The role of the medial prefrontal cortex in cognition, ageing and dementia

Abstract

Humans require a plethora of higher cognitive skills to perform executive functions, such as reasoning, planning, language and social interactions, which are regulated predominantly by the prefrontal cortex. The prefrontal cortex comprises the lateral, medial and orbitofrontal regions. In higher primates, the lateral prefrontal cortex is further separated into the respective dorsal and ventral subregions. However, all these regions have variably been implicated in several fronto-subcortical circuits. Dysfunction of these circuits has been highlighted in vascular and other neurocognitive disorders. Recent advances suggest the medial prefrontal cortex plays an important regulatory role in numerous cognitive functions, including attention, inhibitory control, habit formation and working, spatial or long-term memory. The medial prefrontal cortex appears highly interconnected with subcortical regions (thalamus, amygdala and hippocampus) and exerts top-down executive control over various cognitive domains and stimuli. Much of our knowledge comes from rodent models using precise lesions and electrophysiology readouts from specific medial prefrontal cortex locations. Although, anatomical disparities of the rodent medial prefrontal cortex compared to the primate homologue are apparent, current rodent models have effectively implicated the medial prefrontal cortex as a neural substrate of cognitive decline within ageing and dementia. Human brain connectivity-based neuroimaging has demonstrated that large-scale medial prefrontal cortex networks, such as the default mode network, are equally important for cognition. However, there is little consensus on how medial prefrontal cortex functional connectivity specifically changes during brain pathological states. In context with previous work in rodents and non-human primates, we attempt to convey a consensus on the current understanding of the role of predominantly the medial prefrontal cortex and its functional connectivity measured by resting-state functional MRI in ageing associated disorders, including prodromal dementia states, Alzheimer's disease, post-ischaemic stroke, Parkinsonism and frontotemporal dementia. Previous cross-sectional studies suggest that medial prefrontal cortex functional connectivity abnormalities are consistently found in the default mode network across both ageing and neurocognitive disorders such as Alzheimer's disease and vascular cognitive impairment. Distinct disease-specific patterns of medial prefrontal cortex functional connectivity alterations within specific large-scale networks appear to consistently feature in the default mode network, whilst detrimental connectivity alterations are associated with cognitive impairments independently from structural pathological aberrations, such as grey matter atrophy. These disease-specific patterns of medial prefrontal cortex functional connectivity also precede structural pathological changes and may be driven by ageing-related vascular mechanisms. The default mode network supports utility as a potential biomarker and therapeutic target for dementia-associated conditions. Yet, these associations still require validation in longitudinal studies using larger sample sizes.

Keywords: ageing; default mode network; dementia; prefrontal cortex; vascular cognitive impairment.

Graphical Abstract

Figure 1

Functional divisions of the human, non-human primate and rodent (mouse) prefrontal cortex (A and B) Frontal-side view of the human primate brain with illustration of the prefrontal cortex functional divisions including the ACC, demarcated around the typically reported mPFC subregions of dmPFC, vmPFC and medial OFC. (C–E) Tilted frontal-side view of the rodent mouse brain illustrated with the agranular prefrontal cortex divisions and demarcated around the commonly stated mPFC subregions of ACA, PL, ILA and medial ORB. Dashed black line marks the sagittal midline. ACA, anterior cingulate area; ACC, anterior cingulate cortex; AI, agranular insular area; dlPFC, dorsolateral prefrontal cortex; dmPFC, dorsomedial prefrontal cortex; ILA, infralimbic area; MOs, secondary motor area; OFC, orbitofrontal cortex; ORB, orbital area; PL, prelimbic area; vlPFC, ventrolateral PFC; vmPFC, ventromedial prefrontal cortex. The schematic is adapted from Carlén.

Figure 2

Rodent behavioural paradigms tasking distinct cognitive domains of working memory, decision-making, cognitive flexibility, and attention (A) The radial arm maze (RAM) and T-maze tasks assess working memory with delays and changing reward locations between trials. (B) The rat gambling task (RGT) and risky decision task (RDT) probe uncertainty-based decision-making varying in pellet (P) quantity, probability and punishment during the sessions; ‘safe’ choices are in green, whilst ‘risky’ choices are in red. (C) The attentional set-shifting task (ASST) examines set-shifting ability between changing reward-specific stimuli of odours or textures across trials. (D) The 5-choice serial reaction time task (5-CSRTT) assesses attention of responses to the light stimulus spatially, with correct nose-poke selection receiving a reward. The diagrams are adapted from Bizon et al., Callahan and Terry, and Winstanley and Floresco.

Figure 3

Summary of altered mPFC FC trends across ageing and disorders. (A) Pairwise FC changes (upwards red arrow indicates an increase and downwards blue arrow a decrease) in healthy (thin line), Alzheimer’s disease susceptible (dashed line) or both (thick line) aged subjects between mPFC subregions (green circles) and parietal cortices (PCs), insula (INS), hippocampal formation (HF), posterior cingulate cortex (PCC) and precuneus (PCU) brain regions (orange circles). (B) Pairwise FC changes in MCI (thin line), Alzheimer’s disease (dashed line) or both (thick line) between mPFC subregions and PCC, HF, PCs or inferior parietal lobule (IPL). (C) Pairwise FC changes in PIS (dashed line) between mPFC subregions and PCU; connectivity aberrations (purple box) in svMCI (solid outline) and PIS (dashed outline) between mPFC subregions and HF, PCC/PCU, PCs, superior frontal gyrus/middle frontal gyrus (SFG/MFG), insula (INS) and cuneus (CUN). (D) Pairwise FC changes in PD (thin line), APD (dashed line) or both (thick line) between the mPFC and PCC, caudate (CAU), cerebellum (CER), IPL/lateral parietal lobule (LPL), medial temporal lobe (MTL) and motor cortex (MC). The FTD study trends are not provided in order to remain succinct, as several mPFC connections were displayed across the two studies.