Background
Neuroplasticity constitutes the foundation for all experience-based changes in the brain. The long-term strengthening of synaptic connections, known as long-term potentiation (LTP), represent neuroplasticity on the synaptic level, and is recognized as the strongest candidate mechanism underlying learning and memory. LTP was first demonstrated in vivo five decades ago by inducing synaptic plasticity in the rodent hippocampal formation through repetitive electrical stimulation. It has since been demonstrated throughout the neocortex, indicating that LTP is an omnipresent mechanism of plasticity in the central nervous system. Due to the inherent invasiveness of inducing LTP directly in the brain, the study of human synaptic plasticity has been approached through modulation of sensory event-related potentials following high-frequent or prolonged sensory stimulation. So-called stimulus response modulation (SRM) of visual or auditory evoked potentials (VEP/AEP) represents a promising method as a non-invasive index of synaptic plasticity. As SRM serves as a proxy for long-term potentiation it is therefore referred to as “LTP-like”. Previous studies have demonstrated significant modulation effects within both the visual and auditory domain, and several studies have demonstrated deficits in VEP modulation across clinical populations in disorders marked by both affective and psychotic symptoms. This suggests that LTP-like modulation of sensory-evoked potentials might be a viable probe into impaired neuroplasticity associated with multiple forms of psychopathology.
Aims
The general aims of the current thesis were twofold. A principal aim was to replicate previous studies of non-invasive induction of LTP-like plasticity in both the visual and auditory modality, as well as examining potential cross-modal associations through a multimodal experimental paradigm. Secondly, the thesis aims to explore possible functional correlates of stimulus-response modulation through its associations with psychological distress and performance-based learning and memory function in a healthy population.
Methods
A multi-modal sensory evoked potential paradigm incorporating both visual and auditory high-frequency stimulation (HFS) were used to assess modulation effects from baseline to post-HFS recordings. Paper I included 101 healthy subjects in order to replicate previous demonstrations of modulation of VEP and AEP after high-frequency stimulation, as well as to assess cross-modal associations indicating shared underlying plasticity mechanisms. Paper II&III used a sample of n=111 to explore associations between VEP modulation and psychological distress as well as associations with performance-based learning and memory. Psychological distress in a healthy population was assessed through the questionnaires Beck’s Depression Inventory II and the Perceived Stress Scale – 10. Learning and memory performance was assessed through the Rey Auditory Verbal Learning Test and its visual analogue, Aggie Figures Learning Test. Additional neurocognitive assessment categorized in the domains of attention, executive function, processing speed and verbal fluency were administered.
Results
A replication of previous findings showing robust potentiation of the visual evoked potential was evident, lending further support to the notion that high-frequent visual stimulation is a viable probe into LTP-like synaptic plasticity in the human visual cortex. The auditory evoked potentials did not fully replicate previous work, though a significant modulation of certain components of the auditory evoked potential were found. In contrast to our hypothesis, there were no significant within-subject cross-modality correlations between modulation in the visual and auditory modalities. Examining the functional significance of SRM, we found that reduced LTP-like synaptic plasticity is associated with higher levels of self-reported symptoms of both depressive symptoms and perceived stress in healthy subjects. There were also significant differences between participants showing a higher degree of modulation (> 1 SD above mean) on self-reported symptoms of both depressive symptoms and stress compared with participants showing a lower degree of modulation. Furthermore, several significant age-corrected positive correlations were found between VEP modulation and both visual and verbal learning and memory performance. There were also significant differences in learning and memory performance between healthy participants showing a higher degree of modulation (> 1 SD above mean) compared to participants showing a lower degree of modulation. No significant associations were found between VEP-plasticity and other neurocognitive domains.
Conclusions
The papers included in the current thesis replicated and confirmed previous reports demonstrating a significant effect of high-frequency stimulation in both the visual and the auditory modality, evident as amplitude changes post HFS. The effect was more modest and limited to later ERP components in the auditory domain. In contrast to our hypothesis, no significant correlations were found across sensory modalities. This lack of association might be due to characteristics of the experimental design (i.e., fatigue, habituation). Another possibility is that these measures of LTP-like cortical plasticity represent different mechanisms, explaining why modulation in one sensory domain of cortical plasticity does not necessarily translate to cortical plasticity in another sensory domain.
Exploring the relationship between VEP modulation and psychological distress demonstrated significant moderate negative correlations between visual SRM synaptic plasticity and self-reported assessment of depressive symptoms and stress in a healthy population. This indicates that LTP-like plasticity is sensitive to sub-clinical levels of psychological distress, and the results are in line with previous studies demonstrating reduced VEP-plasticity in clinical populations. A common underlying mechanism driving the impairment in plasticity could potentially be stress, as heightened stress is implicated in most psychiatric disorders. Thus, impaired synaptic plasticity in the visual cortex might not necessarily represent a central pathophysiological mechanism but may rather be associated with a maladaptive response to stress.
Significant associations were also found between VEP modulation and performance-based learning and memory function. This association was specific for learning and memory and not found in other neurocognitive domains, indicating a specificity that support the assumption that LTP play an important role in learning and memory. Though it is unlikely that the complexities of human memory can be reduced to a sole mechanism, LTP might be regarded as necessary but not sufficient for learning and memory processes to occur. SRM represent a promising method to further investigate LTP-like plasticity and human learning and memory mechanisms.