The arcuate fasciculus: Combining structure and function into surgical considerations

Abstract Background Two Centuries from today, Karl Friedrich Burdach attributed the nomenclature “arcuate fasciculus” to a white matter (WM) pathway connecting the frontal to the temporal cortices by arching around the Sylvian fissure. Although this label remained essentially unvaried, the concepts related to it and the characterization of the structural properties of this bundle evolved along with the methodological progress of the past years. Concurrently, the functional relevance of the arcuate fasciculus (AF) classically restricted to the linguistic domain has extended to further cognitive abilities. These features make it a relevant structure to consider in a large variety of neurosurgical procedures. Objective Herein, we build on our previous review uncovering the connectivity provided by the Superior Longitudinal System, including the AF, and provide a handy representation of the structural organization of the AF by considering the frequency of defined reports in the literature. By adopting the same approach, we implement an account of which functions are mediated by this WM bundle. We highlight how this information can be transferred to the neurosurgical field by presenting four surgical cases of glioma resection requiring the evaluation of the relationship between the AF and the nearby structures, and the safest approaches to adopt. Conclusions Our cumulative overview reports the most common wiring patterns and functional implications to be expected when approaching the study of the AF, while still considering seldom descriptions as an account of interindividual variability. Given its extension and the variety of cortical territories it reaches, the AF is a pivotal structure for different cognitive functions, and thorough understanding of its structural wiring and the functions it mediates is necessary for preserving the patient's cognitive abilities during glioma resection.


INTRODUCTION
Most of the vocabulary that we use to refer to the components of the nervous system and the related mechanisms comes from early anatomical studies performed between the 18th and the 19th Century. Karl Friedrich Burdach (1776Burdach ( -1847 is among the main contributors to our established neuroanatomical lexicon (Swanson, 2015). Considering his studies on the cerebral white matter (WM), his legacy entails the identification and labeling of the main association bundles of the human brain (Burdach, 1826). The second volume of "Vom Baue und Leben des Gehirns," published in 1822, contains the first mention of the name "arcuate fasciculus" (AF)-originally "Bogenbündel" (i.e., arcuate fascicle) (Burdach, 1822). Owing to this description, Burdach's name has historically been associated to this WM bundle, to the extent that the Dejerines referred to it as "faisceau arqué de Burdach" (i.e., arcuate fascicle of Burdach (Dejerine & Dejerine-Klumpke, 1895, 1901. Two hundred years went by, and we still use Burdach's denomination. What changed is the definition of this WM structure, including the attributed partonomies, subdivisions, and the respective nomenclatures (Mandonnet et al., 2018;Porto de Oliveira et al., 2021;Vavassori et al., 2021). Indeed, the introduction and fast evolution of neuroimaging techniques (Leemans, 2019), the revisitation of early neuroanatomical discoveries (De Benedictis et al., 2014;Hope et al., 2016;Sarubbo et al., 2016), and the renovation of Klingler's microdissection approach (Agrawal et al., 2011;Klingler, 1935;Martino et al., 2011) led to the production of increasingly more detailed descriptions of the human WM pathways. In particular, the dissemination of diffusion magnetic resonance imaging-based tractography (Basser et al., 2000) enabled the first characterization of the arcuate fascicle in vivo (Catani et al., 2002), leading off a series of innovative studies aimed to achieve the most accurate and comprehensive characterization of the wiring and extension of this bundle. Concurrently with these efforts, the ensuing functional relevance of the AF has become steadily more evident: damages of this bundle, both in terms of altered microstructural features or disconnection, have been implicated in a broad spectrum of syndromes, spanning from psychiatric symptoms (Jiang et al., 2017;Psomiades et al., 2016) to neurological diseases (Nakajima et al., 2018). Moreover, its volume in the right hemisphere has been indicated as a reliable predictor of aphasia recovery after stroke (Forkel et al., 2014). The involvement of the AF in such a variety of syndromes, and therefore of associated cognitive processes, relates to its large volume and long-range extension. Indeed, the AF transverses three lobes (i.e., the frontal, parietal, and temporal cortices) and resides in close relationship with the insula, with longitudinal associative fascicles laterally (Mandonnet et al., 2018) and projection fibers on the medial side. These characteristics make it a fundamental mediator of different cognitive abilities and explain why it must inevitably be considered in many diverse surgical procedures.
The continuous methodological evolutions and the interest of the scientific community in investigating the properties of this specific WM bundle surely contributed to the achievement of a more complete depiction of the AF, but they also led to the production of an intri-cate and non-univocal picture (Becker et al., 2022;Mandonnet et al., 2018;Porto de Oliveira et al., 2021;Vavassori et al., 2021). Therefore, an overview of the complex literature about this bundle is essential to highlight its multiple structural and functional facets that need to be considered when approaching the study of this bundle, especially in the surgical practice. By analyzing the controversies regarding the Superior Longitudinal System's subdivisions and the respective nomenclatures, our recent literature review (Vavassori et al., 2021) already exposed the current knowledge about the structural wiring of the AF intended as a whole ensemble of fibers connecting the frontal and the temporal lobes of the same hemisphere by passing above the insula (Mandonnet et al., 2018).  (Bunevicius et al., 2014;Hervey-Jumper & Berger, 2016;Sanai et al., 2011;Zarino et al., 2020;Zigiotto et al., 2020). With this aim, we append to our literature review a description of surgical approaches to tumor resection that require the careful consideration of this bundle extension, its relationships with the nearby anatomical structures and the related functional implications, and provide a collection of four different surgical cases to highlight how, in practice, extensive knowledge of the AF features can be applied in this field.

OLD AND NEW INSIGHTS ABOUT THE AF
From its first accounts. . .
The classification of the association pathways of the human brain was fostered by the works of pioneering dissectionists who, starting from the early 19th Century up to the beginning of the 20th Century, carried out a systematic exploration of the WM structural organization (Burdach, 1826;Dejerine & Dejerine-Klumpke, 1895, 1901Mayo, 1823;Reil, 1809Reil, , 1812Monakow, 1897). In this instance, different anatomists reported that an orderly ensemble of fibers analogous to the more medial cingulum bundle could be isolated on the lateral aspect of each cerebral hemisphere (Burdach, 1822;Dejerine & Dejerine-Klumpke, 1895, 1901. This WM pathway was described and finely illustrated as a connection running between the temporal and the frontal lobes, passing through the parietal lobe, and arching around F I G U R E 1 Historical drawings and diagrammatic representations of the arcuate fasciculus (AF) from the original works of (a) Reil (1812), (b) Dejerine and Dejerine-Klumpke (1895), (c) Wernicke (1874), and (d) Geschwind (1970).
the posterior limit of the Sylvian fissure (Dejerine & Dejerine-Klumpke, 1895;Reil, 1812) (Figure 1a,b). Its characteristic arched shape granted it the name "arcuate fasciculus" (Burdach, 1822). In this same period, based on the observation of clinical signs related to specific anatomical lesions (Kumar et al., 2011), Carl Wernicke proposed a putative model for the localization of linguistic abilities in the brain: following a previous description of the faculty of speech production being located in the third frontal convolution of the left hemisphere (i.e., pars triangularis (IFGtri) and pars opercularis (IFGop) of the inferior frontal gyrus (IFG)) (Broca, 1865), he advanced that a second area, later established to be represented by the superior temporal gyrus (STG), would support words' sound memory, and therefore language comprehension (Wernicke, 1874). This characterization of the distribution of linguistic abilities led Wernicke himself to postulate that a specific syndrome characterized by spared comprehension with repetition deficits, and defined as conduction aphasia, could arise from a disconnection between these two cortical regions (Figure 1c). In the 1960s, Geschwind formalized that the anatomical substrate for the interaction between Wernicke and Broca's areas is represented by the AF (Geschwind, 1965) (Figure 1d).

. . . to its current definition
Nowadays, it would be reductive to define the AF as a connection running exclusively between the IFG and the STG and purely devoted to language comprehension. Especially throughout the last 20 years, the creation and progressive fine-tuning of innovative techniques for the in vivo representation of the brain's WM and the testing of cognitive functions dramatically enriched the characterization of the AF.
As mentioned above, an exhaustive account of the current definition of the AF structural wiring can be found in Vavassori et al. (2021) con-sidering all the connections running between the frontal and temporal lobes, independently from the adopted nomenclature. Herein, we set the debate on the bundle's partitioning aside and build on these data by analyzing how frequently defined connections have been attributed to the AF description across studies. The present approach aims to highlight the most characterizing patterns of connectivity established by the AF (i.e., those that are more likely to be found when approaching the study of this bundle), while still representing those that have been reported only in few instances. This provides an account of the possible differences in the AF extension across individuals, an important variable that should be accounted for especially in the clinical setting (Forkel et al., 2021). Since very few studies explicitly analyze and report a specific pattern of connectivity between two precise cortical regions and the majority of them rather indicate the overall anterior and posterior terminations of the bundle, we assume all the areas listed in the same description to be mutually interconnected unless differently specified ( Figure 2, see Table 1 for references).
For what concerns the functional counterpart, we adopt the exact same cumulative approach already illustrated for the structural description to present the functional literature about the AF. Indeed, one single bundle is very likely to support multiple cognitive processes by playing different roles in different networks (Forkel et al., 2021).
Since to date there is no recent review paper that summarizes the functional literature of the AF, we sampled the experimental works testing the involvement of this fiber pathway in a defined function, using both direct techniques (i.e., direct electrical stimulation (DES)) and correlational neuroimaging-behavioral measurements (see Table 2 for references), with the aim to highlight the main different cognitive domains whose integration is mediated by this bundle. For this TA B L E 1 Patterns of the arcuate fasciculus (AF) structural connectivity as defined in the studies reviewed in Vavassori et al. (2021) and classified according to the present cumulative approach.

TA B L E 2
List of the studies reviewed that outlined the functional involvement of the arcuate fasciculus (AF) in specific functional classes and the respective domains classified according to the present cumulative approach. purpose, we conducted a literature search in Google Scholar using a combination of the strings "arcuate fasciculus" and "function", "cognitive functions", "behavioral correlates", "linguistic", "non-linguistic", and again, as the research highlighted more specific domains, "verbal memory", "social cognition", "spatial cognition", "music perception".
Those works that imply a putative functional role of the bundle as a consequence of their findings but with no direct testing were not included.
In line with the renowned notion of the left and right AF contributing to different cognitive domains (Nakajima et al., 2019), we will report findings according to the hemisphere they are related to. Although most of the studies considered focused their investigation of AF functionality on a specific hemisphere, there are some works that carried out their analysis on the whole brain and were therefore able to relate different functions to this bundle depending on its hemispheric location, or, on the contrary, to specify that the same function is mediated by the AF from both hemispheres. Those studies that found the same function to be mediated by bilateral AF will be considered as one evidence for each hemisphere. As we described in the historical section, the AF has been implied in linguistic functions since its first characterizations (Broca, 1865;Geschwind, 1965;Wernicke, 1874). This initial assumption based on anatomo-clinical correlation studies was validated with the advent of functional MRI, intraoperative mapping with DES, and correlational studies of tractography-derived bundles' parameters with behavioral testing. Indeed, 41 out of the 59 studies we hereby reviewed support the involvement of direct dorsal frontotemporal connections in the linguistic domain. The congregate analysis of these works enlightens the complexity of language as a multifaceted ability, composed of several components whose coordinated interplay gives rise to more general abilities. Given this complexity and the magnitude of the number of works specifically investigating the role of the AF in language, findings regarding this function and nonlinguistic cognitive domains will be presented separately (Figure 3 for linguistic abilities and Figure 4 for the other domains, for references see Table 2).  the five domains of language (i.e., pragmatics, phonology, syntax, and semantics). Although only few of the works reviewed reported the involvement of the bilateral AF in functions related to the pragmatics domain-the left hemisphere bundle was related to rhyme judgment and speech tone perception, and the right one was proposed to support prosody processing-most of them stressed an association between this WM pathway in the left hemisphere and phonological functions.
Among these, studies using DES mapping described phonemic paraphasia in correspondence of AF stimulation; studies conducted both on healthy participants and with intraoperative stimulation in patients reported an association with repetition abilities, whereas studies conducted on a normative population stressed the role of the AF in phonological awareness, a predictor of reading skills. Moreover, the left AF is reported to play a role in the syntactic domain and in semantic aspects of language. In particular, one of the studies considered reported an association between the bundle's microstructural tractography-derived measures and vocabulary knowledge, whereas another investigation with DES mapping observed semantic paraphasia following AF stimulation.
Up to now, we discussed the involvement of the AF in linguistic domains-related functions mainly in the left hemisphere. Nevertheless, we also identified some reports of linguistic functions being mediated by the right AF (see Figure 3). The evident imbalance between the number of descriptions of an association between left and right AF and language is in line with the notorious strong left-lateralization of this function in the normative population (Frost, 1999;Malik-Moraleda et al., 2022;Wang et al., 2019). Moreover, it is worth considering that all the reports herein reviewed that attribute linguistic abilities to the right AF are studies relating a bilateral activation for that function.
If we regard these works more carefully, it can be inferred that the relationship of the right AF with phonemic paraphasia, general syntactic abilities, and semantic paraphasia is found in left-handed patients for which language is more likely to be lateralized in the right hemisphere compared to the general population (Szaflarski et al., 2002). The only non-neurosurgical description of a correlation between this bundle's tractography-derived measurements in the right hemisphere and phonological abilities was conducted on a cohort of developing children, for whom the fine wiring of linguistic functional networks might still be in progress (Holland et al., 2007).
In the collection of studies we reviewed, there are some other linguistic abilities that, although not being domain-specific but rather arising from the interplay of multiple macrodomains, have been found to be modulated by the AF, namely, word learning and the development of reading abilities. Finally, a very complex ability that relies on F I G U R E 3 Schematic cumulative representation of the number of studies that described the role of the arcuate fasciculus (AF) in mediating linguistic abilities. All the revised works have been classified depending on the general ability, linguistic domain, or specific language-related skills that they tackle (see text for a more detailed description). Each solid-colored square represents one account for the defined category; shaded squares have been added below each of these broad categories in the case of studies specifying a precise subcategory (being it a particular deficit related to AF damage or a defined ability correlating with its features).

F I G U R E 4
Schematic cumulative representation of the number of studies that described the role of the arcuate fasciculus (AF) in mediating nonlinguistic abilities. Each solid-colored square represents one account for the defined category; shaded squares have been added below each of these broad categories in the case of studies specifying a precise subcategory (being it a particular deficit related to AF damage or a defined ability correlating with its features). different linguistic domains, that is, naming, has been defined to be supported by the AF mainly in the left hemisphere: indeed, few studies report anomia after AF stimulation during DES subcortical mapping.
Although it is evident that the left AF mainly mediates linguistic abilities, our review revealed an involvement of this bundle also in verbal memory. However, out of this sample, one work focuses its definition of verbal memory on working memory, whereas one other study specifies that the left AF might be involved in verbal short-term memory since its direct stimulation during surgery causes item errors during a digit span task. Another cognitive function that has been attributed to the AF is social cognition, with a role in false-belief understanding in developing children (bilateral AF) and in face-based mentalizing (right AF).
According to the review we carried out, there are two other nonlinguistic cognitive functions that have been attributed to the right AF: music perception (tone discrimination and grammar learning in the domain of pitch as well as rhythm modulation detection) and spatial cognition (spatial perception and visuospatial attention). The full lists of studies, separated according to specific functions, are reported in Table 2.  Duffau, 2009Duffau, , 2014Duffau, , 2018. Being it a mediator of the communication between frontal and temporal lobes by crossing the parietal one, thorough knowledge of this bundle is mandatory to plan and perform safe surgeries involving all these regions, to avoid severe postsurgical sequelae. Indeed, a recent work contains considerable reports of transient or permanent language deficits (in 11.7%-54.5% and 1.7%-18.2% of cases, respectively) for tumors' resections involving these cortices (Fang et al., 2021). In particular, the worst language prognosis was reported for lesions located around the postcentral (PoCG) and the supramarginal (SMG) gyri, that correspond, in fact, to the segment of the AF course with the highest fiber density, and therefore the lowest compensating capacity in respect to its anterior and posterior portions (Fang et al., 2021;Herbet et al., 2016;Plaza et al., 2009;van Geemen et al., 2014). Moreover, and as previously mentioned, disconnection of the right AF has been related to impairment in face-based mentalizing Yordanova et al., 2017).

AF TOPOGRAPHICAL ANATOMY AND SURGICAL IMPLICATIONS
Consequently, a careful and patient-tailored surgical planning for the preservation of eloquent subcortical structures, including the AF, is of foremost importance. This last section reports four different surgical cases of glioma resection involving the AF territories. Each of them addresses not only how the functional information collected during the procedure drives the definition of the resection boundaries but also how knowledge about the AF possible extension and functional implications drives surgical planning. This envisages (i) an accurate pre-operative neuropsychological assessment for the selection of the most adequate tasks to be administered during systematic cortical and subcortical electrical mapping in awake conditions based on the location of the lesion (Bu et al., 2021;Martino, Gomez et al., 2013;Peraud et al., 2004;Rolland et al., 2018;Sarubbo et al., 2020); (ii) the evaluation of which WM pathways will possibly be impacted by the specific procedure, coupled with a tractographic 3D reconstruction of the WM bundles of interest.
For what concerns intraoperative neuropsychological assessment, the denomination task is normally used for procedures concerning the AF territories within the left language-dominant hemisphere to test the emergence of phonemic paraphasia or pure anomia with DES. Electrostimulation of the right AF can evoke transient mentalizing troubles or spatial neglect: The Reading the Mind in the Eyes ( Baron-Cohen et al., 2001;Herbet et al., 2014;Sarubbo et al., 2020;Vigneau et al., 2006;Yordanova et al., 2017) and the line bisection tasks (Bartolomeo et al., 2007;He et al., 2007;Rolland et al., 2018;Roux et al., 2011;Sarubbo et al., 2015Sarubbo et al., , 2020Thiebaut de Schotten, 2005) are the preferential neuropsychological evaluation tools adopted in this case. In general, intraoperative cognitive testing gives real-time feedback to the operator about the functional relevance of a given structure and, therefore, represents a precious directive on whether it is safe to resect it.
As briefly mentioned above, different surgical procedures require to carefully consider the patient's AF wiring and the related functional networks. For instance, when approaching a tumor located in the frontal lobe, namely, under the IFG, the MFG, and the dorsolateral prefrontal cortex, it should be considered that the AF courses horizontally at this level, and that its fibers are strongly intertwined with the deep layer of the inferior fronto-occipital fasciculus (IFOF), which locally follows a vertical temporo-frontal orientation. In this case, the fibers of the AF that extend to the IFG represent the deep and posterior functional boundary. At this level, AF terminations overlap with the most ventral segment of the superior longitudinal fasciculus (SLF III) and with the superficial layer of the IFOF (De Benedictis et al., 2012;Duffau, 2018;Dziedzic et al., 2022). Figure 5 illustrates the case of a 42-year-old man, who underwent resection of a high-grade glioma located within the left dominant fronto-insular region. Although cortical DES in awake condition allowed to identify one site eliciting speech arrest when stimulated, subcortical mapping during resection revealed eloquent functional sites evoking anomia, semantic paraphasia, and perseveration during denomination task, in correspondence to the IFOF's frontal projections.
When dealing with insular tumors, many studies support the safety and reliability of the transopercular approach, although it requires passing through IFGtri and IFGop (classically known as Broca's area).
For this type of procedure, the AF constitutes the deep, superior, and posterior functional limit of resection (Dziedzic et al., 2022).
At the level of the temporo-parieto-occipital junction, the AF participates in a complex system of connections involving many eloquent pathways, and it is therefore relevant in the case of lesions involving the inferior parietal lobule. Indeed, at this level, the AF forms a compact vertical stem that runs deep and parallel to the  (Martino et al., 2011;Sarubbo et al., 2016). Here, the AF is located at the anterolateral wall of the cavity (De Benedictis et al., 2014). Figure 6   The AF also represents an important functional limit when performing a temporal lobectomy for tumor removal or epilepsy surgery, especially in the dominant hemisphere. In these cases, the AF temporal terminations constitute the subcortical posterolateral boundary of resection (Duffau et al., 2008). When approaching the ventral left temporal region, corresponding to the visual word form area, DES mapping is recommended to differentiate the course of the AF from the one of the ILF: Stimulation of the left AF at this level would induce pure anomia by interfering with the integration of visual information into the language network (Duffau et al., 2008;Mandonnet et al., 2017;Sarubbo et al., 2020). At this level, also the course of the IFOF should be considered. Figure 8  and cortical stimulation of the VPMC elicited speech arrest. No functional response was found at denomination, reading comprehension and motor tasks during stimulation of the middle and posterior parts of the temporal region. Subcortical mapping allowed to identify the resection boundaries represented by the anteroinferior portion of the AF, that once stimulated led to phonemic paraphasia during denomination task, and the IFOF, whose stimulation led to semantic paraphasia.
Finally, the AF is strictly related to the ventricular system. Indeed, the superior part of the AF runs lateral to the superior two thirds of the frontal horn and to the body of the lateral ventricle; its central segment runs lateral to the anterior two thirds of the atrium, whereas its inferior portion runs from the level of the posterior insular point (i.e., the junction between the inferior and the superior insular sulci) to the anterior tip of the temporal horn (Güngör et al., 2017).
The understanding of these anatomical relationships is crucial to perform safe accesses to ventricular tumors, in particular when adopting an anterior frontal transcortical, posterior transcortical, or posterior transtemporal approach (De Benedictis et al., 2022).

F I G U R E 7
Surgical case concerning a 41-year-old man who underwent resection of a high-grade glioma located within the superior parietal lobule of the left dominant hemisphere. (a) Preoperative magnetic resonance imaging (MRI) (from top to bottom: axial, coronal, and 3D-sagittal sequences) combined with tractographic reconstruction of the left arcuate fasciculus (AF) (red), the inferior fronto-occipital fasciculus (IFOF) (green), and the temporoparietal component of the superior longitudinal fasciculus (SLF) (yellow). (b) Intraoperative picture showing the tumor's resection performed according to the "asleep-awake-asleep" protocol. Direct electrical stimulation (DES) allowed to identify eloquent cortical sites including: the postcentral gyrus (PoCG), eliciting right facial paresthesia when stimulated (tag 0); the supramarginal gyrus (SMG), eliciting speech arrest (tag 1) and anomia (tag 2 and 3) during naming tasks. (c) During tumor resection, subcortical mapping allowed to evoke semantic paraphasia at the level of the dorsal part of the IFOF (tag 41) and verbal apraxia during the denomination task, along the temporoparietal component of the SLF and the AF (tag 42). (d) Dissection of the perisylvian region with Klingler technique. The specimen has been oriented according to the surgical perspective. The colored tags correspond to the IFOF (green circle and arrow) and the temporoparietal SLF/AF (yellow circle, red, and yellow arrows). Postoperative MRI shows complete tumor resection.

CONCLUSIONS
The name "arcuate fasciculus" encloses two Centuries of neuroanatomical discoveries and evolutions. Since its first mention in Karl Friedrich Burdach's work (Burdach, 1822), this nomenclature became a pillar for the definition of the human brain's WM, and the associated knowledge increased concurrently with the methodological advancements of the past years. The investigations conducted on the AF concurred that this bundle is a crucial structural pathway for the integration of cognitive functions. Its shape, the large territories it connects, and the critical course it follows-interfacing with eloquent portions of the Superior and Inferior Longitudinal Systems as well as with projection fibersmake it one of the most critical association WM structures that require monitoring during surgical procedures. On the functional counterpart, many works demonstrate that the AF is critical for cognitive processing beyond language on both left and right sides. Indeed, this property can only be featured by a long-range associative bundle connecting multimodal and highly distributed cortical areas, and therefore subserving the integration of different networks.
Given these premises, extensive knowledge about the AF structural extension, its relationship with other nearby WM structures, and the consequent implication in cognitive processes is essential

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/brb3.3107