In the present study, we performed focused parcellation-based micro-dissections to investigate the fiber tracts connecting precuneus and TP. Our study revealed a distinct group of fibers interconnecting the POS2 with areas 35, 36, TI, and TG. These fibers belong to the CB-V system and exhibit a very close relationship with the cingulum, SRF, forceps major, and ILF. Utilizing population-based human and rhesus macaque tractography, we successfully reconstructed the fiber tract connecting precuneus with TP, which closely matched our microdissection findings. Overall, our study enhances our understanding of the intricate connectivity patterns within these brain regions and provides valuable insights into the organization of fiber tracts within the human brain.
Human connectivity
To our knowledge, this is the first comprehensive study that provides detailed insights into the structural connectivity between POS2, area 35, 35, TI, and TG, facilitated by CB-V fibers. Previous studies utilizing resting-state fMRI have demonstrated strong functional connectivity between the posterior precuneus, parahippocampal gyrus, and areas TG and TI of the TP (Fan et al., 2014; Pascual et al., 2015). The term "parahippocampal cingulum" has been used by Jones and colleagues to describe a bundle of fibers connecting the posterior precuneus, posterior cingulate cortex, and medial temporal lobe (Jones, Christiansen et al., 2013). Wu et al. introduced the term "Cingulum Bundle-V" to describe the segment of the cingulum connecting the precuneus with the ventral and medial temporal lobe (Wu et al., 2016). Tanglay et al. referred to the CB-V as the "parahippocampal cingulum" in their investigation of precuneus connectivity, describing it as a group of fibers traveling from the precuneus and terminating in the parahippocampal gyrus (Tanglay et al., 2022). Additionally, Jitsuishi and Yamaguchi reported the existence of a fiber bundle connecting the posterior precuneus and medial temporal lobe using a combination of fiber microdissections and imaging techniques (Jitsuishi & Yamaguchi, 2021). Our previous study focused on the connectivity of the precuneus and temporal lobe (Skandalakis et al., 2020), but did not specifically investigate the connectivity of the TP. Therefore, our current study expands upon the existing literature by elucidating the connectivity patterns of the CB-V in relation to the TP, providing valuable insights into the organization of this fiber tract and its role in connecting key brain regions involved in memory and spatial processing.
Rhesus macaque connectivity
Our rhesus macaque averaged template results demonstrated the presence of a continuous and distinct tract along the medial surface interconnecting the precuneus and temporal pole. Nevertheless, connectivity tract-tracing studies of the precuneus and TP in non-human primates have not demonstrated a connection between the two. (Bakola et al., 2017; Gamberini et al., 2020; Passarelli et al., 2018) Tracer studies report that the continuity of these fiber tracts is disrupted at the level of the retrosplenial cortex, suggesting the presence of anatomical discontinuities or alternative pathways in this region (Table 1). As such, our animal data should be interpreted with caution. Focused tracer or klingler’s microdissection animal studies should investigate anatomy of the parahippocampal cingulum to clarify whether the association tract connecting the area POS2 with regions of the TP is a fiber tract unique in humans. Cross species differences may be due to the more complex cytoarchitecture of the human precuneus and TP which exhibit connections unique to the human brain as well as the differences in connectivity and functional organization between species.( Cavanna & Trimble, 2006; Insausti, 2013). The human precuneus is more vastly connected with the fusiform gyrus and regions of the temporal lobe located more ventrally and anteriorly in comparison to the macaque; this circuit whose functional role has likely reformed over the course of evolution subserves memory, planning, and spatial navigation (Hutchison et al., 2015).
The TP and the precuneus are regions exhibiting differences in their structural anatomy and function between species (Glasser et al., 2014; Schleicher et al.,1999; Van Essen & Dierker, 2007). Differences in the connectivity and functional organization of the precuneus across species have been documented and suggest that the functional role has likely changed over the course of evolution (Hutchison et al., 2015) Gyrification of the TP seems to be higher in humans by the presence of 2 polar sulci which are not present in non-human primates. (Blaizot et al., 2010) Human TP connectivity is more extensive and localized more anteriorly when compared to chimpanzees and macaques. (Bryant et al., 2019) Moreover, the human TP exhibits increased connectivity with parietal regions compared to non-human primates. (Pascual 2015) It is suggested that the augmented connectivity of the human temporal lobe with the parietal lobe may be associated with the high-order functions that are unique in humans. (Catani 2022) TP subregions of non-human primates have distinct anatomical connections with regions of the temporal lobe, prefrontal cortex, and insula. (Table 1) (Borra et al., 2010; Nakamura & Kubota, 1996) Conversely, posterior parietal regions of non-human primates are mostly connected to primary somatosensory and motor cortices, cingulate cortex and areas of the occipital lobe (Gamberini et al., 2020). (Figure 4)
Functional Implications
The precuneus and medial temporal lobe are regions that are implicated in higher-order brain function. (Dadario & Sughrue, 2023; Mesulam, 2023) Data from functional imaging studies show that area POS2 participates in visual, and auditory tasks activated in language domains but also in cognitive and emotional tasks involving social cognition. (Luo et al., 2020) The TP is gaining support as one of the neural systems subserving spatial perception and autobiographical memory, (Kalyvas 2021; Setton et al., 2022; Teghil et al., 2021) brain functions traditionally related to the precuneus. Moreover, the TP has been implicated in memory, emotional processing, and face perception. (Olson et al., 2007; Liu et al., 2016; Liu, Wang et al., 2016) The TP can be considered a cortical convergence hub where social and emotional inputs are integrated (Mesulam 2022; Pascual et al., 2015; Pehrs et al., 2017). The functional connectivity of the precuneus and parahippocampal gyrus is implicated in verbal creativity and episodic memory. (Sun et al., 2018; Wade-Bohleber et al., 2018) Both the precuneus and TP are large association areas subserving a vast array of high-order functions. Studies on the parcellation of the precuneus and TP show that their subregions exhibit a distinct cytoarchitecture pattern and are implicated in different functions. (Ding et al., 2009; Luo et al., 2020) The CB-V fibers interconnecting POS2 and TP shared termination cortical points with ILF and the main bundle of the Cingulum (inferior arm) suggesting that this tract is likely involved in more complex neural processing involving the ILF and cingulum circuits which subserve the connectivity of the occipital and frontal lobe respectively. The existence of the axonal connectivity between the POS2 and medial TP provides original anatomical evidence about the direct connectivity of cortical areas that are heavily implicated in the neural circuit of core cognitive functions such as face and word recognition, facial expression perception, spatial navigation, visuospatial perception memory, and imagery. This constant anatomo-functional “dialogue” between these regions through discret white matter pathways, provides useful insights into the adjustment and integration of the neural inputs and correlates of complex social cognition. Future studies may bear insight in this interesting topic and therefore clarify the functional role of the connection between POS2 and TP in healthy subjects.
Clinical implications
The functional connectivity of parietal and temporal regions is disrupted in Alzheimer’s disease, Parkinson’s disease, epilepsy, schizophrenia, schizotypal personality disorder, and major depression disorder. (Koch et al, 2022; Liu, Bernhard et al. 2016; Zhu et al., 2017; Cheng et al., 2018; De Schipper et al., 2018; Liu et al., 2018; Young et al., 2018) Stimulation of the precuneus by repetitive transcranial magnetic stimulation (rTMS) in healthy individuals modulates the connectivity between the precuneus and TP. (Mancini et al., 2017) Results of a recently published randomized, sham-controlled trial showed that rTMS of the precuneus may slow down cognitive and functional decline in patients with Alzheimer’s disease by strengthening the connectivity between the precuneus and temporal lobe. (Koch et al., 2022) In the same vein, a randomized multiple baseline study showed that rTMS of the precuneus in patients with Alzheimer’s disease can improve cognitive function. (Traikapi et al., 2022)
Corticothalamic networks have been suggested to play a key role in the pathophysiology of epilepsy. (Ji et al., 2015). Nevertheless, extra-thalamic networks have been also identified during seizures (Handforth et al., 2005.) Seizure activity of the precuneus can result in occipital and motor seizures.( Al‐Ramadhani et al., 2021) The connectivity of the precuneus with the fusiform gyrus (Skandalakis et al,. 2020) and motor/ premotor areas (Komaitis et al. 2019) could possibly explain motor and visual semiology during seizures. Given the very high incidence of mesial temporal lobe epilepsy (Engel , 2001) precuneal seizures could originate from mesial temporal regions. Accordingly, the fiber tract connecting the POS2 and TP may represent a structural substrate for occipital or motor extra-thalamic seizures. This pathway should be considered for sampling in addition to pulvinar pathways during the investigation of epileptogenic networks in patients with occipital and/or motor symptoms. Future studies focused on patients suffering from neurological and psychiatric conditions may uncover their underlying pathophysiology and determine the role of connectivity between POS2 and TP in these disorders.
Limitations
One of the main limitations of our study is inherent to Klingler’s technique itself. The fiber micro-dissection technique is highly operator-dependent and as such, prone to human error. Considering this limitation, dissections in our study were carried out by three different authors independently. Furthermore, the fiber micro-dissection technique provides lower spatial resolutions when compared to histology and optical coherence tomography (Wang et al. 2011) and lower structural relationship accuracy during the investigation of crossing/kissing fiber tracts (Kalyvas et al., 2020). The fiber micro-dissection technique in turn displays several advantages. This technique involves the fixation of cadaveric specimens in a formalin solution followed by a freeze - thaw process, during which the formation of ice crystals separates the white matter fibers; thus, facilitating their dissection and recording. It preserves axonal integrity and ultrastructure as shown by transmission electron microscopy-derived evidence, thus allowing the investigation of the termination and connectivity pattern of the subcortical fiber pathways through the cortex-sparing technique as applied in this study. (Martino et al., 2011; Zemmoura al., 2016) As such, it stands as one of the “gold standard” methods used to validate data deriving from DWI-based tractography, as the latter is reported to suffer from inherent limitations particularly when kissing, bending, and crossing fiber populations are explored. (Le Bihan et al. 2006; Jones Knösche et al., 2013; Oouchi et al. 2007; Vos et al. 2011; Fernandez-Miranda et al. 2012; Tournier et al. 2012; Thomas et al., 2014; Yendiki et al., 2022) The CB-V resides in the depth of the POS and medial temporal lobe regions, which are extensively occupied by many fibers belonging to other known fiber tracts such as the SRF, ILF, and forceps major.