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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.
Purpose
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.
Results
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).
Conclusion
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.
doi:10.3349/ymj.2014.55.3.709
PMCID: PMC3990063  PMID: 24719138
Prefrontal cortex; mediodorsal nucleus; thalamus; diffusion tensor imaging
2.  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.
doi:10.1523/JNEUROSCI.5108-12.2013
PMCID: PMC3744647  PMID: 23884933
3.  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.
doi:10.1371/journal.pone.0064578
PMCID: PMC3670907  PMID: 23755128
4.  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.
doi:10.1016/j.neuroimage.2011.05.051
PMCID: PMC3141109  PMID: 21640839
fMRI; Depression; Resting-state; Connectivity; Antidepressants; OFC; vmPFC
5.  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.
Highlights
► 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.
doi:10.1016/j.neuroimage.2011.10.072
PMCID: PMC3391678  PMID: 22075266
Reversal learning; fMRI; Executive function; Attention; Frontal lobe
6.  DIFFUSION-WEIGHTED IMAGING TRACTOGRAPHY-BASED PARCELLATION OF THE HUMAN PARIETAL CORTEX AND COMPARISON WITH HUMAN AND MACAQUE RESTING STATE FUNCTIONAL CONNECTIVITY 
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.
doi:10.1523/JNEUROSCI.5102-10.2011
PMCID: PMC3091022  PMID: 21411650
AIP; MIP; LIP; VIP; IPL; SPL
7.  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.
doi:10.3389/fnsys.2013.00037
PMCID: PMC3738868  PMID: 23950738
prefrontal cortex; memory; executive function; macaque; rodent; animal models; learning
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.  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.
doi:10.1093/schbul/sbn145
PMCID: PMC2894601  PMID: 18990709
schizophrenia; thalamus; connectivity; fcMRI; resting state; cingulate
10.  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.
doi:10.1371/journal.pbio.1001224
PMCID: PMC3246452  PMID: 22215982
11.  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.
doi:10.1093/cercor/bhp135
PMCID: PMC2742600  PMID: 19592571
cerebellum; cognition; fMRI; pontine nucleus; prefrontal cortex; thalamus
12.  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.
doi:10.1093/brain/aws242
PMCID: PMC3470716  PMID: 23065787
multiple sclerosis; post-mortem imaging; diffusion imaging; white matter tracts; neurodegeneration
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.
doi:10.3389/fnana.2010.00138
PMCID: PMC2981419  PMID: 21088699
salience processing; centromedian/parafascicular thalamus; mediodorsal thalamus; basal ganglia; cognition; emotion; high field fMRI; sexual processing
14.  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.
doi:10.3389/fnbeh.2012.00020
PMCID: PMC3356860  PMID: 22661934
orbitofrontal cortex; medial prefrontal cortex; anterior cingulate cortex; nucleus basalis of Meynert; locus coeruleus; prefrontal cortex; norepinephrine; acetylcholine
15.  Strategic lacunes and their relationship to cognitive impairment in cerebral small vessel disease 
NeuroImage : Clinical  2014;4:828-837.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
Highlights
•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
doi:10.1016/j.nicl.2014.05.009
PMCID: PMC4055894  PMID: 24936433
Small vessel disease; Lacunes; Cognitive Impairment
16.  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.
doi:10.1523/JNEUROSCI.6456-10.2011
PMCID: PMC3224993  PMID: 21976525
17.  Prefrontal Response and Frontostriatal Functional Connectivity to Monetary Reward in Abstinent Alcohol-Dependent Young Adults 
PLoS ONE  2014;9(5):e94640.
Although altered function in neural reward circuitry is widely proposed in models of addiction, more recent conceptual views have emphasized the role of disrupted response in prefrontal regions. Changes in regions such as the orbitofrontal cortex, medial prefrontal cortex, and dorsolateral prefrontal cortex are postulated to contribute to the compulsivity, impulsivity, and altered executive function that are central to addiction. In addition, few studies have examined function in these regions during young adulthood, when exposure is less chronic than in typical samples of alcohol-dependent adults. To address these issues, we examined neural response and functional connectivity during monetary reward in 24 adults with alcohol dependence and 24 psychiatrically healthy adults. Adults with alcohol dependence exhibited less response to the receipt of monetary reward in a set of prefrontal regions including the medial prefrontal cortex, lateral orbitofrontal cortex, and dorsolateral prefrontal cortex. Adults with alcohol dependence also exhibited greater negative correlation between function in each of these regions and that in the nucleus accumbens. Within the alcohol-dependent group, those with family history of alcohol dependence exhibited lower mPFC response, and those with more frequent drinking exhibited greater negative functional connectivity between the mPFC and the nucleus accumbens. These findings indicate that alcohol dependence is associated with less engagement of prefrontal cortical regions, suggesting weak or disrupted regulation of ventral striatal response. This pattern of prefrontal response and frontostriatal connectivity has consequences for the behavior patterns typical of addiction. Furthermore, brain-behavior findings indicate that the potential mechanisms of disruption in frontostriatal circuitry in alcohol dependence include family liability to alcohol use problems and more frequent use of alcohol. In all, these findings build on the extant literature on reward-circuit function in addiction and suggest mechanisms for disrupted function in alcohol dependence.
doi:10.1371/journal.pone.0094640
PMCID: PMC4012954  PMID: 24804780
18.  Default Network Connectivity in Medial Temporal Lobe Amnesia 
There is substantial overlap between the brain regions supporting episodic memory and the default network. However, in humans the impact of bilateral medial temporal lobe (MTL) damage on a large-scale neural network such as the default mode network is unknown. To examine this issue, resting functional magnetic resonance imaging (fMRI) was performed with amnesic patients and control participants. Seed-based functional connectivity analyses revealed robust default network connectivity in amnesia in cortical default network regions such as medial prefrontal cortex, posterior medial cortex, and lateral parietal cortex, as well as evidence of connectivity to residual MTL tissue. Relative to control participants, decreased posterior cingulate cortex connectivity to MTL and increased connectivity to cortical default network regions including lateral parietal and medial prefrontal cortex was observed in amnesia. In contrast, somatomotor network connectivity was intact in amnesia, indicating bilateral MTL lesions may selectively impact the default network. Changes in default network connectivity in amnesia were largely restricted to the MTL subsystem, providing preliminary support from MTL amnesic patients that the default network can be fractionated into functionally and structurally distinct components. To our knowledge, this is the first examination of the default network in amnesia.
doi:10.1523/JNEUROSCI.0700-12.2012
PMCID: PMC3573849  PMID: 23077048
fMRI; default mode network; amnesia; episodic memory; hippocampus; prefrontal cortex; posterior cingulate; parietal lobe; diaschisis
19.  Prefrontal cortex modulates desire and dread generated by nucleus accumbens glutamate disruption 
Biological psychiatry  2012;73(4):360-370.
Background
Corticolimbic circuits, including direct projections from prefrontal cortex to nucleus accumbens (NAc), permit “top-down” control of intense motivations generated by subcortical circuits. In rats, localized disruptions of glutamate signaling within medial shell of NAc generate desire or dread, anatomically organized along a rostrocaudal gradient analogous to a limbic “keyboard”. At rostral locations in shell these disruptions generate appetitive eating, but at caudal locations the disruptions generate progressively fearful behaviors (distress vocalizations, escape attempts and antipredator reactions). Here we asked whether medial prefrontal cortex can modulate intense motivations generated by subcortical NAc disruptions.
Methods
We used simultaneous microinjections in medial prefrontal cortex regions and in NAc shell to examine whether the desire or dread generated by NAc shell disruptions is modulated by activation/inhibition of three specific regions of prefrontal cortex: medial orbitofrontal cortex, infralimbic cortex (homologous to area 25 or subgenual anterior cingulate in the human), or prelimbic cortex (midventral anterior cingulate).
Results
We found that activation of medial orbitofrontal cortex biased intense bivalent motivation in an appetitive direction by amplifying generation of eating behavior by middle to caudal NAc disruptions, without altering fear. In contrast, activation of infralimbic prefrontal cortex powerfully and generally suppressed both appetitive eating and fearful behaviors generated by NAc shell disruptions.
Conclusions
These results suggest that corticolimbic projections from discrete prefrontal regions can either bias motivational valence or generally suppress subcortically-generated intense motivations of desire or fear.
doi:10.1016/j.biopsych.2012.08.009
PMCID: PMC3535675  PMID: 22981656
eating; fear; accumbens; prefrontal; medial orbitofrontal; infralimbic
20.  Probing the Frontostriatal Loops Involved in Executive and Limbic Processing via Interleaved TMS and Functional MRI at Two Prefrontal Locations: A Pilot Study 
PLoS ONE  2013;8(7):e67917.
Background
The prefrontal cortex (PFC) is an anatomically and functionally heterogeneous area which influences cognitive and limbic processing through connectivity to subcortical targets. As proposed by Alexander et al. (1986) the lateral and medial aspects of the PFC project to distinct areas of the striatum in parallel but functionally distinct circuits. The purpose of this preliminary study was to determine if we could differentially and consistently activate these lateral and medial cortical-subcortical circuits involved in executive and limbic processing though interleaved transcranial magnetic stimulation (TMS) in the MR environment.
Methods
Seventeen healthy individuals received interleaved TMS-BOLD imaging with the coil positioned over the dorsolateral (EEG: F3) and ventromedial PFC (EEG: FP1). BOLD signal change was calculated in the areas directly stimulated by the coil and in subcortical regions with afferent and efferent connectivity to the TMS target areas. Additionally, five individuals were tested on two occasions to determine test-retest reliability.
Results
Region of interest analysis revealed that TMS at both prefrontal sites led to significant BOLD signal increases in the cortex under the coil, in the striatum, and the thalamus, but not in the visual cortex (negative control region). There was a significantly larger BOLD signal change in the caudate following medial PFC TMS, relative to lateral TMS. The hippocampus in contrast was significantly more activated by lateral TMS. Post-hoc voxel-based analysis revealed that within the caudate the location of peak activity was in the ventral caudate following medial TMS and the dorsal caudate following lateral TMS. Test-retest reliability data revealed consistent BOLD responses to TMS within each individual but a large variation between individuals.
Conclusion
These data demonstrate that, through an optimized TMS/BOLD sequence over two unique prefrontal targets, it is possible to selectively interrogate the patency of these established cortical-subcortical networks in healthy individuals, and potentially patient populations.
doi:10.1371/journal.pone.0067917
PMCID: PMC3706588  PMID: 23874466
21.  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.
doi:10.3389/fnsys.2014.00083
PMCID: PMC4023070  PMID: 24847225
neural synchrony; memory; attention; reward; schizophrenia; anesthesia; reuniens nucleus; mediodorsal nucleus
22.  Morphologic and Functional Connectivity Alterations of Corticostriatal and Default Mode Network in Treatment-Naïve Patients with Obsessive-Compulsive Disorder 
PLoS ONE  2013;8(12):e83931.
Background
Previous studies have demonstrated that structural deficits and functional connectivity imbalances might underlie the pathophysiology of obsessive-compulsive disorder (OCD). The purpose of the present study was to investigate gray matter deficits and abnormal resting-state networks in patients with OCD and further investigate the association between the anatomic and functional alterations and clinical symptoms.
Methods
Participants were 33 treatment-naïve OCD patients and 33 matched healthy controls. Voxel-based morphometry was used to investigate the regions with gray matter abnormalities and resting-state functional connectivity analysis was further conducted between each gray matter abnormal region and the remaining voxels in the brain.
Results
Compared with healthy controls, patients with OCD showed significantly increased gray matter volume in the left caudate, left thalamus, and posterior cingulate cortex, as well as decreased gray matter volume in the bilateral medial orbitofrontal cortex, left anterior cingulate cortex, and left inferior frontal gyrus. By using the above morphologic deficits areas as seed regions, functional connectivity analysis found abnormal functional integration in the cortical-striatum-thalamic-cortical (CSTC) circuits and default mode network. Subsequent correlation analyses revealed that morphologic deficits in the left thalamus and increased functional connectivity within the CSTC circuits positively correlated with the total Y-BOCS score.
Conclusion
This study provides evidence that morphologic and functional alterations are seen in CSTC circuits and default mode network in treatment-naïve OCD patients. The association between symptom severity and the CSTC circuits suggests that anatomic and functional alterations in CSTC circuits are especially important in the pathophysiology of OCD.
doi:10.1371/journal.pone.0083931
PMCID: PMC3865285  PMID: 24358320
23.  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.
doi:10.1093/brain/awt172
PMCID: PMC3722352  PMID: 23824487
diffusion tensor imaging; inhibition; executive function; falls; balance; white matter; microstructure
24.  Brain mediators of cardiovascular responses to social threat, Part II: Prefrontal-subcortical pathways and relationship with anxiety 
NeuroImage  2009;47(3):836-851.
Social evaluative threat (SET) is a potent stressor in humans linked to autonomic and endocrine responses, and multiple health problems. Neuroimaging has recently begun to elucidate the brain correlates of SET, but as yet little is known about the mediating cortical-brainstem pathways in humans. This paper replicates and extends findings in a companion paper (Wager et al., submitted) using an independent cohort of participants and different image acquisition parameters. Here, we focused specifically on relationships between the medial prefrontal cortex (MPFC), midbrain periaqueductal gray (PAG), and heart rate (HR). We applied multi-level path analysis to localize brain mediators of SET effects on HR and self-reported anxiety. HR responses were mediated by opposing signals in two distinct sub-regions of the MPFC—increases in rostral dorsal anterior cingulate cortex (rdACC) and deactivation in ventromedial prefrontal cortex (vmPFC). In addition, HR responses were mediated by PAG. Additional path analyses provided support for two cortical subcortical pathways: one linking vmPFC, PAG, and HR, and another linking rdACC, thalamus, and HR. PAG responses were linked with HR changes both before and during SET, whereas cortical regions showed stronger connectivity with HR during threat. Self-reported anxiety showed a partially overlapping, but weaker, pattern of mediators, including the vmPFC, dorsomedial PFC (dmPFC), and lateral frontal cortex, as well as substantial individual differences that were largely unexplained. Taken together, these data suggest pathways for the translation of social threats into both physiological and experiential responses, and provide targets for future research on the generation and regulation of emotion.
doi:10.1016/j.neuroimage.2009.05.044
PMCID: PMC4169880  PMID: 19465135
25.  Thalamocortical dysconnectivity in schizophrenia 
The American journal of psychiatry  2012;169(10):10.1176/appi.ajp.2012.12010056.
Objective
The thalamus and cerebral cortex are connected via topographically organized, reciprocal connections. Previous studies revealed thalamic abnormalities in schizophrenia; however, it is not known if thalamocortical networks are differentially affected in the disorder. To explore this possibility, we examined functional connectivity in intrinsic low frequency blood-oxygen-level-dependent (BOLD) signal fluctuations between major divisions of the cortex and thalamus using resting-state functional magnetic resonance imaging.
Method
77 healthy subjects and 62 patients with schizophrenia underwent resting-state fMRI. To identify functional subdivisions of the thalamus, we parceled the cortex into six regions-of-interest; prefrontal, motor, somatosensory, temporal, posterior parietal, and occipital cortex. Mean BOLD time-series was extracted from each of the regions-of-interest and entered into a seed-based functional connectivity analysis.
Results
Consistent with prior reports, activity in distinct cortical areas correlated with specific, largely non-overlapping regions of the thalamus in both healthy subjects and schizophrenia patients. Direct comparison between groups revealed reduced prefrontal-thalamic connectivity and increased motor/somatosensory-thalamic connectivity in schizophrenia. The changes in connectivity were unrelated to local grey matter content within the thalamus and antipsychotic medication dosage. No differences were observed in temporal, posterior parietal, and occipital cortex connectivity with the thalamus.
Conclusions
This study establishes differential abnormalities of thalamocortical networks in schizophrenia. The etiology of schizophrenia may disrupt the development of prefrontal-thalamic connectivity and refinement of somatomotor connectivity with the thalamus that occurs during brain maturation.
doi:10.1176/appi.ajp.2012.12010056
PMCID: PMC3810300  PMID: 23032387
Schizophrenia; Resting-state fMRI; Functional Connectivity; Thalamus; Cortex

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