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1.  Thalamocortical Connections between the Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in the Human Brain: A Diffusion Tensor Tractographic Study 
Yonsei Medical Journal  2014;55(3):709-714.
The elucidation of thalamocortical connections between the mediodorsal nucleus (MD) of thalamus and the prefrontal cortex (PFC) is important in the clinical fields of neurorehabilitation and psychiatry. However, little is known about these connections in human brain. We attempted to identify and investigate the anatomical characteristics of the thalamocortical connection between MD and PFC in human brain using diffusion tensor tractography (DTT).
Materials and Methods
Thirty-two healthy volunteers were recruited for this study. Diffusion tensor images were scanned using a 1.5-T. A seed region of interest was placed at the MD of the thalamus on coronal images, and target regions of interest were placed on the dorsolateral prefrontal cortex (DLPFC), the ventrolateral prefrontal cortex (VLPFC), and the orbitofrontal cortex (OFC), respectively. The three thalamocortical connections found were reconstructed using Functional Magnetic Resonance Imaging of the Brain (FMRIB) software.
The three thalamocortical connections were arranged in subcortical white matter in the following order from upper to lower levels: the DLPFC, the VLPFC, and the OFC. In terms of fractional anisotropy and mean diffusivity values, no significant differences were observed between the DLPFC, VLPFC and OFC (p>0.05). In contrast, the OFC tract volume was higher than those of the DLPFC and the VLPFC (p<0.05).
Three thalamocortical connections were reconstructed between MD and PFCs in human brain using DTT. We believe that the results of this study would be helpful to clinicians in treating frontal network syndrome and psychiatric diseases.
PMCID: PMC3990063  PMID: 24719138
Prefrontal cortex; mediodorsal nucleus; thalamus; diffusion tensor imaging
2.  Connectivity-Based Parcellation of the Thalamus Explains Specific Cognitive and Behavioural Symptoms in Patients with Bilateral Thalamic Infarct 
PLoS ONE  2013;8(6):e64578.
A novel approach based on diffusion tractography was used here to characterise the cortico-thalamic connectivity in two patients, both presenting with an isolated bilateral infarct in the thalamus, but exhibiting partially different cognitive and behavioural profiles. Both patients (G.P. and R.F.) had a pervasive deficit in episodic memory, but only one of them (R.F.) suffered also from a dysexecutive syndrome. Both patients had an MRI scan at 3T, including a T1-weighted volume. Their lesions were manually segmented. T1-volumes were normalised to standard space, and the same transformations were applied to the lesion masks. Nineteen healthy controls underwent a diffusion-tensor imaging (DTI) scan. Their DTI data were normalised to standard space and averaged. An atlas of Brodmann areas was used to parcellate the prefrontal cortex. Probabilistic tractography was used to assess the probability of connection between each voxel of the thalamus and a set of prefrontal areas. The resulting map of corticothalamic connections was superimposed onto the patients’ lesion masks, to assess whether the location of the thalamic lesions in R.F. (but not in G. P.) implied connections with prefrontal areas involved in dysexecutive syndromes. In G.P., the lesion fell within areas of the thalamus poorly connected with prefrontal areas, showing only a modest probability of connection with the anterior cingulate cortex (ACC). Conversely, R.F.’s lesion fell within thalamic areas extensively connected with the ACC bilaterally, with the right dorsolateral prefrontal cortex, and with the left supplementary motor area. Despite a similar, bilateral involvement of the thalamus, the use of connectivity-based segmentation clarified that R.F.’s lesions only were located within nuclei highly connected with the prefrontal cortical areas, thus explaining the patient’s frontal syndrome. This study confirms that DTI tractography is a useful tool to examine in vivo the effect of focal lesions on interconnectivity brain patterns.
PMCID: PMC3670907  PMID: 23755128
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.  What does the mediodorsal thalamus do? 
Dense amnesia can result from damage to the medial diencephalon in humans and in animals. In humans this damage is diffuse and can include the mediodorsal nuclei of the thalamus. In animal models, lesion studies have confirmed the mediodorsal thalamus (MD) has a role in memory and other cognitive tasks, although the extent of deficits is mixed. Anatomical tracing studies confirm at least three different subgroupings of the MD: medial, central, and lateral, each differentially interconnected to the prefrontal cortex (PFC). Moreover, these subgroupings of the MD also receive differing inputs from other brain structures, including the basal ganglia thus the MD subgroupings form key nodes in interconnected frontal-striatal-thalamic neural circuits, integrating critical information within the PFC. We will provide a review of data collected from non-human primates and rodents after selective brain injury to the whole of the MD as well as these subgroupings to highlight the extent of deficits in various cognitive tasks. This research highlights the neural basis of memory and cognitive deficits associated with the subgroupings of the MD and their interconnected neural networks. The evidence shows that the MD plays a critical role in many varied cognitive processes. In addition, the MD is actively processing information and integrating it across these neural circuits for successful cognition. Having established that the MD is critical for memory and cognition, further research is required to understand how the MD specifically influences these cognitive processing carried out by the brain.
PMCID: PMC3738868  PMID: 23950738
prefrontal cortex; memory; executive function; macaque; rodent; animal models; learning
5.  A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology 
Brain  2012;135(10):2938-2951.
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
PMCID: PMC3470716  PMID: 23065787
multiple sclerosis; post-mortem imaging; diffusion imaging; white matter tracts; neurodegeneration
Despite the prominence of parietal activity in human neuromaging investigations of sensorimotor and cognitive processes there remains uncertainty about basic aspects of parietal cortical anatomical organization. Descriptions of human parietal cortex draw heavily on anatomical schemes developed in other primate species but the validity of such comparisons has been questioned by claims that there are fundamental differences between the parietal cortex in humans and other primates. A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions. Anatomical connectivity was estimated using diffusion-weighted magnetic resonance image (MRI) based tractography and functional interactions were assessed by correlations in activity measured with functional MRI (fMRI) at rest. Resting state functional connectivity was also assessed directly in the rhesus macaque lateral parietal cortex in an additional experiment and the patterns found reflected known neuroanatomical connections. Cross-correlation in the tractography-based connectivity patterns of parietal voxels reliably parcellated human lateral parietal cortex into ten component clusters. The resting state functional connectivity of human superior parietal and intraparietal clusters with frontal and extrastriate cortex suggested correspondences with areas in macaque superior and intraparietal sulcus. Functional connectivity patterns with parahippocampal cortex and premotor cortex again suggested fundamental correspondences between inferior parietal cortex in humans and macaques. In contrast, the human parietal cortex differs in the strength of its interactions between the central inferior parietal lobule region and the anterior prefrontal cortex.
PMCID: PMC3091022  PMID: 21411650
7.  Antidepressant medications reduce subcortical–cortical resting-state functional connectivity in healthy volunteers 
Neuroimage  2011;57(4):1317-1323.
Studies have revealed abnormalities in resting-state functional connectivity in those with major depressive disorder specifically in areas such as the dorsal anterior cingulate, thalamus, amygdala, the pallidostriatum and subgenual cingulate. However, the effect of antidepressant medications on human brain function is less clear and the effect of these drugs on resting-state functional connectivity is unknown.
Forty volunteers matched for age and gender with no previous psychiatric history received either citalopram (SSRI; selective serotonergic reuptake inhibitor), reboxetine (SNRI; selective noradrenergic reuptake inhibitor) or placebo for 7 days in a double-blind design. Using resting-state functional magnetic resonance imaging and seed based connectivity analysis we selected the right nucleus accumbens, the right amygdala, the subgenual cingulate and the dorsal medial prefrontal cortex as seed regions. Mood and subjective experience were also measured before and after drug administration using self-report scales.
Despite no differences in mood across the three groups, we found reduced connectivity between the amygdala and the ventral medial prefrontal cortex in the citalopram group and the amygdala and the orbitofrontal cortex for the reboxetine group. We also found reduced striatal–orbitofrontal cortex connectivity in the reboxetine group.
These data suggest that antidepressant medications can decrease resting-state functional connectivity independent of mood change and in areas known to mediate reward and emotional processing in the brain. We conclude that hypothesis-driven seed based analysis of resting-state fMRI supports the proposition that antidepressant medications might work by normalising the elevated resting-state functional connectivity seen in depressed patients.
Research highlights
► We examine the effects of 7 day treatment with two antidepressants (citalopram and reboxetine) on resting-state functional connectivity in healthy volunteers. ► Both citalopram and reboxetine reduce functional connectivity between the amygdala seed region and the prefrontal cortex. ► Antidepressant action may involve normalisation of elevated resting-state functional connectivity between key elements of resting-state networks.
PMCID: PMC3141109  PMID: 21640839
fMRI; Depression; Resting-state; Connectivity; Antidepressants; OFC; vmPFC
8.  Circuits for multisensory integration and attentional modulation through the prefrontal cortex and the thalamic reticular nucleus in primates 
Reviews in the neurosciences  2007;18(6):417-438.
Converging evidence from anatomic and physiologic studies suggests that the interaction of high-order association cortices with the thalamus is necessary to focus attention on a task in a complex environment with multiple distractions. Interposed between the thalamus and cortex, the inhibitory thalamic reticular nucleus intercepts and regulates communication between the two structures. Recent findings demonstrate that a unique circuitry links the prefrontal cortex with the reticular nucleus and may underlie the process of selective attention to enhance salient stimuli and suppress irrelevant stimuli in behavior. Unlike other cortices, some prefrontal areas issue widespread projections to the reticular nucleus, extending beyond the frontal sector to the sensory sectors of the nucleus and may influence the flow of sensory information from the thalamus to the cortex. Unlike other thalamic nuclei, the mediodorsal nucleus, which is the principal thalamic nucleus for the prefrontal cortex, has similarly widespread connections with the reticular nucleus. Unlike sensory association cortices, some terminations from prefrontal areas to the reticular nucleus are large, suggesting efficient transfer of information. We propose a model showing that the specialized features of prefrontal pathways in the reticular nucleus may allow selection of relevant information and override distractors, in processes that are deranged in schizophrenia.
PMCID: PMC2855189  PMID: 18330211
corticothalamic projections; dual mode of termination; drivers and modulators; inhibitory control; overlap of terminations; mediodorsal nucleus; association cortices
9.  Dissociable roles for lateral orbitofrontal cortex and lateral prefrontal cortex during preference driven reversal learning 
Neuroimage  2012;59-20(4):4102-4112.
One of the archetypal task manipulations known to depend on frontal-lobe function is reversal learning, where a dominant response must be overridden due to changes in the contingencies relating stimuli, responses, and environmental feedback. Previous studies have indicated that the lateral prefrontal cortex (LPFC), the lateral orbitofrontal cortex (LOFC), the anterior cingulate cortex (ACC), and the caudate nucleus (CN) all contribute to reversal learning. However, the exact contributions that they make during this cognitively complex task remain poorly defined. Here, using functional magnetic resonance imaging, we examine which of the cognitive processes that contribute to the performance of a reversal best predicts the pattern of activation within distinct sub-regions of the frontal lobes. We demonstrate that during reversal learning the LOFC is particularly sensitive to the implementation of the reversal, whereas the LPFC is recruited more generally during attentional control. By contrast, the ACC and CN respond when new searches are initiated regardless of whether the previous response is available, whilst medial orbitofrontal cortex (MOFC) activity is correlated with the positive affect of feedback. These results accord well with the hypothesis that distinct components of adaptable behaviour are supported by anatomically distinct components of the executive system.
► We model fMRI data at distinct stages of a reward driven reversal learning task. ► Lateral orbitofrontal cortex responds particularly strongly at the point of reversal. ► Lateral prefrontal cortex shows a similar response during other switches. ► Medial orbitofrontal cortex activity correlates with the rewarding value of feedback. ► Anterior cingulate cortex and caudate respond whenever new searches are initiated.
PMCID: PMC3391678  PMID: 22075266
Reversal learning; fMRI; Executive function; Attention; Frontal lobe
10.  Low-Frequency BOLD Fluctuations Demonstrate Altered Thalamocortical Connectivity in Schizophrenia 
Schizophrenia Bulletin  2008;36(4):713-722.
The thalamus plays a central and dynamic role in information transmission and processing in the brain. Multiple studies reveal increasing association between schizophrenia and dysfunction of the thalamus, in particular the medial dorsal nucleus (MDN), and its projection targets. The medial dorsal thalamic connections to the prefrontal cortex are of particular interest, and explicit in vivo evidence of this connection in healthy humans is sparse. Additionally, recent neuroimaging evidence has demonstrated disconnection among a variety of cortical regions in schizophrenia, though the MDN thalamic prefrontal cortex network has not been extensively probed in schizophrenia. To this end, we have examined thalamo-anterior cingulate cortex connectivity using detection of low-frequency blood oxygen level dependence fluctuations (LFBF) during a resting-state paradigm. Eleven schizophrenic patients and 12 healthy control participants were enrolled in a study of brain thalamocortical connectivity. Resting-state data were collected, and seed-based connectivity analysis was performed to identify the thalamocortical network. First, we have shown there is MDN thalamocortical connectivity in healthy controls, thus demonstrating that LFBF analysis is a manner to probe the thalamocortical network. Additionally, we have found there is statistically significantly reduced thalamocortical connectivity in schizophrenics compared with matched healthy controls. We did not observe any significant difference in motor networks between groups. We have shown that the thalamocortical network is observable using resting-state connectivity in healthy controls and that this network is altered in schizophrenia. These data support a disruption model of the thalamocortical network and are consistent with a disconnection hypothesis of schizophrenia.
PMCID: PMC2894601  PMID: 18990709
schizophrenia; thalamus; connectivity; fcMRI; resting state; cingulate
11.  Specific Contributions of Ventromedial, Anterior Cingulate, and Lateral Prefrontal Cortex for Attentional Selection and Stimulus Valuation 
PLoS Biology  2011;9(12):e1001224.
Functional clusters of neurons in the monkey prefrontal and anterior cingulate cortex are involved in guiding attention to the most valuable objects in a scene.
Attentional control ensures that neuronal processes prioritize the most relevant stimulus in a given environment. Controlling which stimulus is attended thus originates from neurons encoding the relevance of stimuli, i.e. their expected value, in hand with neurons encoding contextual information about stimulus locations, features, and rules that guide the conditional allocation of attention. Here, we examined how these distinct processes are encoded and integrated in macaque prefrontal cortex (PFC) by mapping their functional topographies at the time of attentional stimulus selection. We find confined clusters of neurons in ventromedial PFC (vmPFC) that predominantly convey stimulus valuation information during attention shifts. These valuation signals were topographically largely separated from neurons predicting the stimulus location to which attention covertly shifted, and which were evident across the complete medial-to-lateral extent of the PFC, encompassing anterior cingulate cortex (ACC), and lateral PFC (LPFC). LPFC responses showed particularly early-onset selectivity and primarily facilitated attention shifts to contralateral targets. Spatial selectivity within ACC was delayed and heterogeneous, with similar proportions of facilitated and suppressed responses during contralateral attention shifts. The integration of spatial and valuation signals about attentional target stimuli was observed in a confined cluster of neurons at the intersection of vmPFC, ACC, and LPFC. These results suggest that valuation processes reflecting stimulus-specific outcome predictions are recruited during covert attentional control. Value predictions and the spatial identification of attentional targets were conveyed by largely separate neuronal populations, but were integrated locally at the intersection of three major prefrontal areas, which may constitute a functional hub within the larger attentional control network.
Author Summary
To navigate within an environment filled with sensory stimuli, the brain must selectively process only the most relevant sensory information. Identifying and shifting attention to the most relevant sensory stimulus requires integrating information about its sensory features as well as its relative value, that is, whether it's worth noticing. In this study, we describe groups of neurons in the monkey prefrontal cortex that convey signals relating to the value of a stimulus and its defining feature and location at the very moment when attention is shifted to the stimulus. We found that signals conveying information about value were clustered in a ventromedial prefrontal region, and were separated from sensory signals within the anterior cingulate cortex and the lateral prefrontal cortex. The integration of valuation and other “top-down” processes, however, was achieved by neurons clustered at the intersection of ventromedial, anterior cingulate, and lateral prefrontal cortex. We conclude that valuation processes are recruited when attention is shifted, independent of any overt behavior. Moreover, our analysis suggests that valuation processes can bias the initiation of attention shifts, as well as ensure sustained attentional focusing.
PMCID: PMC3246452  PMID: 22215982
12.  Segregated Fronto-Cerebellar Circuits Revealed by Intrinsic Functional Connectivity 
Cerebral Cortex (New York, NY)  2009;19(10):2485-2497.
Multiple, segregated fronto-cerebellar circuits have been characterized in nonhuman primates using transneuronal tracing techniques including those that target prefrontal areas. Here, we used functional connectivity MRI (fcMRI) in humans (n = 40) to identify 4 topographically distinct fronto-cerebellar circuits that target 1) motor cortex, 2) dorsolateral prefrontal cortex, 3) medial prefrontal cortex, and 4) anterior prefrontal cortex. All 4 circuits were replicated and dissociated in an independent data set (n = 40). Direct comparison of right- and left-seeded frontal regions revealed contralateral lateralization in the cerebellum for each of the segregated circuits. The presence of circuits that involve prefrontal regions confirms that the cerebellum participates in networks important to cognition including a specific fronto-cerebellar circuit that interacts with the default network. Overall, the extent of the cerebellum associated with prefrontal cortex included a large portion of the posterior hemispheres consistent with a prominent role of the cerebellum in nonmotor functions. We conclude by providing a provisional map of the topography of the cerebellum based on functional correlations with the frontal cortex.
PMCID: PMC2742600  PMID: 19592571
cerebellum; cognition; fMRI; pontine nucleus; prefrontal cortex; thalamus
13.  High Field fMRI Reveals Thalamocortical Integration of Segregated Cognitive and Emotional Processing in Mediodorsal and Intralaminar Thalamic Nuclei 
Thalamocortical loops, connecting functionally segregated, higher order cortical regions, and basal ganglia, have been proposed not only for well described motor and sensory regions, but also for limbic and prefrontal areas relevant for affective and cognitive processes. These functions are, however, more specific to humans, rendering most invasive neuroanatomical approaches impossible and interspecies translations difficult. In contrast, non-invasive imaging of functional neuroanatomy using fMRI allows for the development of elaborate task paradigms capable of testing the specific functionalities proposed for these circuits. Until recently, spatial resolution largely limited the anatomical definition of functional clusters at the level of distinct thalamic nuclei. Since their anatomical distinction seems crucial not only for the segregation of cognitive and limbic loops but also for the detection of their functional interaction during cognitive–emotional integration, we applied high resolution fMRI on 7 Tesla. Using an event-related design, we could isolate thalamic effects for preceding attention as well as experience of erotic stimuli. We could demonstrate specific thalamic effects of general emotional arousal in mediodorsal nucleus and effects specific to preceding attention and expectancy in intralaminar centromedian/parafascicular complex. These thalamic effects were paralleled by specific coactivations in the head of caudate nucleus as well as segregated portions of rostral or caudal cingulate cortex and anterior insula supporting distinct thalamo–striato–cortical loops. In addition to predescribed effects of sexual arousal in hypothalamus and ventral striatum, high resolution fMRI could extent this network to paraventricular thalamus encompassing laterodorsal and parataenial nuclei. We could lend evidence to segregated subcortical loops which integrate cognitive and emotional aspects of basic human behavior such as sexual processing.
PMCID: PMC2981419  PMID: 21088699
salience processing; centromedian/parafascicular thalamus; mediodorsal thalamus; basal ganglia; cognition; emotion; high field fMRI; sexual processing
14.  Intralaminar and medial thalamic influence on cortical synchrony, information transmission and cognition 
The intralaminar and medial thalamic nuclei are part of the higher-order thalamus, which receives little sensory input, and instead forms extensive cortico-thalamo-cortical pathways. The large mediodorsal thalamic nucleus predominantly connects with the prefrontal cortex, the adjacent intralaminar nuclei connect with fronto-parietal cortex, and the midline thalamic nuclei connect with medial prefrontal cortex and medial temporal lobe. Taking into account this connectivity pattern, it is not surprising that the intralaminar and medial thalamus has been implicated in a variety of cognitive functions, including memory processing, attention and orienting, as well as reward-based behavior. This review addresses how the intralaminar and medial thalamus may regulate information transmission in cortical circuits. A key neural mechanism may involve intralaminar and medial thalamic neurons modulating the degree of synchrony between different groups of cortical neurons according to behavioral demands. Such a thalamic-mediated synchronization mechanism may give rise to large-scale integration of information across multiple cortical circuits, consequently influencing the level of arousal and consciousness. Overall, the growing evidence supports a general role for the higher-order thalamus in the control of cortical information transmission and cognitive processing.
PMCID: PMC4023070  PMID: 24847225
neural synchrony; memory; attention; reward; schizophrenia; anesthesia; reuniens nucleus; mediodorsal nucleus
15.  Evidence for Broad Versus Segregated Projections from Cholinergic and Noradrenergic Nuclei to Functionally and Anatomically Discrete Subregions of Prefrontal Cortex 
The prefrontal cortex (PFC) is implicated in a variety of cognitive and executive operations. However, this region is not a single functional unit; rather, it is composed of several functionally and anatomically distinct networks, including anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). These prefrontal subregions serve dissociable behavioral functions, and are unique in their afferent and efferent connections. Each of these subregions is innervated by ascending cholinergic and noradrenergic systems, each of which likewise has a distinct role in cognitive function; yet the distribution and projection patterns of cells in the source nuclei for these pathways have not been examined in great detail. In this study, fluorescent retrograde tracers were injected into ACC, mPFC, and OFC, and labeled cells were identified in the cholinergic nucleus basalis of Meynert (NBM) and noradrenergic nucleus locus coeruleus (LC). Injections into all three cortical regions consistently labeled cells primarily ipsilateral to the injection site with a minimal contralateral component. In NBM, retrogradely labeled neurons were scattered throughout the rostral half of the nucleus, whereas those in LC tended to cluster in the core of the nucleus, and were rarely localized within the rostral or caudal poles. In NBM, more than half of all retrogradely labeled cells possessed axon collaterals projecting two or more PFC subregions. In LC, however, only 4.3% of retrogradely labeled neurons possessed collaterals targeting any two prefrontal subregions simultaneously, and no cells were identified that projected to all three regions. Of all labeled LC neurons, 49.3% projected only to mPFC, 28.5% projected only to OFC, and 18.0% projected only to ACC. These findings suggest that subsets of LC neurons may be capable of modulating neuronal activity in individual prefrontal subregions independently, whereas assemblies of NBM cells may exert a more unified influence on the three areas, simultaneously. This work emphasizes unique aspects of the cholinergic and noradrenergic projections to functionally and anatomically distinct subregions of PFC and provides insights regarding global versus segregated regulation of prefrontal operations by these neuromodulatory pathways.
PMCID: PMC3356860  PMID: 22661934
orbitofrontal cortex; medial prefrontal cortex; anterior cingulate cortex; nucleus basalis of Meynert; locus coeruleus; prefrontal cortex; norepinephrine; acetylcholine
16.  Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait 
Brain  2013;136(8):2405-2418.
Freezing of gait is one of the most debilitating symptoms in Parkinson’s disease as it causes falls and reduces mobility and quality of life. The pedunculopontine nucleus is one of the major nuclei of the mesencephalic locomotor region and has neurons related to anticipatory postural adjustments preceding step initiation as well as to the step itself, thus it may be critical for coupling posture and gait to avoid freezing. Because freezing of gait and postural impairments have been related to frontal lesions and frontal dysfunction such as executive function, we hypothesized that freezing is associated with disrupted connectivity between midbrain locomotor regions and medial frontal cortex. We used diffusion tensor imaging to quantify structural connectivity of the pedunculopontine nucleus in patients with Parkinson’s disease with freezing of gait, without freezing, and healthy age-matched controls. We also included behavioural tasks to gauge severity of freezing of gait, quantify gait metrics, and assess executive cognitive functions to determine whether between-group differences in executive dysfunction were related to pedunculopontine nucleus structural network connectivity. Using seed regions from the pedunculopontine nucleus, we were able to delineate white matter connections between the spinal cord, cerebellum, pedunculopontine nucleus, subcortical and frontal/prefrontal cortical regions. The current study is the first to demonstrate differences in structural connectivity of the identified locomotor pathway in patients with freezing of gait. We report reduced connectivity of the pedunculopontine nucleus with the cerebellum, thalamus and multiple regions of the frontal cortex. Moreover, these structural differences were observed solely in the right hemisphere of patients with freezing of gait. Finally, we show that the more left hemisphere-lateralized the pedunculopontine nucleus tract volume, the poorer the performance on cognitive tasks requiring the initiation of appropriate actions and/or the inhibition of inappropriate actions, specifically within patients with freezing. These results support the notion that freezing of gait is strongly related to structural deficits in the right hemisphere’s locomotor network involving prefrontal cortical areas involved in executive inhibition function.
PMCID: PMC3722352  PMID: 23824487
diffusion tensor imaging; inhibition; executive function; falls; balance; white matter; microstructure
17.  Distinct roles of three frontal cortical areas in reward-guided behavior 
Functional magnetic resonance imaging (fMRI) was used to measure activity in three frontal cortical areas, lateral orbitofrontal cortex (lOFC), medial orbitofrontal cortex/ventromedial frontal cortex (mOFC/vmPFC), and anterior cingulate cortex (ACC) when expectations about type of reward, and not just reward presence or absence, could be learned. Two groups of human subjects learned twelve stimulus-response pairings. In one group (Consistent), correct performances of a given pairing were always reinforced with a specific reward outcome whereas in the other group (Inconsistent), correct performances were reinforced with randomly selected rewards. MOFC/vmPFC and lOFC were not distinguished by simple differences in relative preference for positive and negative outcomes. Instead lOFC activity reflected updating of reward-related associations specific to reward type; lOFC was active whenever informative outcomes allowed updating of reward-related associations regardless of whether the outcomes were positive or negative and the effects were greater when consistent stimulus-outcome and response-outcome mappings were present. A psycho-physiological interaction (PPI) analysis demonstrated changed coupling between lOFC and brain areas for visual object representation, such as perirhinal cortex, and reward-guided learning, such as amygdala, ventral striatum, and habenula /mediodorsal thalamus. By contrast mOFC/vmPFC activity reflected expected values of outcomes and occurrence of positive outcomes, irrespective of consistency of outcome mappings. The third frontal cortical region, ACC, reflected the use of reward type information to guide response selection. ACC activity reflected the probability of selecting the correct response, was greater when consistent outcome mappings were present, and was related to individual differences in propensity to select the correct response.
PMCID: PMC3224993  PMID: 21976525
18.  Laminar and modular organization of prefrontal projections to multiple thalamic nuclei 
Neuroscience  2009;161(4):1067-1081.
The prefrontal cortex projects to many thalamic nuclei, in pathways associated with cognition, emotion, and action. We investigated how multiple projection systems to the thalamus are organized in prefrontal cortex after injection of distinct retrograde tracers in the principal mediodorsal (MD), the limbic anterior medial (AM), and the motor-related ventral anterior/ventral lateral (VA/VL) thalamic nuclei in rhesus monkeys. Neurons projecting to these nuclei were organized in interdigitated modules extending vertically within layers VI and V. Projection neurons were also organized in layers. The majority of projection neurons to MD or AM originated in layer VI (~80%), but a significant proportion (~20%) originated in layer V. In contrast, prefrontal neurons projecting to VA/VL were equally distributed in layers V and VI. Neurons directed to VA/VL occupied mostly the upper part of layer V, while neurons directed to MD or AM occupied mostly the deep part of layer V. The highest proportions of projection neurons in layer V to each nucleus were found in dorsal and medial prefrontal areas. The laminar organization of prefrontal cortico-thalamic projections differs from sensory systems, where projections originate predominantly or entirely from layer VI. Previous studies indicate that layer V cortico-thalamic neurons innervate through some large terminals thalamic neurons that project widely to superficial cortical layers. The large population of prefrontal projection neurons in layer V may drive thalamic neurons, triggering synchronization by recruiting several cortical areas through widespread thalamo-cortical projections to layer I. These pathways may underlie the synthesis of cognition, emotion and action.
PMCID: PMC2700123  PMID: 19376204
Macaca mulatta; mediodorsal thalamic nucleus; anterior thalamic nuclei; layer V pyramidal neurons; cortico-thalamic pathway
19.  Strategic lacunes and their relationship to cognitive impairment in cerebral small vessel disease 
NeuroImage : Clinical  2014;4:828-837.
Lacunes are an important disease feature of cerebral small vessel disease (SVD) but their relationship to cognitive impairment is not fully understood. To investigate this we determined (1) the relationship between lacune count and total lacune volume with cognition, (2) the spatial distribution of lacunes and the cognitive impact of lacune location, and (3) the whole brain anatomical covariance associated with these strategically located regions of lacune damage.
One hundred and twenty one patients with symptomatic lacunar stroke and radiological leukoaraiosis were recruited and multimodal MRI and neuropsychological data acquired. Lacunes were mapped semi-automatically and their volume calculated. Lacune location was automatically determined by projection onto atlases, including an atlas which segments the thalamus based on its connectivity to the cortex. Lacune locations were correlated with neuropsychological results. Voxel based morphometry was used to create anatomical covariance maps for these ‘strategic’ regions.
Lacune number and lacune volume were positively associated with worse executive function (number p < 0.001; volume p < 0.001) and processing speed (number p < 0.001; volume p < 0.001). Thalamic lacunes, particularly those in regions with connectivity to the prefrontal cortex, were associated with impaired processing speed (Bonferroni corrected p = 0.016). Regions of associated anatomical covariance included the medial prefrontal, orbitofrontal, anterior insular cortex and the striatum.
Lacunes are important predictors of cognitive impairment in SVD. We highlight the importance of spatial distribution, particularly of anteromedial thalamic lacunes which are associated with impaired information processing speed and may mediate cognitive impairment via disruption of connectivity to the prefrontal cortex.
•Lacunes are a predictor of cognitive impairment in cerebral small vessel disease•Lacunes in the anteromedial thalamus are associated with impaired processing speed•This region was identified to have connectivity to the prefrontal cortex•We validate this finding with the help of a structural covariance analysis
PMCID: PMC4055894  PMID: 24936433
Small vessel disease; Lacunes; Cognitive Impairment
20.  Structural basis of the fronto-thalamic dysconnectivity in schizophrenia: A combined DCM-VBM study☆ 
NeuroImage : Clinical  2013;3:95-105.
Several lines of evidence suggest that cognitive control deficits may be regarded as a connecting link between reported impairments in different cognitive domains of schizophrenia. However, the precise interplay within the fronto-cingulo-thalamic network known to be involved in cognitive control processes and its structural correlates has only been sparsely investigated in schizophrenia. The present multimodal study was therefore designed to model cognitive control processes within the fronto-cingulo-thalamic network. A disruption in effective connectivity in patients in association with abnormal white matter (WM) structure in this network was hypothesized. 36 patients with schizophrenia and 36 healthy subjects participated in the present study. Using functional magnetic resonance imaging (fMRI) a Stroop task was applied in an event-related design. For modeling effective connectivity dynamic causal modeling (DCM) was used. Voxel-based morphometry (VBM) was employed to study WM abnormalities. In the fMRI analysis, the patients demonstrated a significantly decreased BOLD signal in the fronto-cingulo-thalamic network. In the DCM analysis, a significantly decreased bilateral endogenous connectivity between the mediodorsal thalamus (MD) and the anterior cingulate cortex (ACC) was detected in patients in comparison to healthy controls, which was negatively correlated with the Stroop interference score. Furthermore, an increased endogenous connectivity between the right DLPFC and the right MD was observed in the patients. WM volume decreases were observed in the patients in the MD and the frontal cortex. The present results provide strong evidence for the notion that an abnormal fronto-cingulo-thalamic effective connectivity may represent the basis of cognitive control deficits in schizophrenia. Moreover, the data indicate that disrupted white matter connectivity in the mediodorsal thalamus and in the fronto-cingulo-thalamic network may constitute the determining cause of fronto-cingulo-thalamic dysconnectivity.
•Decreased BOLD signal in the fronto-thalamic network in the Stroop task in patients•Decreased endogenous connectivity between thalamus and the ACC in patients•Decreased WM volume in the thalamus and the frontal cortex in patients•Disrupted WM connectivity as potential cause of the fronto-thalamic dysconnectivity
PMCID: PMC3791293  PMID: 24179853
Schizophrenia; FMRI; Cognitive control; Voxel-based morphometry; Thalamus
21.  The Prefrontal Cortex Achieves Inhibitory Control by Facilitating Subcortical Motor Pathway Connectivity 
The Journal of Neuroscience  2015;35(2):786-794.
Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain controversial. Using a stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree of modulation by the inferior frontal gyrus, predicted individual differences in participants' stopping performance (stop-signal reaction time). We then used diffusion-weighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures. Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control.
PMCID: PMC4293423  PMID: 25589771
diffusion MRI tractography; dynamic causal modelling; inferior frontal gyrus; presupplementary motor area; response inhibition; stop-signal task
22.  Altered Fronto-Striatal Fiber Topography and Connectivity in Obsessive-Compulsive Disorder 
PLoS ONE  2014;9(11):e112075.
Fronto-striatal circuits are hypothesized to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). Within this circuitry, ventral frontal regions project fibers to the ventral striatum (VS) and dorsal frontal regions to the dorsal striatum. Resting state fMRI research has shown higher functional connectivity between the orbitofrontal cortex (OFC) and the dorsal part of the VS in OCD patients compared to healthy controls (HC). Therefore, we hypothesized that in OCD the OFC predominantly project fibers to the more dorsal part of the VS, and that the structural connectivity between the OFC and VS is higher compared to HC. A total of 20 non-medicated OCD patients and 20 HC underwent diffusion-weighted imaging. Connectivity-based parcellation analyses were performed with the striatum as seed region and the OFC, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex as target regions. Obtained connectivity maps for each frontal region of interest (ROI) were normalized into standard space, and Z-component (dorsal–ventral) coordinate of center-of-gravity (COG) were compared between two groups. Probabilistic tractography was performed to investigate diffusion indices of fibers between the striatum and frontal ROIs. COG Z-component coordinates of connectivity maps for OFC ROI were located in the more dorsal part of the VS in OCD patients compared to HC. Fractional anisotropy of fibers between the OFC and the striatum was higher in OCD patients compared to HC. Part of the pathophysiology of OCD might be understood by altered topography and structural connectivity of fibers between the OFC and the striatum.
PMCID: PMC4222976  PMID: 25375933
23.  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
24.  Tics are caused by alterations in prefrontal areas, thalamus and putamen, while changes in the cingulate gyrus reflect secondary compensatory mechanisms 
BMC Neuroscience  2014;15:6.
Despite strong evidence that the pathophysiology of Tourette syndrome (TS) involves structural and functional disturbances of the basal ganglia and cortical frontal areas, findings from in vivo imaging studies have provided conflicting results. In this study we used whole brain diffusion tensor imaging (DTI) to investigate the microstructural integrity of white matter pathways and brain tissue in 19 unmedicated, adult, male patients with TS “only” (without comorbid psychiatric disorders) and 20 age- and sex-matched control subjects.
Compared to normal controls, TS patients showed a decrease in the fractional anisotropy index (FA) bilaterally in the medial frontal gyrus, the pars opercularis of the left inferior frontal gyrus, the middle occipital gyrus, the right cingulate gyrus, and the medial premotor cortex. Increased apparent diffusion coefficient (ADC) maps were detected in the left cingulate gyrus, prefrontal areas, left precentral gyrus, and left putamen. There was a negative correlation between tic severity and FA values in the left superior frontal gyrus, medial frontal gyrus bilaterally, cingulate gyrus bilaterally, and ventral posterior lateral nucleus of the right thalamus, and a positive correlation in the body of the corpus callosum, left thalamus, right superior temporal gyrus, and left parahippocampal gyrus. There was also a positive correlation between regional ADC values and tic severity in the left cingulate gyrus, putamen bilaterally, medial frontal gyrus bilaterally, left precentral gyrus, and ventral anterior nucleus of the left thalamus.
Our results confirm prior studies suggesting that tics are caused by alterations in prefrontal areas, thalamus and putamen, while changes in the cingulate gyrus seem to reflect secondary compensatory mechanisms. Due to the study design, influences from comorbidities, gender, medication and age can be excluded.
PMCID: PMC3893393  PMID: 24397347
Tic; Tourette syndrome; DTI; Putamen; Thalamus; Cingulate gyrus
25.  Synchronization of Isolated Downstates (K-Complexes) May Be Caused by Cortically-Induced Disruption of Thalamic Spindling 
PLoS Computational Biology  2014;10(9):e1003855.
Sleep spindles and K-complexes (KCs) define stage 2 NREM sleep (N2) in humans. We recently showed that KCs are isolated downstates characterized by widespread cortical silence. We demonstrate here that KCs can be quasi-synchronous across scalp EEG and across much of the cortex using electrocorticography (ECOG) and localized transcortical recordings (bipolar SEEG). We examine the mechanism of synchronous KC production by creating the first conductance based thalamocortical network model of N2 sleep to generate both spontaneous spindles and KCs. Spontaneous KCs are only observed when the model includes diffuse projections from restricted prefrontal areas to the thalamic reticular nucleus (RE), consistent with recent anatomical findings in rhesus monkeys. Modeled KCs begin with a spontaneous focal depolarization of the prefrontal neurons, followed by depolarization of the RE. Surprisingly, the RE depolarization leads to decreased firing due to disrupted spindling, which in turn is due to depolarization-induced inactivation of the low-threshold Ca2+ current (IT). Further, although the RE inhibits thalamocortical (TC) neurons, decreased RE firing causes decreased TC cell firing, again because of disrupted spindling. The resulting abrupt removal of excitatory input to cortical pyramidal neurons then leads to the downstate. Empirically, KCs may also be evoked by sensory stimuli while maintaining sleep. We reproduce this phenomenon in the model by depolarization of either the RE or the widely-projecting prefrontal neurons. Again, disruption of thalamic spindling plays a key role. Higher levels of RE stimulation also cause downstates, but by directly inhibiting the TC neurons. SEEG recordings from the thalamus and cortex in a single patient demonstrated the model prediction that thalamic spindling significantly decreases before KC onset. In conclusion, we show empirically that KCs can be widespread quasi-synchronous cortical downstates, and demonstrate with the first model of stage 2 NREM sleep a possible mechanism whereby this widespread synchrony may arise.
Author Summary
EEG in the most common stage of human sleep is dominated by K-complexes (KCs) and sleep spindles (bursts of 10–14 Hz oscillations) occupying the thalamus and cortex. Recently, we discovered that KCs are brief moments when the cortex becomes almost completely silent. Here, using recordings directly from the cortex of epileptic patients, we show that KCs can be quasi-synchronous across widespread cortical areas, and ask what mechanism could produce such a phenomenon. We created the first network model of realistic cortical and thalamic neurons, which spontaneously generate KCs as well as sleep spindles. We showed that the membrane channels in the reticular nucleus of the thalamus can be inactivated by excitatory inputs from the cortex, and this disrupts the spindle-generating network, which can trigger widespread cortical silence. The model prediction that thalamic spindle disruption occurs prior to KC was then observed in simultaneous recordings from the human thalamus and cortex. Understanding the cellular and network mechanisms whereby KCs arise is crucial to understanding its roles in maintaining sleep and consolidating memories.
PMCID: PMC4177663  PMID: 25255217

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