems (Nasrallah et al., 2016). Lashley’s observed correlation between the quantity of cortical lesions and memory impairment may have resulted from the disruption of these interconnected systems that implicate a number of brain areas, the cortex being just one.

Furthermore, the tasks utilised in Lashley’s experiments primarily involve procedural memory. Despite this, his principle of mass action suggests a comprehensive theory of memory storage. It is now known that memory encompasses a number of different cognitions, each with distinct neurobiological foundations (Sridhar et al., 2023). For instance, rats completing maze tasks similar to those used by Lashley engage spatial and nonspatial learning, as well as working memory processes (Terry Jr., 2009), while rats completing olfactory memory assessments primarily utilise episodic memory (Rajic et al., 2018; Panoz-Brown et al., 2016). Thus, Lashley’s conclusion that all ‘memory’ is distributed amongst the cortex based solely on these specific tasks is an inherently flawed conclusion.

Replication attempts of Lashley’s original experiment further undermine the validity of his principle of mass action. Changing the measurement of cortical lesioning from the original linear units to area units of measurement revealed a non-linear relationship between lesioning and memory impairment, contrary to what Lashley originally suggested (Loh Seng Tsai, 1989). Instead, cortical lesioning demonstrated a stepwise, discrete relationship with memory impairment that involved variable thresholds. This supports previous criticisms arguing that Lashley derived his principle of mass action from lesions of insufficient sizes and quantities (Thomas et al., 1971). While Lashley emphasised the linearity of cortical damage and memory impairment, replication attempts with slight methodological changes reveal a more nuanced relationship between the cortex and memory.

Lashley’s exclusive focus on the cortex overlooks the role of sub-cortical structures in memory. This omission is especially significant given the wealth of subsequent research that has underscored the importance of these structures in memory storage. Among them, the hippocampus is particularly significant. The case of H.M. exemplifies this point, a patient who developed retrograde and severe anterograde amnesia following the surgical removal of his medial temporal lobes (Scoville & Milner, 1957). This case was seminal in our understanding of how damage to the medial temporal lobe, including the hippocampal formation and related areas, leads to significant impairments in the formation of long-term declarative memories (Robertson et al., 2002).

Animal studies have consistently shown the fundamental role of the hippocampus in memory, implicating it as one of our earliest evolutionary features (Eichenbaum & Cohen, 2001). Neuroimaging studies have demonstrated its key role in the transfer of explicit information as short-term memories for storage at other cortical sites as well  (Squire, 1992; Kapur et al., 1994). Hippocampal ‘place cells’, neurons that are selectively activated when an animal moves through a particular space, are argued to function by consolidating representations of the outside world into neuronal networks, and would have had particular pertinence amongst Lashley’s maze tasks (Colgin et al., 2008). Moreover, ample evidence has linked the hippocampus to the Papez circuit, indicating its specific involvement in the consolidation and retrieval of declarative memories (e.g., Choi et al., 2019; Ji et al., 2020). However, like the principle of mass action, even this theory fails to comprehensively encapsulate the neurobiological intricacies of memory, although it rightly acknowledges the importance of the hippocampus (Aggleton et al., 2022).

The amygdala, another sub-cortical structure overlooked by Lashley, has been extensively implicated in memory processes. Both animal and human studies provide compelling evidence of its involvement in the encoding and storage of emotional memories, both positive and negative (McGaugh, 2004; Kensinger & Schacter, 2006). Moreover, amygdala neurons active during fear learning are also active during the retrieval of that same fear memory, implicating the amygdala in both the encoding and retrieval of memories (Guzowski et al., 1999). It has even been shown that the number of active amygdaloid neurons correlates with the strength of the retrieved memory. Conversely, disrupting, stimulating, or inactivating the amygdala of rats following a memory involving significant emotion impairs the retention of that memory (Robertson, 2002).

While Lashley may have neglected studying the amygdala directly, Whalen (1998) has demonstrated that during the encoding of an emotive memory, information flows bidirectionally between the amygdala and the cerebral cortex. This nuanced interaction may partly explain Lashley’s observation of a linear relationship between cortical lesioning and memory impairment, as he may have damaged networks involving both the amygdala and cortex. Recent advancements in optogenetic and chemogenetic research, as demonstrated by Roy (2022), reveal that the engrams of specific memories are distributed across multiple functionally connected brain regions – a phenomenon termed the ‘unified engram complex’. As such, while Lashley’s presumption of an exclusively cortical engram appears flawed, his emphasis on the relevance of the cortex remains valid in light of contemporary research.

The amygdala’s involvement in memory stems partly from the impact of stress hormones released during emotional experiences. Animal studies have demonstrated that stress hormones such as epinephrine and corticosterone modulate memory storage and consolidation (Cahill et al., 2003; Nielson & Jensen, 1994). Subsequent research has identified hormones, such as glucocorticoids, sex hormones such as oestrogen and testosterone, and oxytocin, that also have modulating effects on memory (Newcomer et al., 1999; Ali et al., 2018). Importantly, post-training hormonal treatments modulate memory storage, even when they never cross the blood-brain barrier (McGaugh et al., 1996). While evidence is mixed regarding the effects of hormones on rat learning abilities (Spritzer et al., 2013; Sadowski et al., 2009), the complete neglect of the endocrine system through Lashley’s sole focus on the cortex further undermines his principle of mass action.

Despite its methodological flaws and erroneous conclusions, Lashley’s challenge to the functional localisation of memory marked a significant milestone in our understanding of memory’s neurological substrates. The principle of equipotentiality, the sibling principle of mass action, posits that the brain can utilise any functional part to compensate for the lost functions due to damage in another part (Lashley, 1950). Together, the proposition that should a memory trace exist, it would involve a distributed, dynamic network of neurons rather than being strictly localised resonates with our current contemporary understanding of neuroplasticity – the idea that brain networks are capable of flexibility and adaptation (Nadel & Maurer, 2020). Some argue that Lashley’s work paved the way for Hebb’s influential theory of learning, which famously states that ‘cells that fire together, wire together’ (Glickman, 1996).

Nowadays, the notion of distributed processing is foundational for much of today’s neuroimaging research (McIntosh et al., 2003; Friston, 2003). Considerable evidence from molecular, genetic, behavioural, and brain imaging techniques has demonstrated how the acquisition and consolidation of memory is underlain by neuroplastic processes such as long-term potentiation (LTP, Bermúdez-Rattoni et al., 2007). Some argue that LTP, the process by which synaptic connections strengthen, is both necessary and sufficient for the encoding and storage of memory (Lynch, 2004; Takeuchi et al., 2014). Lashley himself did not believe that he failed to find the engram because it did not exist, rather, he believed that the engram itself was much more abstract than previously thought (Nagel & Maurer, 2020). While his principle of mass action may not accurately explain memory storage systems, his recognition of the role of inter-neuronal activity and flexibility in the storage of memory demonstrated remarkable insight.

To conclude, Lashley’s principle of mass action finds little support in light of more recent studies employing more advanced and methodologically rigorous experimental paradigms. Methodological limitations, a narrow definition of ‘memory’, and his neglect of sub-cortical structures and endocrinal influences, all undermine his assertion that memory is stored by an indiscriminate network of ‘engrams’ confined solely to the cortex. Despite this, Lashley’s cortical lesion experiments have significantly contributed to our understanding of the neurobiological foundations of memory. By challenging the notion of functional specialisation, Lashley paved the way for our current understanding of memory as a distributed and dynamic representation of multi-potent neurons and neuronal circuits. Although his principle is largely discredited, his insight into the distributed and flexible nature of memory traces, suggested decades before empirical demonstration, remains noteworthy.

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