“Always in life an idea starts small, it is only a sapling idea . . . an idea so big it could have grown thirty meters through the dark canopy of leaves and touched the face of the sky” – Bryce Courtenay, The Power of One

Many scientists argue that neuropsychological research has benefited through the study of cases, as the in-depth examination of individual patients has contributed to the better understanding of human cognition. However, this single-case research method has received a decreased interest in the last decades (MacPherson & Della Sala, 2019) in favor of the deductive approach and the reasons for this tendency vary. I think that these two approaches are not in opposition, but might address to complementary questions.

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In this essay, I will discuss to what extend the case-study method of scientific research contributes to the understanding of the working memory (WM) function in healthy people. Firstly, I will refer to the theoretical development that cases of patients have provided. Then, I will describe in detail the methodological pros and cons of single-case studies and finally, I will try to illustrate the reasons for the lack of consideration of single-case studies in the current scientific community.
To start with, the definition of the case-study depends on the epistemological perspective which practitioners and analysts of this approach adopt. A review of the different definitions indicated that in general a case-study scientifically investigates the complexity of a real-life phenomenon in its environmental context (Simons, 2009). Hence, in accordance to the aforementioned definition one of the advantages of the case-study approach could be that scientists delve into a deeper level of analysis in order to benefit the theoretical continuum of a specific concept. This contribution can be achieved through two different ways and each one of those alternatives can present significant practical applications.
On the one hand, case data can lead to the identification of patterns and relationships offering a better understanding of “how” and “why” a phenomenon is occurred. Thus, casestudy research may offer the opportunity of the creation of a new theory by expanding constructs within different settings. For instance, the case of H.M. patient reshaped the intellectual landscape of memory. Before the midpoint of 20th century memory functions were thought to be well integrated with perceptual and intellectual functions, and no region of the brain was believed to be disproportionately dedicated to memory (Lashley, 1929).
But, the findings of the H.M. case established the fundamental principle that memory is a distinct cerebral function, while the essential role of the hippocampus – a region which is located in the medial temporal lobe – along with other close brain areas (the amygdala and the adjacent parahippocampal gyrus) for memory was emerged (Squire & Wixted, 2011).
In other words, the acquired deterioration of memory of H.M. patient after a bilateral medial temporal surgery showed evidence for the localization of cognitive processes by identifying the medial aspect of the temporal lobe as an important feature for forming memories, but also for activating past memories. H.M.’s hippocampal damage led to his inability to form new memories and subsequently this difficulty prevent H.M. to retrieve existing memories in order to replace their representations, as non-amnesic individuals normally do. Thus, besides the theoretical knowledge about the memory localization, the case-study of H.M. demonstrated a crucial link between anterograde and retrograde amnesia in amnesic patients (MacKay, 2014).
On the other hand, case studies could restructure or advance existing theories. One such example is the amnesic patient V.C., who was a retired chief engineer. V.C. patient had grave impairment of episodic memory, while certain aspects semantic memory remained preserved, as well as, his IQ, his perceptional, his executive and his language performance (Cipolotti et al., 2001).
The highly selective lesion of the hippocampi (CA1 and CA2 fields) and the patient’s cognitive outcomes changed the perception for the role of the hippocampus region and caused vibrations on the Standard Consolidation Theory (SCT), which claims that mainly the role of hippocampus is referred to the temporary consolidation of memory traces and the memories eventually become independent of the hippocampus as they become more reliant on cortical connectivity (Squire, 1992).
In particular, V.C. provided support for the view that semantic and episodic memory engage the hippocampus in different ways and that the remote memories are not both quantitatively and qualitatively the same in amnesic and normal individuals as Standard Consolidation Theory claimed (Nadel & Moscovitch, 2001).
On the contrary, the findings of this case study brought to the foreground evidence for the Multiple Trace Theory (MTT), whilst highlighted the role of the hippocampus in remote memory, recollection, familiarity and semantic memory (Nadel & Moscovitch, 2001). The MTT assumes that each time an encoded memory trace is re-activated, a new hippocampal trace is created.
This process leads to a formation of multiple memory traces which are composed of a combination of the attributes of the initial trace, but those new traces are not transferred to the neocortex.
Taking all together, the extensive and ungraded remote memory difficulties of V.C. patient for both personal and non-personal events – retrograde amnesia for both autobiographical and public incidents – showed that hippocampus itself is the cornerstone of the retrieval of remote episodic memories.
Therefore, the value of the neuropsychological cases has already proven to be quite inspirational for the theoretical continuum and still continues to motivate current debates (Corkin, 2013; Nadel & Moscovitch, 2001). Both the neuroanatomical localization and the organization of memory are significant contributions of the single-case studies, that have also been confirmed by more recent group studies and animal models (Squire & Wixted, 2011). But, what are the profits of the case-studies especially in the theoretical explanatory models of the WM concept?
The contribution of case studies of patients with brain lesions to the understanding of the functional architecture of WM has been widely acknowledged (Baddeley, 2017). The Shallice and Warrington’s case-study (1969), revealed that the K.F. patient had a defective short-term memory (STM) system while his performance on long-term memory (LTM) tasks was normal.
According to this initial evidence a flow diagram in which information must enter STM before reaching LTM, was considered as inappropriate. Thus, the K.F. case-study was the touchstone for the re-evaluation of Modal Model of WM (Atkinson & Shiffrin, 1968); whilst it opened an alternative path for more integrated theories.
Firstly, the K.F. patient demonstrated that the linear way of information processing, that Atkinson and Shiffrin supported in 1968, was oversimplified. Subsequently, the selective deficits of K.F. in verbal but not in visual presented material indicated that the short-term store might contain more components. In 1974, Baddeley and Hitch proposed a multicomponent model of WM by replacing the unitary short-term store of Modal Model (Baddeley, 2014). This three-component WM model which initially included the phonological loop, the visuospatial sketchpad and the central executive could explain the selective deficits of K.F. patient. More specifically, K.F. impairments could be simply perceived as a selective deficit in phonological loop (Baddeley, 2017).
Two more noteworthy case studies are those of P.V. and J.B. patients, which each of them made important contributions to the empirical and theoretical development of cognitive neuropsychology in general and especially to the field of WM. Both patients exhibited selective short-term memory deficit (auditory-verbal STM impairment or phonological STM disturbance in terms of the Baddeley and Hitch’s WM model); while they presented relatively preserved language and long-term learning abilities (Martin, 2013).
These case studies addressed the question of whether language and STM processes could be selectively impaired. More specifically, the results showed that poor performance on auditory-verbal span tasks is due to a deficit in verbal STM and thus the deficits in language processing are not related to them (Martin, 2013). In addition to this observation, the existence of a dissociation between phonological STM and LTM could be confirmed because the performance on long-term learning tasks in those patients remained intact. Moreover, the studies provided supplementary evidence for the absence of phonological coding of visual presented verbal material in immediate retention tasks (MacPherson & Della Sala, 2019). In other words, the results showed that visual material was not conveyed to the phonological short-term store, but into the visual STM instead.
Patients with discrete and specific patterns of functional impairment, like PV and JB, can help scientists to detect deranged functions of damaged systems. The more selective the functional deficit is, the less confounding effects due to damage to other components of the cognitive system need to be teased apart. This specific localization is crucial both for the construction of theoretical models and clinical interventions.
Likewise, selective deficits may allow better control and understanding of compensatory strategies that patients tend to use after the damage. For instance, the defective recency of patient P.V. in immediate serial and free recall of auditorily presented verbal material (Basso, et al., 1982) and at the same time the preserved ability of the patient to recall the items’ lists according to instructions depicted a distinction between recall strategies based on the precessing of temporal order and the specific stores to which they were applied (Vallar & Papagno, 1986; Vallar, Papagno & Baddeley, 1991). Hence, this conclusion illustrated that recency phenomena may occur in both STM and LTM and result from the application of ordinal retrieval strategies to the content of different stores.
In consideration of the above, we can conclude that case studies provide crucial information to understand the healthy working brain and the functional architecture of normal mental processes. Neuropsychological studies have documented a number of sharply defined dissociations between selective dysfunctions and task performances, thus introducing or confirming important distinctions between memory types, processes and structures. Overall, the causal relations between damaged area and both cognitive and behavioral outcome can determine how the normal human mind is functionally organized.
On the other end of the spectrum, it has been argued that case studies may not be valuable for generalization. Every patient is different in idiosyncratic ways, the lesions of the patients are far too coarse leading to poor spacial localization and modern neuro-imaging techniques have already made the lesion methods obsolete (Adolphs, 2016; Rorden & Karnath, 2004). Researchers who adopt the deductive approach, which is based on a hypothesis-driven research, can recruit both new developed neuro-imaging techniques and computational models in order to examine a theoretical standpoint by using a larger sample of acquired brain injured patients and therefore introduce more solid theories for the normal cognition.
Thus, some scientists believe that group studies might represent better the general population because they can demonstrate similar patterns between the damaged brains of the patients in both within-subjects or between-subjects designed studies and create valid neuropsychological conclusions (Rorden & Karnath, 2004).
For example, Della Sala, Logie, Beschin and Denis (2004), examined patients with representational neglect in several tasks and suggested that representational neglect might reflect damage to the visuo-spatial component of working memory; hence the patients have no difficulty in directing their attention (e.g. impaired exogenous attentional system) to the neglected side as originally claimed (Gainotti, 1996).
Another recent study have shown that AD patients performed statistically significant lower in the color-shape binding task than healthy participants (Parra, Abrahams, Logie, & Della Sala, 2010) and this according to the multi-components models of the structure of the WM can be explained as an impairment of communicationbetween models’ components.
Therefore, we can conclude that the examination of the feature binding process potentially might be a helpful tool for the diagnosis of the Alzheimer disease from early on. Such studies can inform theoretical models of WM and by utilizing larger number of participants might sufficiently provide both concrete informations for complex cognitive processes and significant clinical applications.
Another point of criticism for the single-case approach is the statistical weakness of the observations and beyond that, the difficulty for a scientific generalization. It is well known that individual brains vary in their pattern of folds, size, overall shape and ventricle size (inherent heterogeneity), but also except of the anatomical differences individual brains show plasticity, with different regions changing their function in response to damage (Kerr, Cheng & Jones, 2011; Raineteau & Schwab, 2001).
According to this view, the findings of a longitudinal study of a single patient could not be reliable mainly because the intact regions of the brain do not continue to function in the same manner as before the lesion. It is well documented, that disordered areas of the brain and their structural connections can be reorganized along with the deteriorated functions (Teasell, Bayona & Bitensky, 2005).
On the contrary, brain regions can be disabled but intact after injury. Statistical analysis of large samples can partly overcome those drawbacks by grouping and examining similar patterns between the patients. More specifically, statistical methods, like Brain Vox, permit scientists to analyze and compare the lesioned areas from each patient and then generalize the findings by creating a statistical map which reveals the paths of damage (Rorden & Karnath, 2004).
In spite of this last disadvantage for the single-case approach, cross-case statistical analysis can enhance researchers to understand how cognitive and behavioral patterns exist among discrete cases (Khan & VanWynsberghe, 2008). Thus, comparative statistical models can be implemented in case-studies as a useful tool for the construction of critical linkages between individuals raising the possibility of a typology of individual cases that can be highly insightful.
One such example is the study of Kindell, Wilkinson and Keady (2019), in which the cross-case analysis of five couples where one member had semantic dementia revealed specific facets of the care of patients with this type of dementia.
In addition, while an analysis from a larger sample might reveal potentially more stable and consistent findings, scientists can not assume identical neural, cognitive and behavioral deficits in the groups studies. This issue challenge the researchers of group studies and force them to define appropriate inclusion criteria in order to reduce the heterogeneity of the participants (MacPherson & Della Sala, 2019).
One commonly used method to overcome these barriers is the creation of a neuropsychological profile. But the profiles for different type of neurocognitive deficits are still developing and their form is still under systematic review (Sachdev, 2010). Thus, a categorical system of patients with seemingly high related neurocognitive patterns may not provide more reliable results than single-case studies.
A third statement against the single-case approach is that case-studies they take too much time to provide a concrete document with results (Yin, 2018); while the replication of their findings seem impractical (Smith, 2001). During the long investigation procedure unexpected events can happened leading to difficulties in publication. Clear patterns don’t always emerged, but this could refer not to methodological problems, as barriers can be created by patients themselves. The patient’s decision to quit the series of the examination or even a health event before of the data completion could have the drop of the case as a result.
A final critique of the role of neuropsychological case studies springs up from the computational neuroscience field. Computational modelers support that single-cases of abnormal cognition resulting from brain injury can only provide dissociations (Patterson & Plaut, 2009).
On the contrary, connectionist simulations might give to the researchers the opportunity to investigate not only how a computational model performs under damage but also how well and how quickly it relearns when scientists give it a period of retraining (Plaut, 1996). The latter aspect may be crucial for rehabilitation purposes by specifying the underlined mechanisms of a function and indicating the parallel and interactive functioning of the human brain.
Although, computational modelers support that their models are low in complexity and that they can describe aspects of cognition such as WM in a simplified fashion (Madl, Chen, Montaldi & Trappl, 2015), their models still seem very complicated with little evaluated applicability in real-world environments. For instance, Hazy, Frank and O’Reilly (2007), in their effort to simulate multiple working memory tasks in a single model they admitted that they developed a computational model (PBWM model) nearly as complex as the phenomena that this model is trying to explain.
Furthermore, single-case methods are also not well suited to the competitive grant climate; thus building a research program that depends on funding these cases it is considered as very laborious. Although, this last statement is not referred to a methodological limitation for single-case studies, the aforementioned obstacle combined with the current scientific situation in which a lot of incentives are offered in order researchers to maximize their number of publications, make the longitudinal study of a single patient even harder.
A significant example of the aforementioned claims is referred to the findings of Fellows, Heberlein, Morales, Shivde, Waller and Wu’s study, in 2005. Fellows and colleagues (2005), investigated the citation pattern for cognitive neuroscience papers that used either functional neuro-imaging or lesion-based methods. The research showed an asymmetry in the citation pattern.
More specifically, researchers of studies, in which lesion-based techniques used, tended to cite both previous lesion and neuro-imaging studies, but the same pattern didn’t followed up vice versa. This bias in citation along with the fact that journals which previously published single-case studies no longer accepting submissions suggest probably a nonfriendly environment for researches of case studies in the era of the big data (Medina & Fischer-Baum, 2017).
All in all, the case study approach was undoubtedly a powerful tool for the understanding of the cognitive domain in total and especially of the memory structure and function in healthy people. But, the future contribution of lesion-based case studies is a debatable issue. More specifically, for the memory domain, Rosenbaum, Gilboa and Moscovitch (2014), mentioned that single cases of amnesic patients offer,

“a clear theory that can cultivate and cast light on what is observed, together with an individual with a clear pattern of spared and impaired abilities who, in turn, casts a long shadow over the field”.

As far as I am concerned, it is still worth pursuing single-case methods in memory research. Scientists should wonder if modern neuro-imaging techniques and lesion methods lead to different conclusions because they are answering to slightly different questions. If this is the point then neuro-imaging studies can be guided from single-cases of brain-damaged patients and together create strong evidence for the understanding of mental processes, such as WM function, in healthy people.
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