Executive Function Depression Pathway (EF Pathway)

The proposed EF Pathway encapsulates developmental or environmental deficiencies, biological abnormalities in the PFC and cognitive deficits leading to decreased problem-solving and flexible thinking skills, resulting in negative life events that lead to depression onset (see Figure10.1). Rajkowska, Miguel-Hidalgo et al.’s (1999) histopathological analysis comparing the brain tissue of post mortem depression patients and healthy matched tissue found brain abnormalities in the dlPFC and OFC, including differences in neuronal size, cortical thickness and glial density. According to Rajkowska, Miguel-Hidalgo et al., the reduction in glial density, for example, could result in altered metabolism (performance) of those areas (see Section 1.5 for more details). Blood activation studies have shown that the dlPFC and OFC are pivotal to EF

(Birrell & Brown, 2000; Buckley et al., 2009; Killgore et al., 2007; Owen et al., 2000; Wagner et al., 2006) and therefore, altered metabolism in these areas could contribute to EF deficits. However, no studies have made this link directly.

Biological changes in the PFC have been suggested to be due to developmental or environmental factors rather than the course of depression (Rajkowska, Miguel- Hidalgo et al., 1999; Sheridan & McLaughlin, 2014). This has been demonstrated in animal studies where developmental deficiencies in the form of early adverse life events, result in EF deficits and cellular changes in brain areas that are key to EF (Baarendse et al., 2013; Fone & Porkess, 2008; Makinodan et al., 2012; Stamatakis et al., 2016) However while cellular changes in the above animal studies correspond to brain areas associated with the human dlPFC and OFC whether the PFC of rats and mice can be generalised to the human PFC is debatable (Uylings et al., 2003). Developmental or environmental deficiencies leading to cellular changes and EF deficits forms the initial stages of the EF Pathway (see Figure 10.1).

To observe a possible link between biological abnormalities and cognition, a relevant subgroup such as primary depression was required. As shown in Study 5 of this research (see Table 10.3), a significant correlation between GABA and working

memory (N-back, Word Recall) occurred only in the subgroups primary depression and ordinary mathematics. A rationale for this result is firstly explored in terms of the subgroup primary depression.

Primary depression, depression onset not due to a non-depressive disorder or medical condition, has already demonstrated some form of biological basis with a relationship with low plasma GABA concentration. Petty, Kramer and Feldman (1987) showed that participants with primary depression had significantly lower plasma GABA concentration than the healthy control group or those with secondary depression. As

glial cells affect the uptake of glutamate, which is a precursor to GABA (Öngür et al., 1998), low GABA concentration may simply be an indicator of cellular changes such as reduced glial density in the PFC. If low GABA concentration is an indicator of cellular changes in the PFC then corresponding EF deficits should be evident.

The results of the current study were partially consistent with this. For the primary depression subgroup, there was a significant medium positive correlation for plasma GABA concentration and EF tests 2-back (updating) and Word Recall Trial 4 (verbal learning and memory). In addition, note there is an increase in Table 10.3 in r

for Word Recall Trial 5 for the primary depression subgroup. As explained in the above discussion (see Section 10.5.2), 2-back and Word Recall Trials 4 and 5 are adequate measures of updating and verbal learning and memory, and both these EF function measures have a significant working memory component.

The relationship between low GABA concentration and poor performance in the updating and verbal learning and memory tasks was also evident in the ordinary

mathematics subgroup (see Table 10.3). Due to the overlap in participants in the two subgroups, this result was not unexpected. In Study 5, the results showed that for the ordinary mathematics subgroup, plasma GABA concentration significantly correlated with 2-back, Word Recall Trials 4 and 5, and Total Trials. Whether young adults who study ordinary mathematics is an indicator of higher probability of cellular

abnormalities in the PFC, reflected in lower mathematical ability, can be considered for future investigations.

The above results for the subgroups primary depression and ordinary

mathematics indicate a link between a biological measure, plasma GABA concentration, and EF. Equating low concentration of plasma GABA to cellular deficits is speculative even though there is a literary basis (Gos et al., 2009; Karolewicz et al., 2010; Öngür et

al., 1998; Rajkowska, O’Dwyer et al., 2007). This demonstrates one of the hurdles with investigating the relationship between cognition and human PFC cellular abnormalities as past cellular studies are restricted to post mortem brain tissue. Measuring brain activity using non-evasive techniques such as an electroencephalogram (EEG) or fMRI may provide a stronger link in the relationship between GABA, cellular abnormalities and cognition (See Section 11.9.2.1).

The final stages of the EF Pathway state that deficits in EF, which essentially aid in successfully navigating new and unforeseen challenges, result in negative outcomes, that could include stressful or negative life events, which have been demonstrated to contribute to depression onset (Brown, 1993; Kendler et al., 1993; Phelan et al., 1991). Life events also play a role in depression onset in the Prosodic Pathway (see Figure 8.1), except it is assumed that the life events would be non-severe. There are mixed results regarding whether non-severe life events could result in the onset of an initial depressive episode, rather than only in depression reoccurrence (Brown, 1993; Kendler et al., 1993; Phelan et al., 1991; Stegenga et al., 2012). However, this argument does not apply for the EF Pathway, because life events resulting from an inability to successfully navigate unforeseen challenges could be severe.

Figure 10.1. Executive Function Depression Pathway

In summary, the EF Pathway extends the proposed biological basis for EF deficits model (see Figure 6.1) by suggesting that EF deficits lead to difficulties in coping with unforeseen challenges, result in stressful or negative life events, leading to depression onset (Kendler et al., 1993; Phelan et al., 1991). Both the subgroups primary depression and ordinary mathematics demonstrated a significant relationship between

plasma GABA concentration and working memory, demonstrating a possible link between cellular abnormalities and cognitive deficits. The EF Pathway forms a model for future research.

10.6

Conclusion

This study has examined the relationship between plasma GABA concentration and cognition. It has found that for subgroups primary depression and ordinary

mathematics, plasma GABA concentration significantly correlated with updating and verbal learning and memory. It was suggested that this result represents a relationship between plasma GABA concentration and working memory capacity. The significant result highlighted the importance of recognising subgroups relevant to the ‘pathway’ of the depression that is being researched. It was also suggested a biological basis for cognitive deficits, indicated by low plasma GABA concentration, provides an

explanation for the trait-like properties of cognitive deficits such as verbal learning and memory. The EF Pathway was proposed, postulating that suboptimal developmental and environmental factors can lead to cellular changes and corresponding EF deficits. It was further proposed that these EF deficits would negatively affect skills such as

problem-solving and flexible thinking, resulting in stressful or negative life events, which could lead to depression onset. The EF Pathway is suggested as a model for future research.

Chapter 11:

Conclusion

This chapter summarises the main aims and findings of this thesis. It includes comments regarding the new depression pathways and research limitations, as well as an outline for future research. The aim of this thesis was to explore the cognitive deficits associated with young adults with depression and anxiety disorders. Previous literature, mostly conducted with young to middle-aged adults, had demonstrated that cognitive deficits in the domains of EF are especially relevant to this field (Castaneda, Tuulio- Henriksson et al., 2008; Snyder, 2013). The sample for the current research was subclinical and the majority of participants were recruited from first- and second-year university psychology classes.