AG, as the postero-dorsal portion of the inferior parietal cortex, together with the supramarginal gyrus (SMG), constitute the so-called Geschwind's territories. These cortical territories, and in particular the AG, were demonstrated critical for different brain functions in both hemispheres as, between others, language (i.e., semantic control and phonological/articulatory encoding), spatial attention and awareness, working memory, calculation, and social cognition (Sarubbo et al. 2015; Zaca et al. 2018; Sarubbo et al. 2016; Thiebaut de Schotten et al. 2005; Seghier 2013). Our macrostructural analysis, integrating multimodal anatomical data provided by high-resolution tractography and microdissection, reveals a highly distributed wiring diagram of WM fibers with AG as a cortical hub. It supports AG's multimodal and pivotal functional roles as an integration area, an epicenter in the sense of (Mesulam 2008), between different sensory inputs (visual, auditory, and somato-sensorial) cortices and the temporal and frontal associative and effector areas.
Considering its sulco-gyral anatomy, AG is split into two parts by the elongation of the superior temporal sulcus within the parietal lobe (Kiriyama et al. 2009). The anterior part of AG faces the temporal border of the posterior third of the superior temporal sulcus (STS), and the posterior one faces the occipital side. Even with possible anatomical variations, we demonstrate that this sulco-gyral structure reflects the first level of short-range connection throughout continuous and homogeneous layers of U-fibers allowing a tripodal inter-lobar connection of AG (Sarubbo et al. 2016) with the superior temporal gyrus (STG), the superior and middle occipital gyri (SOG/MOG), and in the parietal lobe, the supramarginal (SMG) and superior parietal (SPG) gyri (Fig. 9). These local (short-range) cortical connections (involving both Wernicke and Geschwind territories and the convexity of the occipital cortex) play a role in the integration of visual stimuli in the verbal semantic processing and could play a role in the local plasticity phenomena supporting language recovery after restricted damage at the temporo-parieto-occipital junction in the left hemisphere (Sarubbo et al. 2012; Jiao et al. 2020).
Beyond this short-range associative connection, we identified mid- and long-range associative connections, belonging mainly to the SLS but also the ILS (Mandonnet et al. 2018). On the dorsal side, the angular gyrus is predominantly connected with the postcentral gyrus, the precentral gyrus (i.e., the ventral premotor cortex, VPMC), and the posterior portion of the IFG, as part of the classical description of the most ventral portion of the superior longitudinal fascicles, namely SLF-III. It is also strongly connected with the posterior portion of the MFG close to the classical description of the frontal-eyes-field (FEF, for a review (Petit and Pouget 2019)). These connections were also previously demonstrated with the cortico-cortical evoked potentials technique (Matsumoto et al. 2012), highlighting a symmetrical dorso-ventral organization between frontal and parietal cortical territories. In particular, the AG-MFG fibers are part of the classical description of the SLF-II (mid-dorsal component of the SLS, (Vavassori et al. 2021). They constitute the structural background for the known involvement of the dorsal portion of AG facing the intra-parietal sulcus in the fronto-parietal network, crucial for spatial attention and awareness (Thiebaut de Schotten et al. 2005; Sarubbo et al. 2020). This pattern of dorsal connectivity of the AG supports its role in integrating sensory input for motor planning and output. On the ventral side, both tractography and microdissection confirm the existence of a mid- and long-range AG connectivity with the mid-dorsal cortices of the frontal lobe throughout the IFOF (the deepest component of the ILS) (Sarubbo et al. 2013; Caverzasi et al. 2014; Hau et al. 2016; Wu et al. 2016a), and the temporal lobe throughout the superficial and deep components of the posterior transverse system, namely the vertical portion of the SLF and middle longitudinal fascicle (MdLF), respectively (Mahdy Ali and Avesani 2021).
The cross-connection pattern between dorsal and ventral language streams supports the multimodal function role of the AG cortex as revealed by fMRI studies showing functional nodes for semantic and phonological/syntactic elaboration (Vigneau et al. 2006). Different direct electrical stimulation (DES) evidences also demonstrated a high probability of evoking anomia during object naming while deactivating these cortical territories (Sarubbo et al. 2015; Sarubbo et al. 2020), supporting a role of AG in the integration between the semantic elaboration of sensory input and speech encoding. As a matter of fact, in the left hemisphere, this fronto-parietal network (including AG) plays a crucial role in semantic control (Xu et al. 2017).
Our results about AG connections with striatal, thalamic, and brainstem structures support different and growing pieces of evidence coming from neurophysiological and neuroimaging studies. A cortico-striatal circuitry including the cortical territories of the fronto-parietal network (AG-MFG), described above and dedicated to spatial attention, awareness, and the integration of sensory input for motor control (including gait, ocular movements, etc.), was hypothesized since the 1990s on the background of neurophysiological evidence. This cortical-subcortical circuitry includes different deep nuclei and brainstem regions, segregated in direct and indirect pathways (between others, the pulvinar thalami, intralaminar nuclei, mesopontine tegmentum, basal forebrain, globus pallidus, subthalamic nucleus, substantia nigra, and caudate nucleus) (LaBerge 1995; Kinomura et al. 1996). More recently, a functional imbalance (hypo- vs. hyper-activation) between the functional connectivity of certain cortical territories of the fronto-parietal network involved in oculomotor control (notably, the frontal and parietal eyes fields) and the striatal structures (putamen and caudate) was demonstrated as a pathological substrate in Parkinson Disease (Rebelo et al. 2021).
Finally, the bilateral homotopic connectivity between left and right AG reflects the most common pattern of inter-hemispheric connection provided by the corpus callosum (De Benedictis et al. 2016). This pattern of inter-hemispheric connection constitutes the essential structural background for balancing functional activity (i.e., inhibitory/excitatory) between left and right homologous cortices. It was demonstrated that direct current stimulation of the posterior cortices of the IPL, i.e., AG, induced modulation of interhemispheric parietal balance, improving visuospatial attention deficits in neglect patients (Sparing et al. 2009).
To conclude, our combined tractography and microdissection study of the AG wiring diagram reveals its highly distributed connected structure with a central representation between the human brain's main associative layers of WM. The angular gyrus is thus a posterior "angular stone" of associative connections belonging to the mid- and long-range dorsal fibers of the SLS and ventral fibers of the ILS, and short-range fibers, namely U-shaped fibers, and the posterior transverse system, locally connecting all the cortical territories of the temporo-parieto-occipital junction. This dorso-ventral pivotal position reflects the critical role of AG in different networks, particularly in language elaboration and spatial attention and awareness in the left and right hemispheres, respectively. Moreover, we reveal deep nuclei and brainstem connections and a typical inter-hemispheric homotopic connectivity supporting the suggested role, in the context of the fronto-parietal network, in the integration of sensory input for modulating motor control and planning. These structural pieces of evidence all together match with the critical and multimodal functional roles attributed to these cortical territories in both hemispheres on the background of brain mapping data from clinical, neuroimaging, neurophysiological studies.