Earliest Amyloid and Tau Deposition Modulate the Influence of Limbic Networks During Closed-loop Hippocampal Downregulation

Stavros Skouras; Jordi Torner; Patrik Andersson; Yury Koush; Carles Falcon; Carolina Minguillon; Karine Fauria; Francesc Alpiste; Kaj Blenow; Henrik Zetterberg; Juan D. Gispert; José L. Molinuevo


Brain. 2020;143(3):976-992. 

In This Article


Adding to our knowledge, this is the first real-time neurofeedback study using CSF biomarker data. The results in cognitively unimpaired participants at risk for Alzheimer's disease corroborate that differences of EC in the cingulate cortex play an important role in the pathophysiological continuum of Alzheimer's disease and show for the first time that such differences may begin at a very early pathophysiological stage. The latter finding suggests that hippocampal self-regulation tasks, enabling functional connectomic analyses, can be of benefit in revealing information of clinical relevance to Alzheimer's disease progression.

During hippocampal downregulation, the decreased EC in the ACC and primary motor cortex, which is associated with abnormally decreased CSF amyloid-β42 levels and, by extension, to increased amyloid-β plaque deposition in the brain, stands out as a potential neural correlate of elevated amyloid deposition, particularly because the ACC is among the first regions where amyloid deposition can be detected with PET imaging (Grothe et al., 2017). Because of the characteristics of our sample (Table 1 and Table 2), these findings represent early pathophysiological alterations, without objectively measurable impact on overall memory performance, that relate to the brain network involved in the regulation of hippocampal hyperactivity. They suggest that in subjects with abnormal amyloid-β42 deposition, the ACC is less influential in regulating hippocampal CA1 (adjusted for risk factors and task performance). According to current models, the ACC, together with the anterior insula, as well as parts of the prefrontal cortex, parietal lobule, ventral striatum and thalamus, comprise the brain network that is primarily responsible for learning to voluntarily regulate other brain areas through neurofeedback training (Sitaram et al., 2017). The perspective provide a mechanistic explanation for the reason most of these areas, specifically, are engaged by the present VR neurofeedback paradigm, leading to enhanced sensitivity in relation to early alterations of their connectivity and systemic network function.

With elevated CSF p-tau levels, EC decreases in the prefrontal cortex and the posterior cingulate cortex, while EC increases in the ACC and ventral striatum; i.e. during early stages, amyloid-β42 accumulation in the brain and tau phosphorylation seem to have opposite effects on EC in the ACC. The ACC is also involved in the brain signature of cognitive resilience, which is related to its metabolic capacity (Arenaza-Urquijo et al., 2019). The possibility of EC in the ACC initially decreasing and later on increasing, in early response to the subsequent steps of a pathophysiological cascade, resembles the concurrent pattern of default mode network (DMN) connectivity, which increases proportionally to CSF amyloid-β42 levels within the range of normal amyloid values, but decreases proportionally to CSF amyloid-β42 levels within the elevated range of abnormal amyloid accumulation (Palmqvist et al., 2017). This is supported by the decrease of EC in the posterior cingulate cortex/precuneus/cuneus that comprises the main DMN hub (Smith et al., 2009; Andrews-Hanna et al., 2010; Spreng and Grady, 2010). Moreover, recent evidence suggests that baseline EC in the posterior cingulate cortex/precuneus region is predictive of first-session DMN neurofeedback regulation learning (Skouras and Scharnowski, 2019). Overall, the EC differences associated with increased CSF p-tau levels and by extension to the formation of neurofibrillary tangles in the brain, resemble results found in advanced patients with Alzheimer's disease with dementia, in the ACC and occipital cortex (Binnewijzend et al., 2014). In this context, the present results corroborate the most relevant literature and support shifting the timeframe for the detection of aberrant functional alterations, earlier than previously evidenced, to the presymptomatic stage of Alzheimer's disease. Of particular importance, the present findings suggest that aberrant EC initially precedes neurodegeneration, rather than resulting from it. This is supported by complementary evidence showing minimal overlap between the ACC cluster and regions with grey matter reductions in patients with Alzheimer's disease (Binnewijzend et al., 2014).

Left BA8, the cluster presenting decreased EC in the left prefrontal cortex, is one of the main loci of autobiographical memory (Janata, 2009) and appears to be suitable as an accessible target region for non-invasive neurostimulation intervention studies (Reinhart and Nguyen, 2019). Following the interpretational framework proposed by recent work with resting-state EC and Alzheimer's disease CSF biomarkers (Skouras et al., 2019a), given the involvement of the ACC, PFC and ventral striatum in the neurofeedback learning network (Sitaram et al., 2017), it is feasible that the decreasing EC of the PFC is being compensated by increasing EC in the ACC and ventral striatum; the latter of which is affected by amyloid deposition only at a relatively advanced stage (Grothe et al., 2017). Considering the crucial roles of the hippocampus, ventral striatum and cingulate in affective processing (Dalgleish, 2004), these findings support proposing that some of the earliest effects along the pathophysiological continuum of Alzheimer's disease are related to dysfunctions of affective processing, similar to almost all neuropsychiatric pathologies (Connan et al., 2003; Leppänen, 2006; Hoekert et al., 2007; Mannie et al., 2007; Kang et al., 2012). Additionally, in a mouse model of Alzheimer's disease, selective neurodegeneration in the ventral tegmental area (VTA) at pre-plaque stages, resulted in lower dopamine outflow in the hippocampus and nucleus accumbens and correlated with impairments of synaptic plasticity in CA1, as well as memory deficits and dysfunction of reward processing (Nobili et al., 2017). The VTA is particularly responsive to neurofeedback training (Macinnes et al., 2016) and outgoing fibres from the VTA connect directly to the hippocampus (Gasbarri et al., 1994; Penner and Mizumori, 2012). Thereby, it is also feasible that the increased EC in the dopaminergic ventral striatum compensates for early aberrancies in VTA function that are undetectable with 3 T whole-brain functional MRI. In addition, a contemporary model proposes that the hippocampus, the prefrontal cortex and the VTA, form the most crucial components of the long-term memory network (Penner and Mizumori, 2012).

As hypothesized, during hippocampal downregulation, cognitively unimpaired subjects with elevated CSF p-tau levels, exhibit a similar increase in EC, as the one present during resting state in patients with Alzheimer's disease (Binnewijzend et al., 2014), despite important improvements in normalization methods across studies (Avants et al., 2008; Klein et al., 2009). This corroborates a replicable resting-state finding that was previously only measurable when investigating across control subjects and patients with dementia due to Alzheimer's disease (Binnewijzend et al., 2014; Skouras et al., 2019a). This observation suggests that the developed VR neurofeedback task may indeed be hypersensitive to preclinical alterations in brain function. In contrast, an important effect of healthy ageing is decreased EC in the cingulate cortex, during hippocampal downregulation. This corroborates previous evidence from task-free functional MRI, showing that healthy older adults (mean age = 63, SD = 7) present significantly lower EC in the cingulate than healthy younger adults (mean age = 24, SD = 4; Antonenko et al., 2018). Overall, the effect of healthy ageing on EC across the cingulate cortex (Figure 4) is opposite to that of elevated CSF p-tau levels (Figure 3), clinical symptoms (Binnewijzend et al., 2014), and Alzheimer's disease progression (Skouras et al., 2019a). Thereby, current evidence suggests that the cingulate decreases in centrality in healthy ageing and increases in centrality in Alzheimer's disease, with noticeable differences even in a very early phase. The effect of healthy ageing on EC in the inferior temporal gyrus, points to the possibility that in healthy ageing, increasing resources are being devoted to semantic memory (Binney et al., 2010). To our knowledge, there is no previous evidence of EC correlation with age in the inferior temporal gyrus; however, no previous ECM ageing study controlled for the effect of any CSF biomarkers. Moreover, recent evidence suggests cognitive decline may emerge from functional decoupling within a neural circuit composed of temporal and frontal regions, which is integral to monitoring real-world information and storing it into memory (Reinhart and Nguyen, 2019).

In general, the EC findings could be different using a hippocampal upregulation task, because upregulation and downregulation learning can be negatively correlated (Skouras and Scharnowski, 2019). It is important to determine the specificity of the present findings to hippocampal downregulation tasks and to replicate them in longitudinal studies that include both downregulation and upregulation, as well as sham neurofeedback conditions. It is equally important to validate the tentative interpretations offered here, using the same self-regulation paradigm in studies involving patients with mild cognitive impairment. With these aims, we have made the developed VR environment publicly available as open-source software, to enable replication studies and multicentre investigations within a standard framework (see 'Code and data availability' section). The latter might enable the aggregation of sufficient datasets to derive accurate functional neuroimaging-based diagnostic models using machine learning algorithms.

As noted, four participants had a subjective impression of cognitive or memory decline, while their cognition was preserved based on objective cognitive testing. These participants did not present a consistently distinctive profile with regards to cognitive scores, hippocampal volume, genetics or CSF biomarkers. One participant was an APOE ε4 heterozygote with normal biomarkers, one was an APOE ε4 non-carrier with abnormal amyloid-β42 level but normal p-tau level, one was an APOE ε4 non-carrier with normal amyloid-β42 level but abnormal p-tau level, and one was an APOE ε4 heterozygote with abnormal amyloid-β42 level and abnormal p-tau level. However, all four participants were female, with a relatively high level of education or a relatively high hippocampal downregulation neurofeedback score. Descriptive statistics for these four participants, in relation to control and preclinical Alzheimer's disease participants are provided in Supplementary Table 2. Based on CSF data from a larger sample (n = 261) from the ALFA cohort, a subjective impression of cognitive or memory decline is relatively uninformative in the context of the present study. Therefore, we have considered the influence of the four described participants identically to that of the other participants, as ordinary instances within the biological and cognitive variability that exists in the healthy to preclinical range of the Alzheimer's disease continuum.

We have demonstrated that amyloid deposition results in aberrancy with regards to the functional brain network used to downregulate hippocampal subfield CA1. Further, significant differences in EC associated with CSF biomarkers in clinical Alzheimer's disease, are also measurable in presymptomatic stages. Moreover, we provide a standard paradigm to replicate and extend this work on a global level. This opens new avenues for further research applications, which quantify and monitor disease progression, by identifying early alterations in the self-regulation of brain function, with potential for non-invasive prognostic screening.