The importance of the dorsal branch of the arcuate fasciculus in phonological working memory.

Phonological working memory (PWM) is important for language learning and processing. The most studied language brain regions are the classical Broca's area on the inferior frontal gyrus and Wernicke's area on the posterior temporal region and their anatomical connection via the classic arcuate fasciculus (AF) referred to here as the ventral AF (AFv). However, areas on the middle frontal gyrus (MFG) are essential for PWM processes. There is also a dorsal branch of the AF (AFd) that specifically links the posterior temporal region with the MFG. Furthermore, there is the temporo-frontal extreme capsule fasciculus (TFexcF) that courses ventrally and links intermediate temporal areas with the lateral prefrontal cortex. The AFv, AFd and TFexcF were dissected virtually in the same participants who performed a PWM task in a functional magnetic resonance imaging study. The results showed that good performance on the PWM task was exclusively related to the properties of the left AFd, which specifically links area 8A (known to be involved in attentional aspects of executive control) with the posterior temporal region. The TFexcF, consistent with its known anatomical connection, was related to brain activation in area 9/46v of the MFG that is critical for monitoring the information in memory.

The ventral pathway of the human brain: A continuous association tract system.

The brain hemispheres can be divided into an upper dorsal and a lower ventral system. Each system consists of distinct cortical regions connected via long association tracts. The tracts cross the central sulcus or the limen insulae to connect the frontal lobe with the posterior brain. The dorsal stream is associated with sensorimotor mapping. The ventral stream serves structural analysis and semantics in different domains, as visual, acoustic or space processing. How does the prefrontal cortex, regarded as the platform for the highest level of integration, incorporate information from these different domains? In the current view, the ventral pathway consists of several separate tracts, related to different modalities. Originally the assumption was that the ventral path is a continuum, covering all modalities. The latter would imply a very different anatomical basis for cognitive and clinical models of processing. To further define the ventral connections, we used cutting-edge in vivo global tractography on high-resolution diffusion tensor imaging (DTI) data from 100 normal subjects from the human connectome project and ex vivo preparation of fiber bundles in the extreme capsule of 8 humans using the Klingler technique. Our data showed that ventral stream tracts, traversing through the extreme capsule, form a continuous band of fibers that fan out anteriorly to the prefrontal cortex, and posteriorly to temporal, occipital and parietal cortical regions. Introduction of additional volumes of interest in temporal and occipital lobes differentiated between the inferior fronto-occipital fascicle (IFOF) and uncinate fascicle (UF). Unequivocally, in both experiments, in all subjects a connection between the inferior frontal and middle-to-posterior temporal cortical region, otherwise known as the temporo-frontal extreme capsule fascicle (ECF) from nonhuman primate brain-tracing experiments was identified. In the human brain, this tract connects the language domains of "Broca's area" and "Wernicke's area". The differentiation in the three tracts, IFOF, UF and ECF seems arbitrary, all three pass through the extreme capsule. Our data show that the ventral pathway represents a continuum. The three tracts merge seamlessly and streamlines showed considerable overlap in their anterior and posterior course. Terminal maps identified prefrontal cortex in the frontal lobe and association cortex in temporal, occipital and parietal lobes as streamline endings. This anatomical substrate potentially facilitates the prefrontal cortex to integrate information across different domains and modalities.

Bidirectional iterative parcellation of diffusion weighted imaging data: separating cortical regions connected by the arcuate fasciculus and extreme capsule.

This paper introduces a Bidirectional Iterative Parcellation (BIP) procedure designed to identify the location and size of connected cortical regions (parcellations) at both ends of a white matter tract in diffusion weighted images. The procedure applies the FSL option "probabilistic tracking with classification targets" in a bidirectional and iterative manner. To assess the utility of BIP, we applied the procedure to the problem of parcellating a limited set of well-established gray matter seed regions associated with the dorsal (arcuate fasciculus/superior longitudinal fasciculus) and ventral (extreme capsule fiber system) white matter tracts in the language networks of 97 participants. These left hemisphere seed regions and the two white matter tracts, along with their right hemisphere homologues, provided an excellent test case for BIP because the resulting parcellations overlap and their connectivity via the arcuate fasciculi and extreme capsule fiber systems are well studied. The procedure yielded both confirmatory and novel findings. Specifically, BIP confirmed that each tract connects within the seed regions in unique, but expected ways. Novel findings included increasingly left-lateralized parcellations associated with the arcuate fasciculus/superior longitudinal fasciculus as a function of age and education. These results demonstrate that BIP is an easily implemented technique that successfully confirmed cortical connectivity patterns predicted in the literature, and has the potential to provide new insights regarding the architecture of the brain.

Dissection of the Temporofrontal Extreme Capsule Fasciculus Using Diffusion MRI Tractography and Association with Lexical Retrieval.

The well-known arcuate fasciculus that connects the posterior superior temporal region with the language production region in the ventrolateral frontal cortex constitutes the classic peri-Sylvian dorsal stream of language. A second temporofrontal white matter tract connects ventrally the anterior to intermediate lateral temporal cortex with frontal areas via the extreme capsule. This temporofrontal extreme capsule fasciculus (TFexcF) constitutes the ventral stream of language processing. The precise origin, course, and termination of this pathway has been examined in invasive tract tracing studies in macaque monkeys, but there have been no standard protocols for its reconstruction in the human brain using diffusion imaging tractography. Here we provide a protocol for the dissection of the TFexcF in vivo in the human brain using diffusion magnetic resonance imaging (MRI) tractography which provides a solid basis for exploring its functional role. A key finding of the current dissection protocol is the demonstration that the TFexcF is left hemisphere lateralized. Furthermore, using the present dissection protocol, we demonstrate that the TFexcF is related to lexical retrieval scores measured with the category fluency test, in contrast to the classical arcuate fasciculus (the dorsal language pathway) that was also dissected and was related to sentence repetition.

The extreme capsule and aphasia: proof-of-concept of a new way relating structure to neurological symptoms.

We present anatomy-based symptom-lesion mapping to assess the association between lesions of tracts in the extreme capsule and aphasia. The study cohort consisted of 123 patients with acute left-hemispheric stroke without a lesion of language-related cortical areas of the Stanford atlas of functional regions of interest. On templates generated through global fibre tractography, lesions of the extreme capsule and of the arcuate fascicle were quantified and correlated with the occurrence of aphasia (n = 18) as defined by the Token Test. More than 15% damage of the slice plane through the extreme capsule was a strong independent predictor of aphasia in stroke patients, odds ratio 16.37, 95% confidence interval: 3.11-86.16, P < 0.01. In contrast, stroke lesions of >15% in the arcuate fascicle were not associated with aphasia. Our results support the relevance of a ventral pathway in the language network running through the extreme capsule.

Extreme capsule is a bottleneck for ventral pathway.

As neuroscience literature suggests, extreme capsule is considered a whiter matter tract. Nevertheless, it is not clear whether extreme capsule itself is an association fiber pathway or only a bottleneck for other association fibers to pass. Via our review, investigating anatomical position, connectivity and cognitive role of the bundles in extreme capsule, and by analyzing data from the dissection, it can be argued that extreme capsule is probably a bottleneck for the passage of uncinated fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF), and these fasciculi are responsible for the respective roles in language processing.

The Role of the Right Hemisphere White Matter Tracts in Chronic Aphasic Patients After Damage of the Language Tracts in the Left Hemisphere.

The involvement of the right hemisphere (RH) in language, and especially after aphasia resulting from left hemisphere (LH) lesions, has been recently highlighted. The present study investigates white matter structure in the right hemisphere of 25 chronic post-stroke aphasic patients after LH lesions in comparison with 24 healthy controls, focusing on the four cortico-cortical tracts that link posterior parietal and temporal language-related areas with Broca's region in the inferior frontal gyrus of the LH: the Superior Longitudinal Fasciculi II and III (SLF II and SLF III), the Arcuate Fasciculus (AF), and the Temporo-Frontal extreme capsule Fasciculus (TFexcF). Additionally, the relationship of these RH white matter tracts to language performance was examined. The patients with post-stroke aphasia in the chronic phase and the healthy control participants underwent diffusion tensor imaging (DTI) examination. The aphasic patients were assessed with standard aphasia tests. The results demonstrated increased axial diffusivity in the RH tracts of the aphasic patients. Patients were then divided according to the extent of the left hemisphere white matter loss. Correlations of language performance with radial diffusivity (RD) in the right hemisphere homologs of the tracts examined were demonstrated for the TFexcF, SLF III, and AF in the subgroup with limited damage to the LH language networks and only with the TFexcF in the subgroup with extensive damage. The results argue in favor of compensatory roles of the right hemisphere tracts in language functions when the LH networks are disrupted.

The effect of cortical and subcortical lesions on spontaneous expression of memory-encoded and emotionally infused information: Evidence for a role of the ventral stream.

The ventral stream of language processing has been implicated in the spontaneous expression of memory-encoded and emotionally infused information. The present study investigated whether left hemispheric lesions in post-stroke right-handed aphasic patients may be selectively associated with specific language functions. Speech rate was assessed with two tasks, one based on autobiographical memory of an emotionally infused event (stroke story narration) and the other based on information that is visually available at the time of speech generation ("cookie theft" picture description). CT and/or MRI scans were obtained for each patient and lesions located in 16 regions of the left hemisphere were identified and coded. The total number of cortical and subcortical areas affected served as a measure of lesion extent. While mean speech rates were similar across conditions, there were different patterns of association between each index and specific lesion sites. Non-parametric quantile regression statistical models constructed to assess dependence of both speech rate indices on each lesion locus indicated that the speech rate in the stroke story had significant inverse associations with total number of lesioned areas, as well as lesions in the inferior frontal gyrus and the external/extreme capsule region. The cookie theft speech rate had significant inverse associations with total number of lesioned areas as well as lesion in the inferior frontal gyrus, but not with the external/extreme capsule region. In sum, integrity of the extreme/external capsule region appears to be important selectively for the Stroke Story task, supporting the hypothesis that the ventral stream plays a central role in spontaneous expression of memory-encoded and emotionally infused information.

Three-Dimensional Anatomy of the White Matter Fibers of the Temporal Lobe: Surgical Implications.

BACKGROUND: The aim of this work is to describe in detail the complex 3-dimensional organization of the white matter of the temporal lobe and discuss the surgical implications of the approaches to lesions located into the mesial temporal region and within the temporal horn and the atrium of the lateral ventricles. METHODS: Sixteen human cerebral hemispheres fixed in a 10% formalin solution for at least 40 days were studied. After removal of the arachnoid membrane, the hemispheres were frozen at -15°C for at least 14 days, and the Klingler technique, which consists of the microscopic dissection and progressive identification of white matter fibers, was performed. RESULTS: The dissection allowed us to appreciate the topographical organization of the white matter of the temporal lobe identifying the most important association, projection, and commissural fasciculi. The dissection from the lateral side allowed the progressive visualization of the superior longitudinal fasciculus and its components, the extreme and external capsule, the uncinate fasciculus, the inferior fronto-occipital fasciculus, the anterior commissure, the internal capsule, and the optic radiations. The dissection was completed from the inferior and medial side for identification of the cingulum and the fornix. CONCLUSIONS: The complex 3-dimensional organization of the white matter substance of the temporal lobe is characterized by 2 main systems of boundaries: the sagittal stratum and the temporal stem. Their knowledge is essential for the appropriate treatment of pathologies localized in this region as demonstrated by the 2 clinical cases presented in this work.

Machine-learning classification of 22q11.2 deletion syndrome: A diffusion tensor imaging study.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a genetic neurodevelopmental syndrome that has been studied intensively in order to understand relationships between the genetic microdeletion, brain development, cognitive function, and the emergence of psychiatric symptoms. White matter microstructural abnormalities identified using diffusion tensor imaging methods have been reported to affect a variety of neuroanatomical tracts in 22q11.2DS. In the present study, we sought to combine two discovery-based approaches: (1) white matter query language was used to parcellate the brain's white matter into tracts connecting pairs of 34, bilateral cortical regions and (2) the diffusion imaging characteristics of the resulting tracts were analyzed using a machine-learning method called support vector machine in order to optimize the selection of a set of imaging features that maximally discriminated 22q11.2DS and comparison subjects. With this unique approach, we both confirmed previously-recognized 22q11.2DS-related abnormalities in the inferior longitudinal fasciculus (ILF), and identified, for the first time, 22q11.2DS-related anomalies in the middle longitudinal fascicle and the extreme capsule, which may have been overlooked in previous, hypothesis-guided studies. We further observed that, in participants with 22q11.2DS, ILF metrics were significantly associated with positive prodromal symptoms of psychosis.

Cortico-cortical connections of areas 44 and 45B in the macaque monkey.

In the human brain, areas 44 and 45 constitute Broca's region, the ventrolateral frontal region critical for language production. The homologues of these areas in the macaque monkey brain have been established by direct cytoarchitectonic comparison with the human brain. The cortical areas that project monosynaptically to areas 44 and 45B in the macaque monkey brain require clarification. Fluorescent retrograde tracers were placed in cytoarchitectonic areas 44 and 45B of the macaque monkey, as well as in the anterior part of the inferior parietal lobule and the superior temporal gyrus. The results demonstrate that ipsilateral afferent connections of area 44 arise from local frontal areas, including rostral premotor cortical area 6, from secondary somatosensory cortex, the caudal insula, and the cingulate motor region. Area 44 is strongly linked with the anterior inferior parietal lobule (particularly area PFG and the adjacent anterior intraparietal sulcus). Input from the temporal lobe is limited to the fundus of the superior temporal sulcus extending caudal to the central sulcus. There is also input from the sulcal part of area Tpt in the upper bank of the superior temporal sulcus. Area 45B shares some of the connections of area 44, but can be distinguished from area 44 by input from the caudal inferior parietal lobule (area PG) and significant input from the part of the superior temporal sulcus that extends anterior to the central sulcus. Area 45B also receives input from visual association cortex that is not observed in area 44. The results have provided a clarification of the relative connections of areas 44 and 45B of the ventrolateral frontal region which, in the human brain, subserves certain aspects of language processing.

Fiber anatomy of dorsal and ventral language streams.

Recent advances in neuroimaging have led to new insights into the organization of language related networks. Increasing evidence supports the model of dorsal and ventral streams of information flow between language-related areas. Therefore, a review of the descriptions of language-related fiber anatomy in the human and monkey brain was performed. In addition, case studies of macroscopical fiber dissection and polarized light imaging (PLI) with special focus on the ventral stream were done. Several fiber structures can be identified to play a role in language, i.e. the arcuate fasciculus as a part of the superior longitudinal fasciculus, the middle longitudinal fasciculus, the inferior fronto-occipital fasciculus, and extreme and external capsules. Substantial differences between human and monkey fiber architecture have been identified. Despite inconsistencies based on different terminologies used, there can be no doubt that dorsal and ventral language streams have a clear correlation in the structure of white matter tracts.

Continuity, divergence, and the evolution of brain language pathways.

Recently, the assumption of evolutionary continuity between humans and non-human primates has been used to bolster the hypothesis that human language is mediated especially by the ventral extreme capsule pathway that mediates auditory object recognition in macaques. Here, we argue for the importance of evolutionary divergence in understanding brain language evolution. We present new comparative data reinforcing our previous conclusion that the dorsal arcuate fasciculus pathway was more significantly modified than the ventral extreme capsule pathway in human evolution. Twenty-six adult human and twenty-six adult chimpanzees were imaged with diffusion-weighted MRI and probabilistic tractography was used to track and compare the dorsal and ventral language pathways. Based on these and other data, we argue that the arcuate fasciculus is likely to be the pathway most essential for higher-order aspects of human language such as syntax and lexical-semantics.

Microstructural analysis of human white matter architecture using polarized light imaging: views from neuroanatomy.

To date, there are several methods for mapping connectivity, ranging from the macroscopic to molecular scales. However, it is difficult to integrate this multiply-scaled data into one concept. Polarized light imaging (PLI) is a method to quantify fiber orientation in gross histological brain sections based on the birefringent properties of the myelin sheaths. The method is capable of imaging fiber orientation of larger-scale architectural patterns with higher detail than diffusion MRI of the human brain. PLI analyses light transmission through a gross histological section of a human brain under rotation of a polarization filter combination. Estimates of the angle of fiber direction and the angle of fiber inclination are automatically calculated at every point of the imaged section. Multiple sections can be assembled into a 3D volume. We describe the principles of PLI and present several studies of fiber anatomy as a synopsis of PLI: six brainstems were serially sectioned, imaged with PLI, and 3D reconstructed. Pyramidal tract and lemniscus medialis were segmented in the PLI datasets. PLI data from the internal capsule was related to results from confocal laser scanning microscopy, which is a method of smaller scale fiber anatomy. PLI fiber architecture of the extreme capsule was compared to macroscopical dissection, which represents a method of larger-scale anatomy. The microstructure of the anterior human cingulum bundle was analyzed in serial sections of six human brains. PLI can generate highly resolved 3D datasets of fiber orientation of the human brain and has high comparability to diffusion MR. To get additional information regarding axon structure and density, PLI can also be combined with classical histological stains. It brings the directional aspects of diffusion MRI into the range of histology and may represent a promising tool to close the gap between larger-scale diffusion orientation and microstructural histological analysis of connectivity.