The functional role of the precuneus

Abstract

Recent advancements in computational approaches and neuroimaging techniques have refined our understanding of the precuneus. While previously believed to be largely a visual processing region, the importance of the precuneus in complex cognitive functions has been previously less familiar due to a lack of focal lesions in this deeply seated region, but also a poor understanding of its true underlying anatomy. Fortunately, recent studies have revealed significant information on the structural and functional connectivity of this region, and this data has provided a more detailed mechanistic understanding of the importance of the precuneus in healthy and pathologic states. Through improved resting-state functional MRI analyses, it has become clear that the function of the precuneus can be better understood based on its functional association with large scale brain networks. Dual default mode network systems have been well explained in recent years in supporting episodic memory and theory of mind; however, a novel ‘para-cingulate’ network, which is a subnetwork of the larger central executive network, with likely significant roles in self-referential processes and related psychiatric symptoms is introduced here and requires further clarification. Importantly, detailed anatomic studies on the precuneus structural connectivity inside and beyond the cingulate cortex has demonstrated the presence of large structural white matter connections, which provide an additional layer of meaning to the structural-functional significance of this region and its association with large scale brain networks. Together, the structural-functional connectivity of the precuneus has provided central elements which can model various neurodegenerative diseases and psychiatric disorders, such as Alzheimer’s disease and depression.

Introduction

The medial surface of the parietal cortex between the sensorimotor cortices of the paracentral lobule and the parieto-occipital cortex is commonly known as the precuneus. Given it is named in reference to the cuneus, a visual region,¹ and is wedged between visual and sensorimotor regions, most have previously suggested the precuneus primarily facilitates some form of sensory integration, higher level sensory processing, or other similar functions. While such propositions seemed like a reasonable hypothesis, years of clinical experience have demonstrated that surgical unilateral transgression of the precuneus does not universally cause obvious deficits in visuospatial processing or visual integration especially if occipital connections are spared.^2–4 Thus, these cortices are either not essential for this process, or at least these functions are very bilaterally represented. More recently, significant computational advancements and neuroimaging techniques have allowed for an improved mapping of the structural and functional connectivity of the precuneus.^5,6 These connectomic data provide significance to recent anatomic delineations of the precuneus and provides a mechanistic understanding behind the more recently described roles of the precuneus in complex cognitive functions.^7–10 Importantly, insight into the structural and functional connectivity of the precuneus also opens up important avenues behind its pathophysiological and therapeutic relevance in disease states.

In this review, we aim to synthesize a large and diverse body of evidence to provide some insight into the question of what the precuneus does if it is not solely a visuo-sensory integration area (or at least not a critical one).

A modern view of precuneus cortical organization and nomenclature

In most anatomic diagrams, the term ‘precuneus’ refers to the interhemispheric surface of the superior parietal lobe with the cingulate sulcus serving as an inferior boundary.¹¹ As we have learned more about the anatomy of this structure, its network organization and its functions, this gross anatomic boundary we would argue is inappropriately artificial, for reasons which should become obvious in this review.

In our definition of the precuneus (Fig. 1A and B), its anterior and posterior boundaries as the marginal ramus of the cingulate sulcus and the parieto-occipital sulcus, respectively, and its superior and inferior boundaries as the angle between the cerebral convexity and interhemispheric angle, and the fibres of the corpus callosum, respectively. This roughly defines the region as a triangular shaped area of medial parietal cortex with two concave edges. The antero-inferior and postero-inferior apices lie within the cingulate gyrus and are best defined as lying the coronal plane of the leg motor region of the paracentral lobule, and inside the isthmus of the cingulate gyrus, respectively.

Brodmann identified six cytoarchitectural regions in this anatomic area (Fig. 1C). Area 7 forms the superior and postero-superior boundary of the precuneus proper, while area 23 forms the bulk of the posterior cingulate gyrus. Area 31 is a small triangular area just posterior to the marginal ramus of the cingulate sulcus. The posterior bank of marginal ramus of the cingulate sulcus seems to be included in Brodmann area 31, which is not an irrelevant point, as described later. Areas 28, 29 and 30 lie in the retrosplenial cortex (RSC) which lies within the banks of the callosal sulcus.

These boundaries have been adjusted by several subsequent efforts in both cytoarchitectural and multimodal neuroimaging based methods (Fig. 1D and E). For the sake of brevity, we will not attempt to cover all the rationales for subdividing these regions and will simply describe the approach of the Human Connectome project (HCP).⁵ This approach used a detailed effort in multimodal neuroimaging, but further used cytoarchitectural frameworks as the naming and to guide their definition of areal boundaries, which provides some ability to link future observations with previous work.

The HCP approach indicated that the precuneus cortices contain 14 distinct areas (Fig. 1B).⁵ Area 23 was divided into area 23 part d (23d), which lies in the body of the cingulate gyrus, area 23c, in the posterior bank of the marginal ramus of the cingulate sulcus, and two areas, ventral 23ab (v23ab) and dorsal 23ab (d23ab), which lie in the retrosplenial cingulate gyrus and posterior body of the cingulate gyrus, respectively. These areas were redivided from a previous scheme, which had subdivided Brodmann area 23 into four regions, 23a, 23b, 23c and 23d; note that the placement of 23c in the marginal ramus of the cingulate sulcus differed somewhat from Brodmann’s maps and gives the 23 subunits a v-shape. Areas 28, 29 and 30 were found to be a single region called RSC. Compared to Brodmann’s initial description, area 31 was reduced in the anterior-posterior direction by both 23c anteriorly, and by a slight inferior extension of area 7 in the form of area 7 medial (7m). The small triangular remnant of area 31 was subdivided into three subunits, 31 anterior (31a), 31 posterior-dorsal (31pd) and 31 posterior-ventral (31pv). In addition to the aforementioned 7m, area 7 extends along the superior boundary of the precuneus, including area 7 anterior-medial (7Am) and 7 posterior-medial (7Pm). A new subregion of area 7, the precuneus visual (PCV) area, was defined in the space between the subdivisions of areas 7 and 31. Finally, while Brodmann did not characterize the banks of the parieto-occipital sulcus in detail, the HCP identified two areas, which they called parieto-occipital sulcus areas 1 and 2 (POS2 and POS1).

The precuneus is intrinsically organized into three functionally relevant brain networks

While having a detailed cortical map seems intuitively useful, particularly for communication and replication of results in the scientific community, the challenge of highly granular parcellations of the cortex is that, without insight into the functional significance of these distinctions, focusing on such minor distinctions seems unnecessary esoterica. However, improvements in our understanding of the large-scale network organization of the human connectome has provided these specific anatomic differences important meaning. Based on the recent literature, the functional significance and connectivity of the precuneus can best be understood by considering its functional involvement in three separate networks, and that these network affiliations are further evident according to differences in underlying structural connectivity of the precuneus.

An updated dual theory of two DMN systems for theory of mind and episodic memory

The first two networks involved in the precuneus have commonly been discussed in relation to two separate aspects of the default mode network (DMN). Raichle et al.¹² first described the DMN as a network which is displays brain activity when the individual is ‘awake and alert and yet not actively engaged in an attention-demanding task’, specifically including the medial prefrontal cortex and the posterior cingulate and precuneus. Others have further elucidated that the DMN likely has two prominent subnetworks which can also be understood based on its connectivity to the anterior versus posterior precuneus. Namely, the anterior portion of the DMN largely includes the key hubs—medial prefrontal cortex as well as the anterior portion of the precuneus—and is believed to facilitate theory of mind and self-referential thinking, while the posterior system of the DMN, involving the posterior precuneus and posterior cingulate cortex along with extensions of the superior and medial frontal gyri and temporal gyri, is related to episodic memory and visuo-spatial imagery.¹³ According to the Yeo-Buckner 17 network model, the anterior portion of the DMN likely represents the core of the DMN, while the episodic memory system is a separate DMN subnetwork with distinct features (Fig. 2A).¹⁴

A ‘para-cingulate’ network in the precuneus

Yeo et al.¹⁴ published a widely used network definition from resting-state functional MRI (fMRI) connectivity, which divided the human cerebral cortex into two forms: a coarse 7-network model and a finer-resolution 17-network model. These maps were created through rigorous clustering-based analyses of functionally coupled regions and confirmatory region-based intrinsic functional connectivity analyses in ways which are generalizable and reproducible between studies.^15–17 Specific to the structure and function of the precuneus is the observation that when parcellating the cerebral cortex into a finer network organization (e.g. from 7 networks to 17), an additional subnetwork of the central executive network (CEN) becomes apparent, specifically seen flanking the cingulate cortex and core DMN (Fig. 2A). For simplicity, we will refer to this network as the ‘para-cingulate’ network. While insufficient attention has been paid to the para-cingulate network, its existence is confirmed by numerous converging methods, including parcellation studies,¹⁵ graph theoretical work¹⁸ and independent component analyses.^14,18,19 Thus, while authors have generally not drawn specific attention to this para-cingulate network explicitly, it appears likely that a small CEN aligned resting-state network exists straddling the posterior cingulate component of the core DMN network in the precuneus region.

The anatomy of the para-cingulate network

The para-cingulate network can be seen as a two-part system (Fig. 2B). Its ventral component can be seen beginning at the isthmus of the cingulate gyrus bordering the parahippocampal gyrus and then extending to the middle cingulate gyrus (corresponding to Brodmann areas 23 and 28–30). This inferior-ventral portion includes the HCP parcels RSC, 23c, 23d and area 33 prime (33pr). Its more superior-dorsal component at the opposite side of the core DMN begins at the most superior portion of the precuneus and then extends in an inverse ‘V’ fashion. This superior-dorsal region includes the HCP parcels POS2, 7Pm, and PCV. What is particularly interesting is, according to Brodmann’s map, the marginal ramus of the cingulate sulcus includes Brodmann areas 5, 31 and 7, but the HCP includes this marginal ramus as area 23 and displaces Brodmann area 31 anteriorly as well as posteriorly by area 7. Importantly, both of these changes to anterior and posterior portions of Brodmann area 31 correspond to the starting boundaries of portions of the para-cingulate network.

Short and long-range structural fibres connect the para-cingulate

The para-cingulate network is a task active network located entirely in the precuneus and associates into the larger CEN in more coarse parcellation analyses demonstrating it is a CEN subnetwork.¹⁴ Our lab and others have previously used a variety of tract-tracing approaches, including diffusion tensor imaging (DTI) and anatomical cadaver dissections, and have found there are consistent and distinct structural connections which likely facilitate para-cingulate network functions and differentiate them from surrounding networks in the precuneus (Fig. 3A).²⁰ In general, this is a highly connected network seated in the precuneus that demonstrates both short-range and long-range connections to surrounding cortices. Local association fibres and short-range bundles are most commonly seen connecting areas 7Pm, PCV and POS2 of the para-cingulate network. They are extensively interconnected with each other within the precuneus, forming a local hub-like region of the network. Additionally, these short range fibres connect these regions to the adjacent parietal and occipital cortices, including areas PCV and 7Pm to the paracentral lobule and superior/inferior parietal lobe, and area POS2 to the occipital cortices (Fig. 2B).

Long-range white matter connections of the para-cingulate are largely comprised of the cingulum bundle, which connects the precuneus to frontal regions, but also include the middle longitudinal fasciculus (MdLF) to connect with insular-opercular cortices and temporal regions, superior longitudinal fasciculus (SLF) connections to motor cortices and inferior fronto-occipital fasciculus (IFOF) connections linking the precuneus to frontal and visual cortices.^17,21,22 Anatomic dissections highlight that divisions of these major white matter bundles in particular can differentiate the different network anatomy of the precuneus. While one branch of the cingulum bundle (CB-I) specific to the DMN can be seen connecting the precuneus to the orbitofrontal and anterior cingulate cortices to connect anterior and posterior DMN nodes, a larger and distinct cingulum branch (CB-III) can be seen travelling from the precuneus and terminating along the medial aspect of the superior frontal gyrus (SFG) (Fig. 3B).⁶ This specific branch connects regions of the para-cingulate network and may facilitate internetwork communication with other portions of the CEN, such as its anterior nodes in the SFG, to facilitate functions such as reward anticipation and related responses.²³ Additional functions in the context of known structural connectivity are explained in the next section.

Functional roles of the para-cingulate network in the precuneus

Structural-functional relationships provide fundamental knowledge to understanding various brain regions, given that the function of a region can be in part determined by its underlying structural architecture.²⁴ As such, recent work on the structural connectivity of the para-cingulate network can provide further information on its speculative functional relevance. The para-cingulate network has been suggested to perhaps have a memory-related role (see Fig. 3 in Power et al.²⁵) as well as associated age-related decreases in connectivity over time.²⁶ However, work by our team on these regions suggests the functional relevance of this network likely extends far beyond memory alone and into various complex cognitive functions, hence its importance in distinction from a broader CEN system.^6,27 Here, we reviewed the available task-based fMRI literature and mapped out possible functions of the para-cingulate network according to the Research Domain Criteria (RDoC) linking the activation to HCP parcellations (Table 1). We see that the para-cingulate network has a number of functions involved in memory, but many other functions of importance also arise. In fact, the literature supports that many of these internally focused processes are also found when examining the DMN in RDoC, which may be related in part to their close physical proximity. However, despite this anatomic proximity and some similarities in functional relevance, important differences are found in the activation of various precuneus subregions and their associated networks (e.g. DMN subnetworks versus para-cingulate) according to neuroimaging studies during various tasks or at rest (Table 1). We illustrate these functions and the potential underlying structural connections underlying these functions as estimated from DTI and previous work in Fig. 3A, and they are highlighted below in this section.

In general, as a task-positive network positioned within the precuneus, the para-cingulate network is in a strategic position to facilitate the integration of internal and external stimuli and link it with previous knowledge to guide subsequent behaviour. Studies have demonstrated activation of these regions in actions related to various internal dynamics (i.e. self-knowledge²⁸), anticipation and effort for specific tasks,^23,29 as well as monitoring the internal sensorimotor dynamics for optimal performance (Table 1).^30,31 Such functions are important to appropriately approach a complex situation that requires interpretation of a situation based on prior knowledge, completion of risk/reward assessments, updating working memory according to new cognitively relevant information and then choosing or guiding an appropriate motor response. Within this example and framework for the para-cingulate network, prefrontal and anterior/middle cingulate connections with the precuneus through the cingulum are likely responsible for the interpretation of stimuli and risk calculation, which can then be filtered through to the motor system through SLF connections, such as with the supplementary motor area (Fig. 3A).

The role of the precuneus in memory has been studied extensively in the past, and updated network anatomy in this region can provide additional insight. Precuneus regions in both the para-cingulate and DMN networks share some overlap in memory functions (Table 1). In general, such memory functions support the greater role of the para-cingulate network as a task-positive network, given the CEN is known to be vital for the active maintenance and manipulation of information in working memory.^32–34 For instance, RDoC analyses demonstrated the importance of 7pc in the function of updating working memory (Table 1). Given this region in many individuals is connected via the IFOF bundle, which maintains cognitively relevant representations of the visual system,²¹ and demonstrates connections to the SMA region, these connections likely facilitate guiding motor actions based on acquiring new information.^35,36 Previous neuroimaging work on declarative memory in healthy subjects demonstrated that tasks which require learning words through repeated sequential associations (‘sequential learning’) or through learning words via spatial locations along a well-known path (‘spatial learning’) activate para-cingulate areas POS2 and 7Pm, respectively.³⁷ The authors highlight that these two tasks elicited no hippocampal activity, which instead was present with autobiographically associated words. In line with these results, previous work by our team demonstrated that the posterior precuneus (DMN) exhibits robust structural connections with the hippocampus.⁶ Thus, the network organization of the precuneus may lend additional insight into its larger role in various memory functions, namely through a posterior DMN network involved in episodic memory and a para-cingulate network involved primarily in working memory. Given that it is well known that these two networks interact to control various functions like memory,^10,38,39 future work should look to examine how dysfunction of the para-cingulate and related (dis)inhibition of the DMN contributes to pathophysiological states.

Another interesting observation worth noting is that facial communication and interoception arise as main functions of this network, and that work on the structural connectivity in this region may support these function.^6,27 We have previously found connections extending from the superior para-cingulate portion of the precuneus to a number of areas involved in the face-motor network via the MdLF (Fig. 3C). Specifically, along the marginal ramus of the cingulate sulcus, there are areas, PCV and 23c, of the para-cingulate network that co-activate with a number of opercular regions involved with facial recognition (Fig. 3D). Thus, these structural connections may support the functional roles of interoception and facial communication of the para-cingulate network.

Structural and functional relationships of the precuneus in pathophysiological states

Resting-state fMRI has provided unique insights into how the precuneus and other cerebral cortex is organized, and these are well supported by cytoarchitectural studies when refined. More recently, clarified data on the underlying structural connectivity of the precuneus in particular have provided an additional layer of meaning to the structural-functional significance of this region and its association with large-scale brain networks.^6,27 The precuneus is a highly interconnected ‘rich club’, and its importance for complex cognitive functioning can be understood based on its involvement in three distinct brain networks. Two of these networks have been well described previously, including the core of the DMN and an episodic memory subnetwork of the DMN. A third, which we refer to as the ‘para-cingulate’ network here, extends from the CEN network in finer parcellation models flanking the cingulate cortex and core DMN, and based on available literature demonstrates importance in many internally focused functions beyond just memory, as supported by structural connectivity in this update. An improved understanding of this underlying connectivity within and beyond the precuneus has opened up a number of ideas to examine their pathophysiological relevance.

An impressive amount of data now supports that various neurodegenerative diseases, brain tumours and psychiatric disorders commonly target highly connected brain regions. These ‘hubs’ are believed to be the targets of pathophysiological processes likely due to the increased neurovascular and metabolic demand required to maintain their highly connected states.^40,41 The precuneus remains one of the most connected hub regions in the human cerebrum and accounts for approximately 35% of glucose metabolism within all DMN brain regions.⁴² It is therefore positioned as a key vulnerability, which when damaged or disrupted can catalyse various metabolic and structural cascades relevant to a number of disease states.⁴³ In line with this idea, an increasing amount of evidence has revealed the central role of the precuneus in various neurological and neurodegenerative diseases such as autism,⁴⁴ schizophrenia^45–47 and Alzheimer’s disease.^48–51 In particular, it is now relatively clear that functional and structural connectivity abnormalities in precuneus are central to the development of Alzheimer’s disease, perhaps even before symptoms emerge, as pathology accumulates.⁴⁸ This network dysfunction can be measured with fMRI or DTI, and allows for early detection of Alzheimer’s disease progression. Numerous studies have demonstrated that the connections discussed above, between the posterior precuneus of the episodic memory portion of the DMN and temporal regions, show increased activity during the preclinical stages of Alzheimer’s disease^49,50,52 and can identify individuals at increased risk.⁵¹ By identifying these connectivity abnormalities, targeted neuromodulatory treatments at connectomic structures of the precuneus may slow cognitive and functional decline.⁵³ Ultimately, recent work has highlighted the ability to use an improved connectivity map of the precuneus to identify biomarkers for disease risk as well as novel therapeutic targets for disease progression.

Connectivity dysfunction or disruption in the precuneus has been identified as a key feature in the development of many symptoms, which together classify various psychiatric illnesses. Structural and functional evidence has suggested that disruption in precuneus connectivity strongly underlines symptoms of depression,^54–58 bipolar disorder⁵⁹ and psychotic disorders.^46,60 However, to facilitate effective treatment of complex mental illnesses, it is becoming increasingly clear that each pathology is generally heterogenous according to vague DSM-5 classifications, and treatment may instead benefit from considering each symptom individually according to the specific network localization. As an example, although the association of precuneus connectivity features with depression is well classified and commonly targeted for neuromodulation, the efficacy of these treatments remains unpredictable and often poor, likely due to interindividual differences in network dysfunction as well as a lack of complete understanding of the networks involved.⁶¹

Worthy of future work is the role of the para-cingulate network in mental illnesses like depression. Using RDoC to examine the available literature, our results suggest that the para-cingulate network likely has important roles in a number of self-referential processes beyond just memory, including interference control, fear, grief, interoception and self-knowledge. Evidence about area PCV in this network has suggested its importance in normal functions such as working memory as well as the recognition of emotional faces over neutral objects.^6,27,62 Such connections can enable many of the known mood-congruent processing biases seen in depressed individuals, such as hyperactive processing of negative faces.⁵⁴ Examining this connectivity in mood disorders can not only further our understanding of heterogenous functional impairments between individuals, but also offer novel targeted therapies between individuals with similar diagnoses,^61,63 as well as provide prognostic biomarkers based on network dysfunction.^58,64 Future work should look to further clarify how para-cingulate network connectivity may better model various symptoms of affective disorders like depression to better understand disease characterization, progression and treatment.

Conclusion

Substantial improvements in neuroimaging and mathematical approaches have demonstrated that the precuneus is a highly functional region with important roles in complex cognitive functions, such as memory, theory of mind and self-referential processing. These functions can be explained by the unique functional organization of the precuneus within distinct brain networks. Namely, the core of the DMN and episodic memory subnetwork of the DMN support processes of theory of mind and episodic memory, while the ‘para-cingulate’ network is a novel subnetwork of the CEN requiring further study due to likely significant importance in working memory and many self-referential and sensorimotor processes, such as interoception, consciousness and sensorimotor dynamics. Structural connectivity studies support these network associations and provide tangible white matter tracts underlying these functional roles, as well as provide additional insight into their pathophysiological relevance. The precuneus is a highly interconnected hub region with greater susceptibility to various neuropathological processes, such as Alzheimer’s disease and possibly glioma localization. Studies which have recently better clarified the structural-functional connectivity in this region have provided a number of new avenues to examine its prognostic and therapeutic importance in clinical neuroscience. Future work should look to correlate neuroimaging findings with underlying electrophysiology work to better understand distinct region-specific patterns of neural activity and the biological relevance of these unique structural-functional relationships.

Funding

No funding was received towards this work.

Competing interests

M.E.S. is a co-founder of Omniscient Neurotechnology. No aspects related to these products were discussed in the current work. N.B.D. reports no competing interests.

References