Silvio Sarubbo

Frontal terminations for the inferior fronto-occipital fascicle: anatomical dissection, DTI study and functional considerations on a multi-component bundle

The anatomy and functional role of the inferior fronto-occipital fascicle (IFOF) remain poorly known. We accurately analyze its course and the anatomical distribution of its frontal terminations. We propose a classification of the IFOF in different subcomponents. Ten hemispheres (5 left, 5 right) were dissected with Klingler’s technique. In addition to the IFOF dissection, we performed a 4-T diffusion tensor imaging study on a single healthy subject. We identified two layers of IFOF. The first one is superficial and antero-superiorly directed, terminating in the inferior frontal gyrus. The second is deeper and consists of three portions: posterior, middle and anterior. The posterior component terminates in the middle frontal gyrus (MFG) and dorso-lateral prefrontal cortex. The middle component terminates in the MFG and lateral orbito-frontal cortex. The anterior one is directed to the orbito-frontal cortex and frontal pole. In vivo tractography study confirmed these anatomical findings. We suggest that the distribution of IFOF fibers within the frontal lobe corresponds to a fine functional segmentation. IFOF can be considered as a “multi-function” bundle, with each anatomical subcomponent subserving different brain processing. The superficial layer and the posterior component of the deep layer, which connects the occipital extrastriate, temporo-basal and inferior frontal cortices, might subserve semantic processing. The middle component of the deep layer could play a role in a multimodal sensory–motor integration. Finally, the anterior component of the deep layer might be involved in emotional and behavioral aspects.

Towards a functional atlas of human white matter

Although diffusion tensor imaging (DTI) and postmortem dissections improved the knowledge of white matter (WM) anatomy, functional information is lacking. Our aims are: to provide a subcortical atlas of human brain functions; to elucidate the functional roles of different bundles; to provide a probabilistic resection map of WM.

Complete recovery after surgical resection of left Wernicke's area in awake patient: a brain stimulation and functional MRI study.

The left Wernickes area is a cornerstone of language. Although its anatomical boundaries were debated and renewed over the years [1, 3, 30], Wernickes territory [2] is now defined as the posterior two thirds of the superior and middle temporal gyrus [1]. This area plays a multimodal role in language, with involvement in phonological, semantic, and syntactic processing [4, 13, 28]. Its damage generates dramatic aphasia, with a poor recovery. Consequently, Wernickes area has been considered one of the main “inoperable” brain regions for many decades. Here, we report the first observation of surgical resection of the left Wernickes area invaded by a WHO grade II glioma in a right-handed patient, with a complete functional recovery. The mechanisms of compensation were discussed on the basis of the combined data provided by intraoperative electrical mapping and postoperative functional MRI.

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 Klinglers 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.

Brain Interstitial Nociceptin/Orphanin FQ Levels are Elevated in Parkinson's Disease

Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6‐hydroxydopamine‐hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinsons disease. In this study, we investigated whether elevation of N/OFQ expression in 6‐hydroxydopamine‐hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinsons disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (−20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be ∼3.5‐fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinsons disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.

Pallidal stimulation for segmental dystonia: Long term follow up of 11 consecutive patients†

Pallidal stimulation is a convincing and valid alternative for primary generalized dystonia refractory to medical therapy or botulinum toxin. However, the clinical outcome reported in literature is variable most likely because of heterogeneity DBS techniques employed and /or to clinical dystonic pattern of the patients who undergo surgery. In this study, we report the long term follow up of a homogeneous group of eleven subjects affected by segmental dystonia who were treated with bilateral stimulation of the Globus Pallidus pars interna (GPi) from the years 2000 to 2008. All the patients were evaluated, before surgery and at 6‐12‐24‐36 months after the treatment, in accordance with the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS). Our study indicates that DBS promotes an early and significant improvement at 6 months with an even and a better outcome later on. The analysis of specific sub items of the BFMDRS revealed an earlier and striking benefit not only as far as segmental motor function of the limbs but also for the complex cranial functions like face, (eyes and mouth), speech and swallowing, differently from results reported in primary generalized dystonia. Deep Brain Stimulation of GPi should be considered a valid indication for both generalized and segmental dystonia when other therapies appear ineffective.

Cortical Terminations of the Inferior Fronto-Occipital and Uncinate Fasciculi: Anatomical Stem-Based Virtual Dissection

We combined the neuroanatomists’ approach of defining a fascicle as all fibers passing through its compact stem with diffusion-weighted tractography to investigate the cortical terminations of two association tracts, the inferior fronto-occipital fasciculus (IFOF) and the uncinate fasciculus (UF), which have recently been implicated in the ventral language circuitry. The aim was to provide a detailed and quantitative description of their terminations in 60 healthy subjects and to do so to apply an anatomical stem-based virtual dissection, mimicking classical post-mortem dissection, to extract with minimal a priori the IFOF and UF from tractography datasets. In both tracts, we consistently observed more extensive termination territories than their conventional definitions, within the middle and superior frontal, superior parietal and angular gyri for the IFOF and the middle frontal gyrus and superior, middle and inferior temporal gyri beyond the temporal pole for the UF. We revealed new insights regarding the internal organization of these tracts by investigating for the first time the frequency, distribution and hemispheric asymmetry of their terminations. Interestingly, we observed a dissociation between the lateral right-lateralized and medial left-lateralized fronto-occipital branches of the IFOF. In the UF, we observed a rightward lateralization of the orbito-frontal and temporal branches. We revealed a more detailed map of the terminations of these fiber pathways that will enable greater specificity for correlating with diseased populations and other behavioral measures. The limitations of the diffusion tensor model in this study are also discussed. We conclude that anatomical stem-based virtual dissection with diffusion tractography is a fruitful method for studying the structural anatomy of the human white matter pathways.

The course and the anatomo‐functional relationships of the optic radiation: a combined study with ‘post mortem’ dissections and ‘in vivo’ direct electrical mapping

Even if different dissection, tractographic and connectivity studies provided pure anatomical evidences about the optic radiations (ORs), descriptions of both the anatomical structure and the anatomo‐functional relationships of the ORs with the adjacent bundles were not reported. We propose a detailed anatomical and functional study with ‘post mortem’ dissections and ‘in vivo’ direct electrical stimulation (DES) of the OR, demonstrating also the relationships with the adjacent eloquent bundles in a neurosurgical ‘connectomic’ perspective. Six human hemispheres (three left, three right) were dissected after a modified Klinglers preparation. The anatomy of the white matter was analysed according to systematic and topographical surgical perspectives. The anatomical results were correlated to the functional responses collected during three resections of tumours guided by cortico‐subcortical DES during awake procedures. We identified two groups of fibres forming the OR. The superior component runs along the lateral wall of the occipital horn, the trigone and the supero‐medial wall of the temporal horn. The inferior component covers inferiorly the occipital horn and the trigone, the lateral wall of the temporal horn and arches antero‐medially to form the Meyers Loop. The inferior fronto‐occipital fascicle (IFOF) covers completely the superior OR along its entire course, as confirmed by the subcortical DES. The inferior longitudinal fascicle runs in a postero‐anterior and inferior direction, covering the superior OR posteriorly and the inferior OR anteriorly. The IFOF identification allows the preservation of the superior OR in the anterior temporal resection, avoiding post‐operative complete hemianopia. The identification of the superior OR during the posterior temporal, inferior parietal and occipital resections leads to the preservation of the IFOF and of the eloquent functions it subserves. The accurate knowledge of the OR course and the relationships with the adjacent bundles is crucial to optimize quality of resection and functional outcome.

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

The 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.

Revisiting the human uncinate fasciculus, its subcomponents and asymmetries with stem-based tractography and microdissection validation

Despite its significant functional and clinical interest, the anatomy of the uncinate fasciculus (UF) has received little attention. It is known as a ‘hook-shaped’ fascicle connecting the frontal and anterior temporal lobes and is believed to consist of multiple subcomponents. However, the knowledge of its precise connectional anatomy in humans is lacking, and its subcomponent divisions are unclear. In the present study, we evaluate the anatomy of the UF and provide its detailed normative description in 30 healthy subjects with advanced particle-filtering tractography with anatomical priors and robustness to crossing fibers with constrained spherical deconvolution. We extracted the UF by defining its stem encompassing all streamlines that converge into a compact bundle, which consisted not only of the classic hook-shaped fibers, but also of straight horizontally oriented. We applied an automatic-clustering method to subdivide the UF bundle and revealed five subcomponents in each hemisphere with distinct connectivity profiles, including different asymmetries. A layer-by-layer microdissection of the ventral part of the external and extreme capsules using Klingler’s preparation also demonstrated five types of uncinate fibers that, according to their pattern, depth, and cortical terminations, were consistent with the diffusion-based UF subcomponents. The present results shed new light on the UF cortical terminations and its multicomponent internal organization with extended cortical connections within the frontal and temporal cortices. The different lateralization patterns we report within the UF subcomponents reconcile the conflicting asymmetry findings of the literature. Such results clarifying the UF structural anatomy lay the groundwork for more targeted investigations of its functional role, especially in semantic language processing.