Flavio Dell’Acqua

Short frontal lobe connections of the human brain.

Advances in our understanding of sensory-motor integration suggest a unique role of the frontal lobe circuits in cognition and behaviour. Long-range afferent connections convey higher order sensory information to the frontal cortex, which in turn responds to internal and external stimuli with flexible and adaptive behaviour. Long-range connections from and to frontal lobes have been described in detail in monkeys but little is known about short intralobar frontal connections mediating local connectivity in humans. Here we used spherical deconvolution diffusion tractography and post-mortem dissections to visualize the short frontal lobe connections of the human brain. We identified three intralobar tracts connecting: i) posterior Brocas region with supplementary motor area (SMA) and pre-supplementary motor area (pre-SMA) (i.e., the frontal aslant tract - FAT); ii) posterior orbitofrontal cortex with anterior polar region (i.e., fronto-orbitopolar tract - FOP); iii) posterior pre-central cortex with anterior prefrontal cortex (i.e., the frontal superior longitudinal - FSL faciculus system). In addition more complex systems of short U-shaped fibres were identified in the regions of the central, pre-central, perinsular and fronto-marginal sulcus (FMS). The connections between Broca and medial frontal areas (i.e. FAT) and those between the hand-knob motor region and post-central gyrus (PoCG) were found left lateralized in a group of twelve healthy right-handed subjects. The existence of these short frontal connections was confirmed using post-mortem blunt dissections. The functional role of these tracts in motor learning, verbal fluency, prospective behaviour, episodic and working memory is discussed. Our study provides a general model for the local connectivity of the frontal lobes that could be used as an anatomical framework for studies on lateralization and future clinical research in neurological and psychiatric disorders.

Monkey to human comparative anatomy of the frontal lobe association tracts

The greater expansion of the frontal lobes along the phylogeny scale has been interpreted as the signature of evolutionary changes underlying higher cognitive abilities in humans functions in humans. However, it is unknown how an increase in number of gyri, sulci and cortical areas in the frontal lobe have coincided with a parallel increase in connectivity. Here, using advanced tractography based on spherical deconvolution, we produced an atlas of human frontal association connections that we compared with axonal tracing studies of the monkey brain. We report several similarities between human and monkey in the cingulum, uncinate, superior longitudinal fasciculus, frontal aslant tract and orbito-polar tract. These similarities suggest to preserved functions across anthropoids. In addition, we found major differences in the arcuate fasciculus and the inferior fronto-occipital fasciculus. These differences indicate possible evolutionary changes in the connectional anatomy of the frontal lobes underlying unique human abilities.

A novel frontal pathway underlies verbal fluency in primary progressive aphasia

The frontal aslant tract is a direct pathway connecting Brocas region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks.

A revised limbic system model for memory, emotion and behaviour

Emotion, memories and behaviour emerge from the coordinated activities of regions connected by the limbic system. Here, we propose an update of the limbic model based on the seminal work of Papez, Yakovlev and MacLean. In the revised model we identify three distinct but partially overlapping networks: (i) the Hippocampal-diencephalic and parahippocampal-retrosplenial network dedicated to memory and spatial orientation; (ii) The temporo-amygdala-orbitofrontal network for the integration of visceral sensation and emotion with semantic memory and behaviour; (iii) the default-mode network involved in autobiographical memories and introspective self-directed thinking. The three networks share cortical nodes that are emerging as principal hubs in connectomic analysis. This revised network model of the limbic system reconciles recent functional imaging findings with anatomical accounts of clinical disorders commonly associated with limbic pathology.

Fronto-striatal circuitry and inhibitory control in autism: findings from diffusion tensor imaging tractography.

INTRODUCTIONnRepetitive behaviour and inhibitory control deficits are core features of autism; and it has been suggested that they result from differences in the anatomy of striatum; and/or the connectivity of subcortical regions to frontal cortex. There are few studies, however, that have measured the micro-structural organisation of white matter tracts connecting striatum and frontal cortex.nnnAIMSnTo investigate differences in bulk volume of striatum and micro-structural organisation of fronto-striatal white matter in people with autism; and their association with repetitive behaviour and inhibitory control.nnnMETHODSnWe compared the bulk volume of striatum (caudate nucleus, putamen and nucleus accumbens) and white matter organisation of fronto-striatal tracts using (respectively) structural magnetic resonance imaging (sMRI) and tract specific diffusion tensor imaging (DTI) measures in 21 adults with autism and 22 controls. We also assessed performance on a cognitive inhibition (go/nogo) task.nnnRESULTSnBulk volume of striatal structures did not differ between groups. However, adults with autism had a significantly smaller total brain white matter volume, lower fractional anisotropy of white matter tracts connecting putamen to frontal cortical areas, higher mean diffusivity of white matter tracts connecting accumbens to frontal cortex and worse performance on the go/nogo task. Also, performance on the go/nogo task was significantly related to anatomical variation when both groups were combined; but not within the autism group alone.nnnCONCLUSIONSnThese data suggest that autism may be associated with differences in the anatomy of fronto-striatal white matter tracts.

Non-invasive imaging of transplanted human neural stem cells and ECM scaffold remodeling in the stroke-damaged rat brain by 19F- and diffusion-MRI

Transplantation of human neural stem cells (hNSCs) is emerging as a viable treatment for stroke related brain injury. However, intraparenchymal grafts do not regenerate lost tissue, but rather integrate into the host parenchyma without significantly affecting the lesion cavity. Providing a structural support for the delivered cells appears important for cell based therapeutic approaches. The non-invasive monitoring of therapeutic methods would provide valuable information regarding therapeutic strategies but remains a challenge. Labeling transplanted cells with metal-based (1)H-magnetic resonance imaging (MRI) contrast agents affects the visualization of the lesion cavity. Herein, we demonstrate that a (19)F-MRI contrast agent can adequately monitor the distribution of transplanted cells, whilst allowing an evaluation of the lesion cavity and the formation of new tissue on (1)H-MRI scans. Twenty percent of cells labeled with the (19)F agent were of host origin, potentially reflecting the re-uptake of label from dead transplanted cells. Both T(2)- and diffusion-weighted MRI scans indicated that transplantation of hNSCs suspended in a gel form of a xenogeneic extracellular matrix (ECM) bioscaffold resulted in uniformly distributed cells throughout the lesion cavity. However, diffusion MRI indicated that the injected materials did not yet establish diffusion barriers (i.e. cellular network, fiber tracts) normally found within striatal tissue. The ECM bioscaffold therefore provides an important support to hNSCs for the creation of de novo tissue and multi-nuclei MRI represents an adept method for the visualization of some aspects of this process. However, significant developments of both the transplantation paradigm, as well as regenerative imaging, are required to successfully create new tissue in the lesion cavity and to monitor this process non-invasively.

Anatomical predictors of aphasia recovery: a tractography study of bilateral perisylvian language networks

Stroke-induced aphasia is associated with adverse effects on quality of life and the ability to return to work. For patients and clinicians the possibility of relying on valid predictors of recovery is an important asset in the clinical management of stroke-related impairment. Age, level of education, type and severity of initial symptoms are established predictors of recovery. However, anatomical predictors are still poorly understood. In this prospective longitudinal study, we intended to assess anatomical predictors of recovery derived from diffusion tractography of the perisylvian language networks. Our study focused on the arcuate fasciculus, a language pathway composed of three segments connecting Wernickes to Brocas region (i.e. long segment), Wernickes to Geschwinds region (i.e. posterior segment) and Brocas to Geschwinds region (i.e. anterior segment). In our study we were particularly interested in understanding how lateralization of the arcuate fasciculus impacts on severity of symptoms and their recovery. Sixteen patients (10 males; mean age 60 ± 17 years, range 28-87 years) underwent post stroke language assessment with the Revised Western Aphasia Battery and neuroimaging scanning within a fortnight from symptoms onset. Language assessment was repeated at 6 months. Backward elimination analysis identified a subset of predictor variables (age, sex, lesion size) to be introduced to further regression analyses. A hierarchical regression was conducted with the longitudinal aphasia severity as the dependent variable. The first model included the subset of variables as previously defined. The second model additionally introduced the left and right arcuate fasciculus (separate analysis for each segment). Lesion size was identified as the only independent predictor of longitudinal aphasia severity in the left hemisphere [beta = -0.630, t(-3.129), P = 0.011]. For the right hemisphere, age [beta = -0.678, t(-3.087), P = 0.010] and volume of the long segment of the arcuate fasciculus [beta = 0.730, t(2.732), P = 0.020] were predictors of longitudinal aphasia severity. Adding the volume of the right long segment to the first-level model increased the overall predictive power of the model from 28% to 57% [F(1,11) = 7.46, P = 0.02]. These findings suggest that different predictors of recovery are at play in the left and right hemisphere. The right hemisphere language network seems to be important in aphasia recovery after left hemispheric stroke.

Structural human brain networks: hot topics in diffusion tractography.

PURPOSE OF REVIEWnAfter more than 10 years of methodological developments and clinical applications, diffusion imaging tractography has reached a crossroad. Although the method is still in its infancy, the time has come to address some important questions. Can tractography reproduce reliably known anatomy or describe new anatomical pathways? Are interindividual differences, for example in tract lateralization, important to understand heterogeneity of clinical manifestations? Do novel tractography algorithms provide a real advantage over previous methods? Here we focus on some of the most exciting recent advancements in diffusion tractography and critically highlight their advantages and limitations.nnnRECENT FINDINGSnA flourishing of diffusion methods and models are bringing new solutions to the well known limitations of classical tractography based on the tensor model. However, these methods pose also new challenges and require the convergence and integration of different disciplines before they can replace what is currently widely available.nnnSUMMARYnRigorous postmortem validation, clinical optimization and experimental confirmation are obligatory steps before advanced diffusion technologies can translate into clear benefits for neurological patients.

White matter integrity as a predictor of response to treatment in first episode psychosis.

The integrity of brain white matter connections is central to a patient’s ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response.

The challenge of mapping the human connectome based on diffusion tractography

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.