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1.  Distinct Parietal and Temporal Pathways to the Homologues of Broca's Area in the Monkey 
PLoS Biology  2009;7(8):e1000170.
An unprecedented detailed analysis of ventrolateral frontal cortical circuitry in Broca's area of the non-human primate brain clarifies the functional pathways permitting interaction between posterior cortical areas and the anterior language zone, providing important clues about the evolution of language.
The homologues of the two distinct architectonic areas 44 and 45 that constitute the anterior language zone (Broca's region) in the human ventrolateral frontal lobe were recently established in the macaque monkey. Although we know that the inferior parietal lobule and the lateral temporal cortical region project to the ventrolateral frontal cortex, we do not know which of the several cortical areas found in those regions project to the homologues of Broca's region in the macaque monkey and by means of which white matter pathways. We have used the autoradiographic method, which permits the establishment of the cortical area from which axons originate (i.e., the site of injection), the precise course of the axons in the white matter, and their termination within particular cortical areas, to examine the parietal and temporal connections to area 44 and the two subdivisions of area 45 (i.e., areas 45A and 45B). The results demonstrated a ventral temporo-frontal stream of fibers that originate from various auditory, multisensory, and visual association cortical areas in the intermediate superolateral temporal region. These axons course via the extreme capsule and target most strongly area 45 with a more modest termination in area 44. By contrast, a dorsal stream of axons that originate from various cortical areas in the inferior parietal lobule and the adjacent caudal superior temporal sulcus was found to target both areas 44 and 45. These axons course in the superior longitudinal fasciculus, with some axons originating from the ventral inferior parietal lobule and the adjacent superior temporal sulcus arching and forming a simple arcuate fasciculus. The cortex of the most rostral part of the inferior parietal lobule is preferentially linked with the ventral premotor cortex (ventral area 6) that controls the orofacial musculature. The cortex of the intermediate part of the inferior parietal lobule is linked with both areas 44 and 45. These findings demonstrate the posterior parietal and temporal connections of the ventrolateral frontal areas, which, in the left hemisphere of the human brain, were adapted for various aspects of language production. These precursor circuits that are found in the nonlinguistic, nonhuman, primate brain also exist in the human brain. The possible reasons why these areas were adapted for language use in the human brain are discussed. The results throw new light on the prelinguistic precursor circuitry of Broca's region and help understand functional interactions between Broca's ventrolateral frontal region and posterior parietal and temporal association areas.
Author Summary
Two distinct cortical areas in the frontal lobe of the human brain, known as Broca's region, are involved with language production. This region has also been shown to exist in nonhuman primates. In this study, we explored the precise neural connectivity of Broca's region in macaque monkeys using the autoradiographic method to achieve a level of detail impossible in the human brain. We identified two major streams of connections feeding into Broca's area: a ventral stream from the temporal region, which includes areas processing auditory, multisensory, and visual information and a dorsal stream originating from the inferior parietal lobule and the adjacent superior temporal sulcus. Our detailed connectivity analysis illuminates the pathways via which posterior cortical areas can interact functionally with Broca's region, in addition to contributing to an understanding of the evolution of language. We suggest that a fundamental function of Broca's region is to retrieve information in a controlled strategic way from posterior cortical regions and to translate this information into action. This fundamental function was adapted during evolution of the left hemisphere of the human brain to serve language.
PMCID: PMC2714989  PMID: 19668354
2.  Differentiated parietal connectivity of frontal regions for “what” and “where” memory 
Brain Structure & Function  2012;218(6):1551-1567.
In a previous meta-analysis across almost 200 neuroimaging experiments, working memory for object location showed significantly stronger convergence on the posterior superior frontal gyrus, whereas working memory for identity showed stronger convergence on the posterior inferior frontal gyrus (dorsal to, but overlapping with Brodmann’s area BA 44). As similar locations have been discussed as part of a dorsal frontal—superior parietal reach system and an inferior frontal grasp system, the aim of the present study was to test whether the regions of working-memory related “what” and “where” processing show a similar distinction in parietal connectivity. The regions that were found in the previous meta-analysis were used as seeds for functional connectivity analyses using task-based meta-analytic connectivity modelling and task-independent resting state correlations. While the ventral seed showed significantly stronger connectivity with the bilateral intraparietal sulcus (IPS), the dorsal seed showed stronger connectivity with the bilateral posterior inferior parietal and the medial superior parietal lobule. The observed connections of regions involved in memory for object location and identity thus clearly demonstrate a distinction into separate pathways that resemble the parietal connectivity patterns of the dorsal and ventral premotor cortex in non-human primates and humans. It may hence be speculated that memory for a particular location and reaching towards it as well as object memory and finger positioning for manipulation may rely on shared neural systems. Moreover, the ensuing regions, in turn, featured differential connectivity with the bilateral ventral and dorsal extrastriate cortex, suggesting largely segregated bilateral connectivity pathways from the dorsal visual cortex via the superior and inferior parietal lobules to the dorsal posterior frontal cortex and from the ventral visual cortex via the IPS to the ventral posterior frontal cortex that may underlie action and cognition.
PMCID: PMC3825581  PMID: 23143344
Action; ALE; Cognition; Premotor; Resting state; Streams
3.  The Organization of Dorsal Frontal Cortex in Humans and Macaques 
The Journal of Neuroscience  2013;33(30):12255-12274.
The human dorsal frontal cortex has been associated with the most sophisticated aspects of cognition, including those that are thought to be especially refined in humans. Here we used diffusion-weighted magnetic resonance imaging (DW-MRI) and functional MRI (fMRI) in humans and macaques to infer and compare the organization of dorsal frontal cortex in the two species. Using DW-MRI tractography-based parcellation, we identified 10 dorsal frontal regions lying between the human inferior frontal sulcus and cingulate cortex. Patterns of functional coupling between each area and the rest of the brain were then estimated with fMRI and compared with functional coupling patterns in macaques. Areas in human medial frontal cortex, including areas associated with high-level social cognitive processes such as theory of mind, showed a surprising degree of similarity in their functional coupling patterns with the frontal pole, medial prefrontal, and dorsal prefrontal convexity in the macaque. We failed to find evidence for “new” regions in human medial frontal cortex. On the lateral surface, comparison of functional coupling patterns suggested correspondences in anatomical organization distinct from those that are widely assumed. A human region sometimes referred to as lateral frontal pole more closely resembled area 46, rather than the frontal pole, of the macaque. Overall the pattern of results suggest important similarities in frontal cortex organization in humans and other primates, even in the case of regions thought to carry out uniquely human functions. The patterns of interspecies correspondences are not, however, always those that are widely assumed.
PMCID: PMC3744647  PMID: 23884933
4.  Dissociated Pathways for Successful Memory Retrieval from the Human Parietal Cortex: Anatomical and Functional Connectivity Analyses 
Cerebral Cortex (New York, NY)  2007;18(8):1771-1778.
The parietal cortex has traditionally been implicated in spatial attention and eye-movement processes. Recent functional neuroimaging studies have found that activation in the parietal cortex is related to successful recognition memory. The activated regions consistently include the intraparietal sulcus in the lateral parietal cortex and the precuneus in the medial parietal cortex. However, little is known about the functional differences between lateral and medial parietal cortices in the memory retrieval process. In this study, we examined whether the human lateral and medial parietal lobes have differential anatomical and functional connectivity with the temporal lobe. To this end, we used functional magnetic resonance imaging to constrain the analysis of anatomical connectivity obtained by diffusion tensor imaging (DTI). Both DTI tractography and functional connectivity analysis showed that the lateral parietal region has anatomical and functional connections with the lateral temporal lobe, and the medial parietal region has connections with the medial temporal lobe. These results suggest the existence of segregated lateral and medial parieto-temporal pathways in successful memory retrieval.
PMCID: PMC2790392  PMID: 18165283
diffusion tensor imaging; functional connectivity; long-term memory; parietal cortex; temporal lobe
5.  Cytoarchitectonic identification and probabilistic mapping of two distinct areas within the anterior ventral bank of the human intraparietal sulcus 
Anatomical studies in the macaque cortex and functional imaging studies in humans have demonstrated the existence of different cortical areas within the IntraParietal Sulcus (IPS). Such functional segregation, however, does not correlate with presently available architectonic maps of the human brain. This is particularly true for the classical Brodmann map, which is still widely used as an anatomical reference in functional imaging studies. The aim of this cytoarchitectonic mapping study was to use previously defined algorithms to determine whether consistent regions and borders can be found within the cortex of the anterior IPS in a population of ten postmortem human brains. Two areas, the human IntraParietal area 1 (hIP1) and the human IntraParietal area 2 (hIP2), were delineated in serial histological sections of the anterior, lateral bank of the human IPS. The region hIP1 is located posterior and medial to hIP2, and the former is always within the depths of the IPS. The latter, on the other hand, sometimes reaches the free surface of the superior parietal lobule. The delineations were registered to standard reference space, and probabilistic maps were calculated, thereby quantifying the intersubject variability in location and extent of both areas. In the future, they can be a tool in analyzing structure – function relationships and a basis for determining degrees of homology in the IPS among anthropoid primates. We conclude that the human intraparietal sulcus has a finer grained parcellation than shown in Brodmann’s map.
PMCID: PMC3429851  PMID: 16432904
stereotaxic maps; cytoarchitecture; parietal cortex; human intraparietal sulcus; mapping
6.  Mapping Putative Hubs in Human, Chimpanzee (Pan troglodytes) and Rhesus Macaque (Macaca mulatta) Connectomes via Diffusion Tractography 
NeuroImage  2013;80:462-474.
Mapping anatomical brain networks with graph-theoretic analysis of diffusion tractography has recently gained popularity, because of its presumed value in understanding brain function. However, this approach has seldom been used to compare brain connectomes across species, which may provide insights into brain evolution. Here, we employed a data-driven approach to compare interregional brain connections across three primate species: 1) the intensively studied rhesus macaque, 2) our closest living primate relative, the chimpanzee, and 3) humans. Specifically, we first used random parcellations and surface-based probabilistic diffusion tractography to derive the brain networks of the three species under various network densities and resolutions. We then compared the characteristics of the networks using graph-theoretic measures. In rhesus macaques, our tractography-defined hubs showed reasonable overlap with hubs previously identified using anterograde and retrograde tracer data. Across all three species, hubs were largely symmetric in the two hemispheres and were consistently identified in medial parietal, insular, retrosplenial cingulate and ventrolateral prefrontal cortices, suggesting a conserved structural architecture within these regions. However, species differences were observed in the inferior parietal cortex, polar and medial prefrontal cortices. The potential significance of these interspecies differences is discussed.
PMCID: PMC3720835  PMID: 23603286
brain networks; graph theory; prefrontal cortex; parietal cortex; tracer; random parcellation
7.  Defining functional SMA and pre-SMA subregions in human MFC using resting state fMRI: functional connectivity-based parcellation method 
NeuroImage  2009;49(3):2375.
Noninvasive parcellation of the human cerebral cortex is an important goal for understanding and examining brain functions. Recently, the patterns of anatomical connections using diffusion tensor imaging (DTI) have been used to parcellate brain regions. Here, we present a noninvasive parcellation approach that uses “functional fingerprints” obtained by correlation measures on resting-state functional Magnetic Resonance Imaging (fMRI) data to parcellate brain regions. In other terms, brain regions are parcellated based on the similarity of their connection – as reflected by correlation during resting-state – to the whole brain. The proposed method was used to parcellate the medial frontal cortex (MFC) into supplementary motor areas (SMA) and pre-SMA subregions. In agreement with anatomical landmark-based parcellation, we find that functional fingerprint clustering of the MFC results in anterior and posterior clusters. The probabilistic maps from 12 subjects showed that the anterior cluster is mainly located rostral to the vertical commissure anterior (VCA) line, whereas the posterior cluster is mainly located caudal to VCA line, suggesting the homologues of pre-SMA and SMA. The functional connections from the putative pre-SMA cluster were connected to brain regions which are responsible for complex/cognitive motor control, whereas those from the putative SMA cluster were connected to brain regions which are related to the simple motor control. These findings demonstrate the feasibility of the functional connectivity-based parcellation of the human cerebral cortex using resting state fMRI.
PMCID: PMC2819173  PMID: 19837176
8.  Broca’s Region: Linking Human Brain Functional Connectivity Data and Nonhuman Primate Tracing Anatomy Studies 
Brodmann areas 6, 44, and 45 in the ventrolateral frontal cortex of the left hemisphere of the human brain constitute the anterior language production zone. The anatomic connectivity of these areas with parietal and temporal cortical regions was recently examined in an autoradiographic tract-tracing study in the macaque monkey. Studies suggest strong correspondence between human resting state functional connectivity (RSFC) based on functional magnetic resonance imaging data and experimentally demonstrated anatomical connections in non-human primates. Accordingly, we hypothesized that areas 6, 44 and 45 of the human brain would exhibit patterns of RSFC consistent with patterns of anatomical connectivity observed in the macaque. In a primary analysis, we examined the RSFC associated with regions-of-interest placed in ventrolateral frontal areas 6, 44 and 45, on the basis of local sulcal and gyral anatomy. We validated the results of the primary hypothesis-driven analysis with a data-driven partitioning of ventrolateral frontal cortex into regions exhibiting distinct RSFC patterns, using a spectral clustering algorithm. The RSFC of ventrolateral frontal areas 6, 44 and 45 was consistent with patterns of anatomical connectivity shown in the macaque. We observed a striking dissociation between RSFC for the ventral part of area 6 that is involved in orofacial motor control and RSFC associated with Broca’s region (areas 44 and 45). These findings indicate rich and differential RSFC patterns for the ventrolateral frontal areas controlling language production, consistent with known anatomical connectivity in the macaque brain, and suggest conservation of connectivity during the evolution of the primate brain.
PMCID: PMC3111969  PMID: 20662902
fMRI; resting state; inferior frontal gyrus; language; clustering
9.  Altered resting-state functional connectivity in patients with chronic bilateral vestibular failure 
NeuroImage : Clinical  2014;4:488-499.
Patients with bilateral vestibular failure (BVF) suffer from gait unsteadiness, oscillopsia and impaired spatial orientation. Brain imaging studies applying caloric irrigation to patients with BVF have shown altered neural activity of cortical visual–vestibular interaction: decreased bilateral neural activity in the posterior insula and parietal operculum and decreased deactivations in the visual cortex. It is unknown how this affects functional connectivity in the resting brain and how changes in connectivity are related to vestibular impairment.
We applied a novel data driven approach based on graph theory to investigate altered whole-brain resting-state functional connectivity in BVF patients (n= 22) compared to age- and gender-matched healthy controls (n= 25) using resting-state fMRI. Changes in functional connectivity were related to subjective (vestibular scores) and objective functional parameters of vestibular impairment, specifically, the adaptive changes during active (self-guided) and passive (investigator driven) head impulse test (HIT) which reflects the integrity of the vestibulo-ocular reflex (VOR).
BVF patients showed lower bilateral connectivity in the posterior insula and parietal operculum but higher connectivity in the posterior cerebellum compared to controls. Seed-based analysis revealed stronger connectivity from the right posterior insula to the precuneus, anterior insula, anterior cingulate cortex and the middle frontal gyrus. Excitingly, functional connectivity in the supramarginal gyrus (SMG) of the inferior parietal lobe and posterior cerebellum correlated with the increase of VOR gain during active as compared to passive HIT, i.e., the larger the adaptive VOR changes the larger was the increase in regional functional connectivity.
Using whole brain resting-state connectivity analysis in BVF patients we show that enduring bilateral deficient or missing vestibular input leads to changes in resting-state connectivity of the brain. These changes in the resting brain are robust and task-independent as they were found in the absence of sensory stimulation and without a region-related a priori hypothesis. Therefore they may indicate a fundamental disease-related change in the resting brain. They may account for the patients' persistent deficits in visuo-spatial attention, spatial orientation and unsteadiness. The relation of increasing connectivity in the inferior parietal lobe, specifically SMG, to improvement of VOR during active head movements reflects cortical plasticity in BVF and may play a clinical role in vestibular rehabilitation.
•Resting-state connectivity was investigated in bilateral vestibular failure patients.•Patients showed lower connectivity in the posterior insula and parietal operculum.•Connectivity increased with improved VOR gain during self-initiated head movements.•This may indicate adaptive mechanisms in response to bilateral vestibular failure.
PMCID: PMC3984447  PMID: 24818075
Resting-state fMRI; Functional connectivity; Degree; Bilateral vestibular failure; Vestibulo-ocular reflex
10.  Across-study and within-subject functional connectivity of a right temporo-parietal junction subregion involved in stimulus–context integration 
Neuroimage  2012;60(4):2389-2398.
Bidirectional integration between sensory stimuli and contextual framing is fundamental to action control. Stimuli may entail context-dependent actions, while temporal or spatial characteristics of a stimulus train may establish a contextual framework for upcoming stimuli. Here we aimed at identifying core areas for stimulus–context integration and delineated their functional connectivity (FC) using meta-analytic connectivity modeling (MACM) and analysis of resting-state networks. In a multi-study conjunction, consistently increased activity under higher demands on stimulus–context integration was predominantly found in the right temporo-parietal junction (TPJ), which represented the largest cluster of overlap and was thus used as the seed for the functional connectivity analyses. The conjunction between task-dependent (MACM) and task-free (resting state) FC of the right TPJ revealed a shared network comprising bilaterally inferior parietal and frontal cortices, anterior insula, premotor cortex, putamen and cerebellum, i.e., a ‘ventral’ action / attention network. Stronger task-dependent (vs. task-free) connectivity was observed with the pre-SMA, dorsal pre-motor cortex, intraparietal sulcus, basal ganglia and primary sensory-motor cortex, while stronger resting-state (vs. task-dependent) connectivity was found with the dorsolateral prefrontal and medial parietal cortex.
Our data provide strong evidence that the right TPJ may represent a key region for the integration of sensory stimuli and contextual frames in action control. Task-dependent associations with regions related to stimulus processing and motor responses indicate that the right TPJ may integrate ‘collaterals’ of sensory processing and apply (ensuing) contextual frames, most likely via modulation of preparatory loops. Given the pattern of resting-state connectivity, internal states and goal representations may provide the substrates for the contextual integration within the TPJ in the absence of a specific task.
PMCID: PMC3321133  PMID: 22387170
fMRI; resting state; meta-analysis; connectivity modelling; right temporo-parietal junction
11.  Episodic memory retrieval, parietal cortex, and the Default Mode Network: functional and topographic analyses 
The default mode network (DMN) is often considered a functionally homogeneous system that is broadly associated with internally directed cognition (e.g. episodic memory, theory of mind, self-evaluation). However, few studies have examined how this network interacts with other networks during putative “default” processes such as episodic memory retrieval. Using fMRI, we investigated the topography and response profile of human parietal regions inside and outside the DMN, independently defined using task-evoked deactivations and resting state functional connectivity, during episodic memory retrieval. Memory retrieval activated posterior nodes of the DMN, particularly the angular gyrus, but also more anterior and dorsal parietal regions that were anatomically separate from the DMN. The two sets of parietal regions showed different resting-state functional connectivity and response profiles. During memory retrieval, responses in DMN regions peaked sooner than non-DMN regions, which in turn showed responses that were sustained until a final memory judgment was reached. Moreover, a parahippocampal region that showed strong resting-state connectivity with parietal DMN regions also exhibited a pattern of task-evoked activity similar to that exhibited by DMN regions. These results suggest that DMN parietal regions directly supported memory retrieval, whereas non-DMN parietal regions were more involved in post-retrieval processes such as memory-based decision making. Finally, a robust functional dissociation within the DMN was observed. While angular gyrus and posterior cingulate/precuneus were significantly activated during memory retrieval, an anterior DMN node in medial prefrontal cortex was strongly deactivated. This latter finding demonstrates functional heterogeneity rather than homogeneity within the DMN during episodic memory retrieval.
PMCID: PMC3098040  PMID: 21430142
fMRI; default mode network; episodic memory; medial prefrontal; parietal; functional connectivity
12.  Developmental Maturation of Dynamic Causal Control Signals in Higher-Order Cognition: A Neurocognitive Network Model 
PLoS Computational Biology  2012;8(2):e1002374.
Cognitive skills undergo protracted developmental changes resulting in proficiencies that are a hallmark of human cognition. One skill that develops over time is the ability to problem solve, which in turn relies on cognitive control and attention abilities. Here we use a novel multimodal neurocognitive network-based approach combining task-related fMRI, resting-state fMRI and diffusion tensor imaging (DTI) to investigate the maturation of control processes underlying problem solving skills in 7–9 year-old children. Our analysis focused on two key neurocognitive networks implicated in a wide range of cognitive tasks including control: the insula-cingulate salience network, anchored in anterior insula (AI), ventrolateral prefrontal cortex and anterior cingulate cortex, and the fronto-parietal central executive network, anchored in dorsolateral prefrontal cortex and posterior parietal cortex (PPC). We found that, by age 9, the AI node of the salience network is a major causal hub initiating control signals during problem solving. Critically, despite stronger AI activation, the strength of causal regulatory influences from AI to the PPC node of the central executive network was significantly weaker and contributed to lower levels of behavioral performance in children compared to adults. These results were validated using two different analytic methods for estimating causal interactions in fMRI data. In parallel, DTI-based tractography revealed weaker AI-PPC structural connectivity in children. Our findings point to a crucial role of AI connectivity, and its causal cross-network influences, in the maturation of dynamic top-down control signals underlying cognitive development. Overall, our study demonstrates how a unified neurocognitive network model when combined with multimodal imaging enhances our ability to generalize beyond individual task-activated foci and provides a common framework for elucidating key features of brain and cognitive development. The quantitative approach developed is likely to be useful in investigating neurodevelopmental disorders, in which control processes are impaired, such as autism and ADHD.
Author Summary
The human brain undergoes significant maturational changes between childhood and adulthood that are thought to enable increasingly sophisticated thoughts and behaviors. One of the skills that we develop over time is the ability to problem solve, which relies in turn on the ability to control our attention and successfully direct our cognitive efforts. Using a novel multi-pronged neuroimaging approach, we identify for the first time the dynamic brain systems underlying the maturation of problem solving abilities. We find that the anterior insula, part of a larger network of regions previously shown to be important for salience processing and generating influential control signals, shows weaker influences over other key brain regions important for task performance in children compared to adults. In addition, structural connections between the anterior insula and other key regions were found to be weaker in children compared to adults. Importantly, measures of causal influences between key regions could be used to predict individual differences in behavioral performance. Our study is the first to show that the anterior insula, by virtue of its dynamic influences on other key brain regions, shows developmental differences in both structural and functional connectivity, which may contribute to more mature cognitive abilities in adulthood compared to childhood.
PMCID: PMC3271018  PMID: 22319436
13.  Brain networks of spatial awareness: evidence from diffusion tensor imaging tractography 
Left unilateral neglect, a dramatic condition which impairs awareness of left-sided events, has been classically reported after right hemisphere cortical lesions involving the inferior parietal region. More recently, the involvement of long-range white matter tracts has been highlighted, consistent with the idea that awareness of events occurring in space depends on the coordinated activity of anatomically distributed brain regions. Damage to the superior longitudinal fasciculus (SLF), linking parietal to frontal cortical regions, or to the inferior longitudinal fasciculus (ILF), connecting occipital and temporal lobes, have been described in neglect patients. In this study four right-handed patients with right-hemisphere strokes were submitted to a high-definition anatomical MRI with diffusion tensor imaging (DTI) sequences and to a paper-and-pencil neglect battery. We used DTI tractography to visualize the SLF, the ILF and the inferior fronto-occipital fasciculus (IFOF), a pathway running in the depth of the temporal lobe, not hitherto associated with neglect. Two patients with cortical involvement of the inferior parietal and superior temporal regions, but intact and symmetrical fasciculi, showed no signs of neglect. The other two patients with signs of left neglect had superficial damage to the inferior parietal cortex and white matter damage involving the IFOF. These findings suggest that superficial damage to the inferior parietal cortex per se may not be sufficient to produce visual neglect. In some cases, a lesion to the direct connections between ventral occipital and frontal regions (i.e. IFOF) may contribute to the manifestation of neglect by impairing the top-down modulation of visual areas from frontal cortex.
PMCID: PMC2386830  PMID: 17991702
Aged; 80 and over; Awareness; physiology; Cerebral Cortex; physiopathology; Diffusion Magnetic Resonance Imaging; Dominance; Cerebral; physiology; Female; Humans; Image Processing; Computer-Assisted; Imaging; Three-Dimensional; Kinesthesis; physiology; Male; Middle Aged; Nerve Fibers; Myelinated; physiology; Nerve Net; physiopathology; Perceptual Disorders; diagnosis; physiopathology; Stroke; complications; physiopathology
14.  Multiple parietal-frontal pathways mediate grasping in macaque monkeys 
The nodes of a parietal-frontal pathway that mediates grasping in primates are in anterior intraparietal area (AIP) and ventral premotor cortex (PMv). Nevertheless, multiple somatosensory and motor representations of the hand, respectively in parietal and frontal cortex, suggest that additional pathways remain unrealized. We explored this possibility in macaque monkeys by injecting retrograde tracers into grasp zones identified in M1, PMv, and area 2 with long train electrical stimulation. The M1 grasp zone was densely connected with other frontal cortex motor regions. The remainder of the connections originated from somatosensory areas 3a and S2/PV, and from the medial bank and fundus of the intraparietal sulcus (IPS). The PMv grasp zone was also densely connected with frontal cortex motor regions, albeit to a lesser extent than the M1 grasp zone. The remainder of the connections originated from areas S2/PV and aspects of the inferior parietal lobe such as PF, PFG, AIP, and the tip of the IPS. The area 2 grasp zone was densely connected with the hand representations of somatosensory areas 3b, 1, and S2/PV. The remainder of the connections was with areas 3a and 5 and the medial bank and fundus of the IPS. Connections with frontal cortex were relatively weak and concentrated in caudal M1. Thus, the three grasp zones may be nodes of parallel parietal-frontal pathways. Differential points of origin and termination of each pathway suggest varying functional specializations. Direct and indirect connections between those parietal-frontal pathways likely coordinate their respective functions into an accurate grasp.
PMCID: PMC3166522  PMID: 21832196
15.  Functional connectivity changes between parietal and prefrontal cortices in primary insomnia patients: evidence from resting-state fMRI 
Primary insomnia can severely impair daytime function by disrupting attention and working memory and imposes a danger to self and others by increasing the risk of accidents. We speculated that the neurobiological changes impeding working memory in primary insomnia patients would be revealed by resting-state functional MRI (R-fMRI), which estimates the strength of cortical pathways by measuring local and regional correlations in blood oxygen level dependent (BOLD) signs independent of specific task demands.
We compared the R-fMRI activity patterns of 15 healthy controls to 15 primary insomnia patients (all 30 participants were right-handed) using a 3.0 T MRI scanner. The SPM8 and REST1.7 software packages were used for preprocessing and analysis. Activity was expressed relative to the superior parietal lobe (SPL, the seed region) to reveal differences in functional connectivity to other cortical regions implicated in spatial working memory.
In healthy controls, bilateral SPL activity was associated with activity in the posterior cingulate gyrus, precuneus, ventromedial prefrontal cortex, and superior frontal gyrus, indicating functional connectivity between these regions. Strong functional connectivity between the SPL and bilateral pre-motor cortex, bilateral supplementary motor cortex, and left dorsolateral prefrontal cortex was observed in both the control group and the primary insomnia group. However, the strength of several other functional connectivity pathways to the SPL exhibited significant group differences. Compared to healthy controls, connectivity in the primary insomnia group was stronger between the bilateral SPL and the right ventral anterior cingulate cortex, left ventral posterior cingulate cortex, right splenium of the corpus callosum, right pars triangularis (right inferior frontal gyrus/Broca’s area), and right insular lobe, while connectivity was weaker between the SPL and right superior frontal gyrus (dorsolateral prefrontal cortex).
Primary insomnia appears to alter the functional connectivity between the parietal and frontal lobes, cortical structures critical for spatial and verbal working memory.
PMCID: PMC4062281  PMID: 24915847
Functional MRI; Primary insomnia; Working memory; Superior parietal lobule
16.  Language networks in semantic dementia 
Brain  2009;133(1):286-299.
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.
PMCID: PMC2801321  PMID: 19759202
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
17.  Dissociable Connectivity within Human Angular Gyrus and Intraparietal Sulcus: Evidence from Functional and Structural Connectivity 
Cerebral Cortex (New York, NY)  2010;20(11):2636-2646.
The inferior parietal lobule (IPL) of the human brain is a heterogeneous region involved in visuospatial attention, memory, and mathematical cognition. Detailed description of connectivity profiles of subdivisions within the IPL is critical for accurate interpretation of functional neuroimaging studies involving this region. We separately examined functional and structural connectivity of the angular gyrus (AG) and the intraparietal sulcus (IPS) using probabilistic cytoarchitectonic maps. Regions-of-interest (ROIs) included anterior and posterior AG subregions (PGa, PGp) and 3 IPS subregions (hIP2, hIP1, and hIP3). Resting-state functional connectivity analyses showed that PGa was more strongly linked to basal ganglia, ventral premotor areas, and ventrolateral prefrontal cortex, while PGp was more strongly connected with ventromedial prefrontal cortex, posterior cingulate, and hippocampus—regions comprising the default mode network. The anterior-most IPS ROIs, hIP2 and hIP1, were linked with ventral premotor and middle frontal gyrus, while the posterior-most IPS ROI, hIP3, showed connectivity with extrastriate visual areas. In addition, hIP1 was connected with the insula. Tractography using diffusion tensor imaging revealed structural connectivity between most of these functionally connected regions. Our findings provide evidence for functional heterogeneity of cytoarchitectonically defined subdivisions within IPL and offer a novel framework for synthesis and interpretation of the task-related activations and deactivations involving the IPL during cognition.
PMCID: PMC2951845  PMID: 20154013
attention; Brodmann area 39; default mode network; inferior parietal lobule; mathematical cognition
18.  Connectivity-based structural and functional parcellation of the human cortex using diffusion imaging and tractography 
The parcellation of the cortex via its anatomical properties has been an important research endeavor for over a century. To date, however, a universally accepted parcellation scheme for the human brain still remains elusive. In the current review, we explore the use of in vivo diffusion imaging and white matter tractography as a non-invasive method for the structural and functional parcellation of the human cerebral cortex, discussing the strengths and limitations of the current approaches. Cortical parcellation via white matter connectivity is based on the premise that, as connectional anatomy determines functional organization, it should be possible to segregate functionally-distinct cortical regions by identifying similarities and differences in connectivity profiles. Recent studies have provided initial evidence in support of the efficacy of this connectional parcellation methodology. Such investigations have identified distinct cortical subregions which correlate strongly with functional regions identified via fMRI and meta-analyses. Furthermore, a strong parallel between the cortical regions defined via tractographic and more traditional cytoarchitectonic parcellation methods has been observed. However, the degree of correspondence and relative functional importance of cytoarchitectonic- versus connectivity-derived parcellations still remains unclear. Diffusion tractography remains one of the only methods capable of visualizing the structural networks of the brain in vivo. As such, it is of vital importance to continue to improve the accuracy of the methodology and to extend its potential applications in the study of cognition in neurological health and disease.
PMCID: PMC3429885  PMID: 22952459
connectivity; cytoarchitecture; diffusion; functional specialization; tractography
19.  A Parcellation Scheme for Human Left Lateral Parietal Cortex 
Neuron  2010;67(1):156-170.
The parietal lobe has long been viewed as a collection of architectonic and functional subdivisions. Though much parietal research has focused on mechanisms of visuospatial attention and control-related processes, more recent functional neuroimaging studies of memory retrieval have reported greater activity in left lateral parietal cortex (LLPC) when items are correctly identified as previously studied (“old”) vs. unstudied (“new”). These studies have suggested functional divisions within LLPC that may provide distinct contributions towards recognition memory judgments. Here, we define regions within LLPC by developing a novel parcellation scheme that integrates data from resting state functional connectivity MRI (rsfcMRI) and functional MRI (fMRI). This combined approach results in a six-fold parcellation of LLPC based on the presence (or absence) of memory retrieval-related activity, dissociations in the profile of task-evoked timecourses, and membership in large-scale brain networks. This parcellation should serve as a roadmap for future investigations aimed at understanding LLPC function.
PMCID: PMC2913443  PMID: 20624599
parietal; memory; functional connectivity; fMRI; fcMRI; parcellation; module; angular gyrus; intraparietal sulcus; inferior parietal lobule
20.  Modulating Intrinsic Connectivity: Adjacent Subregions within Supplementary Motor Cortex, Dorsolateral Prefrontal Cortex, and Parietal Cortex Connect to Separate Functional Networks during Task and Also Connect during Rest 
PLoS ONE  2014;9(3):e90672.
Supplementary motor area (SMA), the inferior frontal junction (IFJ), superior frontal junction (SFJ) and parietal cortex are active in many cognitive tasks. In a previous study, we found that subregions of each of these major areas were differentially active in component processes of executive function during working memory tasks. In the present study, each of these subregions was used as a seed in a whole brain functional connectivity analysis of working memory and resting state data. These regions show functional connectivity to different networks, thus supporting the parcellation of these major regions into functional subregions. Many regions showing significant connectivity during the working memory residual data (with task events regressed from the data) were also significantly connected during rest suggesting that these network connections to subregions within major regions of cortex are intrinsic. For some of these connections, task demands modulate activity in these intrinsic networks. Approximately half of the connections significant during task were significant during rest, indicating that some of the connections are intrinsic while others are recruited only in the service of the task. Furthermore, the network connections to traditional ‘task positive’ and ‘task negative’ (a.k.a ‘default mode’) regions shift from positive connectivity to negative connectivity depending on task demands. These findings demonstrate that such task-identified subregions are part of distinct networks, and that these networks have different patterns of connectivity for task as they do during rest, engaging connections both to task positive and task negative regions. These results have implications for understanding the parcellation of commonly active regions into more specific functional networks.
PMCID: PMC3956459  PMID: 24637793
21.  Distinct and Overlapping Functional Zones in the Cerebellum Defined by Resting State Functional Connectivity 
Cerebral Cortex (New York, NY)  2009;20(4):953-965.
The cerebellum processes information from functionally diverse regions of the cerebral cortex. Cerebellar input and output nuclei have connections with prefrontal, parietal, and sensory cortex as well as motor and premotor cortex. However, the topography of the connections between the cerebellar and cerebral cortices remains largely unmapped, as it is relatively unamenable to anatomical methods. We used resting-state functional magnetic resonance imaging to define subregions within the cerebellar cortex based on their functional connectivity with the cerebral cortex. We mapped resting-state functional connectivity voxel-wise across the cerebellar cortex, for cerebral–cortical masks covering prefrontal, motor, somatosensory, posterior parietal, visual, and auditory cortices. We found that the cerebellum can be divided into at least 2 zones: 1) a primary sensorimotor zone (Lobules V, VI, and VIII), which contains overlapping functional connectivity maps for domain-specific motor, somatosensory, visual, and auditory cortices; and 2) a supramodal zone (Lobules VIIa, Crus I, and II), which contains overlapping functional connectivity maps for prefrontal and posterior-parietal cortex. The cortical connectivity of the supramodal zone was driven by regions of frontal and parietal cortex which are not directly involved in sensory or motor processing, including dorsolateral prefrontal cortex and the frontal pole, and the inferior parietal lobule.
PMCID: PMC2837094  PMID: 19684249
cerebellum; fMRI; functional connectivity; networks; resting-state
22.  Probabilistic Tractography Recovers a Rostrocaudal Trajectory of Connectivity Variability in the Human Insular Cortex 
Human Brain Mapping  2011;33(9):2005-2034.
The insular cortex of macaques has a wide spectrum of anatomical connections whose distribution is related to its heterogeneous cytoarchitecture. Although there is evidence of a similar cytoarchitectural arrangement in humans, the anatomical connectivity of the insula in the human brain has not yet been investigated in vivo. In the present work, we used in vivo probabilistic white-matter tractography and Laplacian eigenmaps (LE) to study the variation of connectivity patterns across insular territories in humans. In each subject and hemisphere, we recovered a rostrocaudal trajectory of connectivity variation ranging from the anterior dorsal and ventral insula to the dorsal caudal part of the long insular gyri. LE suggested that regional transitions among tractography patterns in the insula occur more gradually than in other brain regions. In particular, the change in tractography patterns was more gradual in the insula than in the medial premotor region, where a sharp transition between different tractography patterns was found. The recovered trajectory of connectivity variation in the insula suggests a relation between connectivity and cytoarchitecture in humans resembling that previously found in macaques: tractography seeds from the anterior insula were mainly found in limbic and paralimbic regions and in anterior parts of the inferior frontal gyrus, while seeds from caudal insular territories mostly reached parietal and posterior temporal cortices. Regions in the putative dysgranular insula displayed more heterogeneous connectivity patterns, with regional differences related to the proximity with either putative granular or agranular regions. Hum Brain Mapp 33:2005–2034, 2012. © 2011 Wiley Periodicals, Inc.
PMCID: PMC3443376  PMID: 21761507
DTI; insula; laplacian eigenmaps; diffusion-weighted imaging; connectivity-based parcellation
23.  Q-Ball of Inferior Fronto-Occipital Fasciculus and Beyond 
PLoS ONE  2014;9(6):e100274.
The inferior fronto-occipital fasciculus (IFOF) is historically described as the longest associative bundle in the human brain and it connects various parts of the occipital cortex, temporo-basal area and the superior parietal lobule to the frontal lobe through the external/extreme capsule complex. The exact functional role and the detailed anatomical definition of the IFOF are still under debate within the scientific community. In this study we present a fiber tracking dissection of the right and left IFOF by using a q-ball residual-bootstrap reconstruction of High-Angular Resolution Diffusion Imaging (HARDI) data sets in 20 healthy subjects. By defining a single seed region of interest on the coronal fractional anisotropy (FA) color map of each subject, we investigated all the pathways connecting the parietal, occipital and posterior temporal cortices to the frontal lobe through the external/extreme capsule. In line with recent post-mortem dissection studies we found more extended anterior-posterior association connections than the “classical” fronto-occipital representation of the IFOF. In particular the pathways we evidenced showed: a) diffuse projections in the frontal lobe, b) fronto-parietal lobes connections trough the external capsule in almost all the subjects and c) widespread connections in the posterior regions. Our study represents the first consistent in vivo demonstration across a large group of individuals of these novel anterior and posterior terminations of the IFOF detailed described only by post-mortem anatomical dissection. Furthermore our work establishes the feasibility of consistent in vivo mapping of this architecture with independent in vivo methodologies. In conclusion q-ball tractography dissection supports a more complex definition of IFOF, which includes several subcomponents likely underlying specific function.
PMCID: PMC4063757  PMID: 24945305
24.  Perisylvian white matter connectivity in the human right hemisphere 
BMC Neuroscience  2009;10:15.
By using diffusion tensor magnetic resonance imaging (DTI) and subsequent tractography, a perisylvian language network in the human left hemisphere recently has been identified connecting Brocas's and Wernicke's areas directly (arcuate fasciculus) and indirectly by a pathway through the inferior parietal cortex.
Applying DTI tractography in the present study, we found a similar three-way pathway in the right hemisphere of 12 healthy individuals: a direct connection between the superior temporal and lateral frontal cortex running in parallel with an indirect connection. The latter composed of a posterior segment connecting the superior temporal with the inferior parietal cortex and an anterior segment running from the inferior parietal to the lateral frontal cortex.
The present DTI findings suggest that the perisylvian inferior parietal, superior temporal, and lateral frontal corticies are tightly connected not only in the human left but also in the human right hemisphere.
PMCID: PMC2653039  PMID: 19257886
25.  I remember you: A role for memory in social cognition and the functional neuroanatomy of their interaction 
Brain Research  2010;1428C:43-50.
Remembering events from the personal past (autobiographical memory) and inferring the thoughts and feelings of other people (mentalizing) share a neural substrate. The shared functional neuroanatomy of these processes has been demonstrated in a meta-analysis of independent task domains (Spreng, Mar & Kim, 2009) and within subjects performing both tasks (Rabin, Gilboa, Stuss, Mar, & Rosenbaum, 2010; Spreng & Grady, 2010). Here, we examine spontaneous low-frequency fluctuations in fMRI BOLD signal during rest from two separate regions key to memory and mentalizing, the left hippocampus and right temporal parietal junction, respectively. Activity in these two regions was then correlated with the entire brain in a resting-state functional connectivity analysis. Although the left hippocampus and right temporal parietal junction were not correlated with each other, both were correlated with a distributed network of brain regions. These regions were consistent with the previously observed overlap between autobiographical memory and mentalizing evoked brain activity found in past studies. Reliable patterns of overlap included the superior temporal sulcus, anterior temporal lobe, lateral inferior parietal cortex (angular gyrus), posterior cingulate cortex, dorsomedial and ventral prefrontal cortex, inferior frontal gyrus, and the amygdala. We propose that the functional overlap facilitates the integration of personal and interpersonal information and provides a means for personal experiences to become social conceptual knowledge. This knowledge, in turn, informs strategic social behavior in support of personal goals. In closing, we argue for a new perspective within social cognitive neuroscience, emphasizing the importance of memory in social cognition.
PMCID: PMC3085056  PMID: 21172325
Autobiographical memory; theory of mind; mentalizing; resting-state functional connectivity; fMRI; default mode network

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