Uncovering the inferior fronto-occipital fascicle and its topological organization in non-human primates: the missing connection for language evolution

International audienceWhether brain networks underlying the multimodal processing of language in humans are present in non-human primates is an unresolved question in primate evolution. Conceptual awareness in humans, which is the backbone of verbal and non-verbal semantic elaboration, involves intracerebral connectivity via the inferior fronto-occipital fascicle (IFOF). While non-human primates can communicate through visual information channels, there has been no formal demonstration that they possess a functional homologue of the human IFOF. Therefore, we undertook a post-mortem diffusion MRI tractography study in conjunction with Klingler micro-dissection to search for IFOF fiber tracts in brain of Old-World (vervet) monkeys. We found clear and concordant evidence from both techniques for the existence of bilateral fiber tracts connecting the frontal and occipital lobes. These tracts closely resembled the human IFOF with respect to trajectory, topological organization, and cortical terminal fields. Moreover, these fibers are clearly distinct from other bundles previously described in this region of monkey brain, i.e., the inferior longitudinal and uncinate fascicles, and the external and extreme capsules. This demonstration of an IFOF in brain of a species that diverged from the human lineage some 22 millions years ago enhances our comprehension about the evolution of language and social behavior

The use of Grauer classification in the management of type II odontoid fracture in elderly: prognostic factors and outcome analysis in a single centre patient series

Objective: To evaluate the results of Type II odontoid fractures management in the elderly, according to the Grauer classification. Methods: Consecutive patients with type II odontoid fracture, age > 65 years and follow-up longer than 3 months were included. Fracture management was proposed according to Grauer classification. Peri-surgical risk factors, NDI, VAS and rate of fusion were evaluated according to the treatment modality and compared between conservative and surgical groups. Results: Thirty-four patients were considered eligible for the study; 2 patients showed a Type IIa fracture, 30 patients a type IIb, and 2 patients a type IIc. Type IIa patients underwent conservative treatment that resulted in failure. A conservative management was adopted in 9 cases with type IIb due to patient preference or anaesthesiologic reasons with a treatment success at 6 months of 11%. Trans-odontoid stabilization was adopted in 21 type IIb cases with an evidence of bony or fibrous union at 6 months of 95% and a median NDI of 20%. A posterior approach was reserved for 2 type IIc fracture patients and in 6 cases as rescue surgery (bony union at 6 months of 100%; median NDI 37%). Higher Lakshmanan grade, gap and displacement of the fracture were found as significant risk factor for fracture non-union (p < 0.05). Conclusions: The surgical group presented better clinical and radiological outcome and the anterior approach proved to achieve the best results in type IIb fractures. The presence of osteoporosis and fracture spatial features should be duly considered in the decision-making process

Impact of mass effect, tumor location, age, and surgery on the cognitive outcome of patients with high-grade gliomas: a longitudinal study

Background. High-grade gliomas are the most frequently occurring brain tumors and carry unfavorable prognosis. Literature is controversial regarding the effects of surgery on cognitive functions. Methods. We analyzed a homogenous population of 30 patients with high-grade glioma who underwent complete resection. Patients underwent extensive neuropsychological analysis before surgery, 7 days after surgery, and approximately 40 days after surgery, before adjuvant treatments. Thirty-four neuropsychological tests were administered in the language, memory, attention, executive functions, and praxis domains. Results. The preoperative percentage of patients with impairment in the considered tests ranged from 0% to 53.3% (mean 20.9%). Despite a general worsening at early follow-up, a significant recovery was observed at late follow-up. Preoperative performances in language and verbal memory tasks depended on the joint effect of tumor volume, volume of surrounding edema, and tumor localization, with major deficits in patients with left lateralized tumor, especially insular and temporal. Preoperative performances in attention and constructive abilities tasks depended on the joint effect of tumor volume, volume of surrounding edema, and patient age, with major deficits in patients ≥ 65 years old. Recovery at late follow-up depended on the volume of resected tumor, edema resorption, and patient age. Conclusions. Longitudinal neuropsychological performance of patients affected by high-grade glioma depends, among other factors, on the complex interplay of tumor volume, volume of surrounding edema, tumor localization, and patient age. Reported results support the definition of criteria for surgical indication based on the above factors. They may be used to propose more customized surgical, oncological, and rehabilitative strategies

Structural and functional integration between dorsal and ventral language streams as revealed by blunt dissection and direct electrical stimulation

International audienceThe most accepted framework of language processing includes a dorsal phonological and a ventral semantic pathway, connecting a wide network of distributed cortical hubs. However, the cortico-subcortical connectivity and the reciprocal anatomical relationships of this dual-stream system are not completely clarified. We performed an original blunt microdissection of 10 hemispheres with the exposition of locoregional short fibers and six long-range fascicles involved in language elaboration. Special attention was addressed to the analysis of termination sites and anatomical relationships between long- and short-range fascicles. We correlated these anatomical findings with a topographical analysis of 93 functional responses located at the terminal sites of the language bundles, collected by direct electrical stimulation in 108 right-handers. The locations of phonological and semantic paraphasias, verbal apraxia, speech arrest, pure anomia, and alexia were statistically analyzed, and the respective barycenters were computed in the MNI space. We found that terminations of main language bundles and functional responses have a wider distribution in respect to the classical definition of language territories. Our analysis showed that dorsal and ventral streams have a similar anatomical layer organization. These pathways are parallel and relatively segregated over their subcortical course while their terminal fibers are strictly overlapped at the cortical level. Finally, the anatomical features of the U-fibers suggested a role of locoregional integration between the phonological, semantic, and executive subnetworks of language, in particular within the inferoventral frontal lobe and the temporoparietal junction, which revealed to be the main criss-cross regions between the dorsal and ventral pathways. Hum Brain Mapp 37:3858-3872, 2016. © 2016 Wiley Periodicals, Inc

Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous A\u3b242 prompted by exogenous fibrillary or soluble A\u3b225-35 in human cortical astrocytes and neurons: therapeutic relevance to Alzheimer's disease

The "amyloid-\u3b2 (A\u3b2) hypothesis" posits that accumulating A\u3b2 peptides (A\u3b2s) produced by neurons cause Alzheimer's disease (AD). However, the A\u3b2s contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)A\u3b225-35, an A\u3b242 proxy, evokes a surplus endogenous A\u3b242 production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fA\u3b225-35 and soluble (s)A\u3b225-35 on A\u3b242 and A\u3b240 accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds A\u3b2s, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fA\u3b225-35-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of A\u3b242, while A\u3b240 also accrued but its secretion was unchanged. Accordingly, secreted A\u3b242/A\u3b240 ratio values rose for astrocytes and neurons. While slightly enhancing A\u3b240 secretion by fA\u3b225-35-treated astrocytes, NPS 2143 specifically suppressed the fA\u3b225-35-elicited surges of endogenous A\u3b242 secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept A\u3b242/A\u3b240 values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/\u3b2-secretase and \u3b3-secretase activity in fA\u3b225-35-treated astrocytes. Compared to fA\u3b225-35, sA\u3b225-35 also stimulated A\u3b242 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any A\u3b2/CaSR-induced surplus secretion of endogenous A\u3b242 and hence further vicious cycles of A\u3b2 self-induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD.Peer reviewed: YesNRC publication: Ye

The A\u3b2 peptides-activated calcium-sensing receptor stimulates the production and secretion of vascular endothelial growth factor-A by normoxic adult human cortical astrocytes

The excess vascular endothelial growth factor (VEGF) produced in the Alzheimer's disease (AD) brain can harm neurons, blood vessels, and other components of the neurovascular units (NVUs). But could astrocytes partaking in networks of astrocyte-neuron teams and connected to blood vessels of NVUs contribute to VEGF production? We have shown with cultured cerebral cortical normal (i.e., untransformed) adult human astrocytes (NAHAs) that exogenous amyloid-\u3b2 peptides (A\u3b2s) stimulate the astrocytes to make and secrete large amounts of A\u3b2s and nitric oxide by a mechanism mediated through the calcium-sensing receptor (CaSR). Here, we report that exogenous A\u3b2s stimulate the NAHAs to produce and secrete even VEGF-A through a CaSR-mediated mechanism. This is indicated by the ability of A\u3b2s to specifically bind the CaSR, and the capability of a CaSR activator, the "calcimimetic" NPS R-568, to imitate, and of the CaSR antagonist, "calcilytic" NPS 2143, to inhibit, the A\u3b2s stimulation of VEGF-A production and secretion by the NAHAs. Thus, A\u3b2s that accumulate in the AD brain may make the astrocytes that envelop and functionally collaborate with neurons into multi-agent AD-driving "machines" via a CaSR signaling mechanism(s). These observations suggest the possibility that CaSR allosteric antagonists such as NPS 2143 might impede AD progression.Peer reviewed: YesNRC publication: Ye

Anatomo-functional study of the temporo-parieto-occipital region: dissection, tractographic and brain mapping evidence from a neurosurgical perspective

The temporo-parieto-occipital (TPO) junction is a complex brain territory heavily involved in several high-level neurological functions, such as language, visuo-spatial recognition, writing, reading, symbol processing, calculation, self-processing, working memory, musical memory, and face and object recognition. Recent studies indicate that this area is covered by a thick network of white matter (WM) connections, which provide efficient and multimodal integration of information between both local and distant cortical nodes. It is important for neurosurgeons to have good knowledge of the three-dimensional subcortical organisation of this highly connected region to minimise post-operative permanent deficits. The aim of this dissection study was to highlight the subcortical functional anatomy from a topographical surgical perspective. Eight human hemispheres (four left, four right) obtained from four human cadavers were dissected according to Klingler's technique. Proceeding latero-medially, the authors describe the anatomical courses of and the relationships between the main pathways crossing the TPO. The results obtained from dissection were first integrated with diffusion tensor imaging reconstructions and subsequently with functional data obtained from three surgical cases, all resection of infiltrating glial tumours using direct electrical mapping in awake patients. The subcortical limits for performing safe lesionectomies within the TPO region are as follows: within the parietal region, the anterior horizontal part of the superior longitudinal fasciculus and, more deeply, the arcuate fasciculus; dorsally, the vertical projective thalamo-cortical fibres. For lesions located within the temporal and occipital lobes, the resection should be tailored according to the orientation of the horizontal associative pathways (the inferior fronto-occipital fascicle, inferior longitudinal fascicle and optic radiation). The relationships between the WM tracts and the ventricle system were also examined. These results indicate that a detailed anatomo-functional awareness of the WM architecture within the TPO area is mandatory when approaching intrinsic brain lesions to optimise surgical results and to minimise post-operative morbidity

Whole-Brain Network Connectivity Underlying the Human Speech Articulation as Emerged Integrating Direct Electric Stimulation, Resting State fMRI and Tractography

Production of fluent speech in humans is based on a precise and coordinated articulation of sounds. A speech articulation network (SAN) has been observed in multiple brain studies typically using either neuroimaging or direct electrical stimulation (DES), thus giving limited knowledge about the whole brain structural and functional organization of this network. In this study, seven right-handed patients underwent awake surgery resection of low-grade gliomas (4) and cavernous angiomas. We combined pre-surgical resting state fMRI (rs-fMRI) and diffusion MRI together with speech arrest sites obtained intra-operatively with DES to address the following goals: (i) determine the cortical areas contributing to the intrinsic functional SAN using the speech arrest sites as functional seeds for rs-fMRI; (ii) evaluate the relative contribution of gray matter terminations from the two major language dorsal stream bundles, the superior longitudinal fasciculus (SLF III) and the arcuate fasciculus (AF); and (iii) evaluate the possible pre-surgical prediction of SAN with rs-fMRI. In all these right-handed patients the intrinsic functional SAN included frontal, inferior parietal, temporal, and insular regions symmetrically and bilaterally distributed across the two hemispheres regardless of the side (four right) of speech arrest evocation. The SLF III provided a much higher density of terminations in the cortical regions of SAN in respect to AF. Pre-surgical rs-fMRI data demonstrated moderate ability to predict the SAN. The set of functional and structural data provided in this multimodal study characterized, at a whole-brain level, a distributed and bi-hemispherical network subserving speech articulation