Human Functional Connectivity Research Articles

Static magnetic field stimulation over motor cortex modulates resting functional connectivity in humans

Focal application of transcranial static magnetic field stimulation (tSMS) over the human motor cortex induces local changes in cortical excitability. Whether tSMS can also induce distant network effects, and how these local and distant effects may vary over time, is currently unknown. In this study, we applied 10 min tSMS over the left motor cortex of healthy subjects using a real/sham parallel design. To measure tSMS effects at the sensori-motor network level, we used resting-state fMRI. Real tSMS, but not sham, reduced functional connectivity within the stimulated sensori-motor network. This effect of tSMS showed time-dependency, returning to sham levels after the first 5 min of fMRI scanning. With 10 min real tSMS over the motor cortex we did not observe effects in other functional networks examined (default mode and visual system networks). In conclusion, 10 min of tSMS over a location within the sensori-motor network reduces functional connectivity within the same functional network.

There is a topographic organization in human cortico-pontine connectivity.

Of the three largest outputs of the cerebral cortex, two have been extensively studied and mapped. Topographic maps of cortico-thalamic and cortico-striatal functional connectivity in humans are well established. However, for the third largest cerebral output, to the pontine nuclei, which connect the cerebrum to the cerebellum, the existence of such an organized connectivity pattern in humans is unknown. Here, using high-resolution functional MRI and a large sample size, we found a topographically organized pattern of functional connectivity between the human cerebral cortex and pons. Our results indicate a rostral-caudal topography; rostral (frontal) cerebral cortex shows connectivity to the rostral pons, and the more caudal cortical areas (i.e. the sensorimotor cortices) show functional connectivity more caudally in the pons, with the occipital lobe connectivity being most caudal. While prefrontal, sensorimotor and occipital cortices have a connectivity to the medial pontine nuclei, posterior parietal cortex and temporal lobe correlate with lateral pontine nuclei. Topography is sufficiently detailed to identify distinct connectivity for leg, trunk, hand and face areas of the motor cortex. These findings reveal the existence of a topographic organization in human cortico-pontine connectivity and provide the topographic map for future studies of cortico-ponto-cerebellum pathway in a variety of disorders.

Activation of the dorsal, but not the ventral, hippocampus relieves neuropathic pain in rodents.

Accumulating evidence suggests hippocampal impairment under the chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here, we enhanced hippocampal activity by pharmacological, optogenetic, and chemogenetic techniques to determine hippocampal influence on neuropathic pain behaviors. We found that excitation of the dorsal (DH), but not the ventral (VH) hippocampus induces analgesia in 2 rodent models of neuropathic pain (SNI and SNL) and in rats and mice. Optogenetic and pharmacological manipulations of DH neurons demonstrated that DH-induced analgesia was mediated by N-Methyl-D-aspartate and μ-opioid receptors. In addition to analgesia, optogenetic stimulation of the DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where the DH was activated, a finding consistent with pain relief. Similar manipulations in the VH were ineffective. Using chemo-functional magnetic resonance imaging (fMRI), where awake resting-state fMRI was combined with viral vector-mediated chemogenetic activation (PSAM/PSEM89s) of DH neurons, we demonstrated changes of functional connectivity between the DH and thalamus and somatosensory regions that tracked the extent of relief from tactile allodynia. Moreover, we examined hippocampal functional connectivity in humans and observe differential reorganization of its anterior and posterior subdivisions between subacute and chronic back pain. Altogether, these results imply that downregulation of the DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of the DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, this study exhibits a novel causal role for the DH but not the VH in controlling neuropathic pain-related behaviors.

NREM sleep stages specifically alter dynamical integration of large-scale brain networks.

SummaryFunctional dissociations in the brain observed during non-rapid eye movement (NREM) sleep have been associated with reduced information integration and impaired consciousness that accompany increasing sleep depth. Here, we explored the dynamical properties of large-scale functional brain networks derived from transient brain activity using functional magnetic resonance imaging. Spatial brain maps generally display significant modifications in terms of their tendency to occur across wakefulness and NREM sleep. Unexpectedly, almost all networks predominated in activity during NREM stage 2 before an abrupt loss of activity is observed in NREM stage 3. Yet, functional connectivity and mutual dependencies between these networks progressively broke down with increasing sleep depth. Thus, the efficiency of information transfer during NREM stage 2 is low despite the high attempt to communicate. Critically, our approach provides relevant data for evaluating functional brain network integrity and our findings robustly support a significant advance in our neural models of human sleep and consciousness.

Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans.

Transcranial focused ultrasound (tFUS) is an emerging method for non-invasive neuromodulation akin to transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). tFUS offers several advantages over electromagnetic methods including high spatial resolution and the ability to reach deep brain targets. Here we describe two experiments assessing whether tFUS could modulate mood in healthy human volunteers by targeting the right inferior frontal gyrus (rIFG), an area implicated in mood and emotional regulation. In a randomized, placebo-controlled, double-blind study, participants received 30 s of 500 kHz tFUS or a placebo control. Visual Analog Mood Scales (VAMS) assessed mood four times within an hour (baseline and three times after tFUS). Participants who received tFUS reported an overall increase in Global Affect (GA), an aggregate score from the VAMS scale, indicating a positive shift in mood. Experiment 2 examined resting-state functional (FC) connectivity using functional magnetic resonance imaging (fMRI) following 2 min of 500 kHz tFUS at the rIFG. As in Experiment 1, tFUS enhanced self-reported mood states and also decreased FC in resting state networks related to emotion and mood regulation. These results suggest that tFUS can be used to modulate mood and emotional regulation networks in the prefrontal cortex.

On the role of the corpus callosum in interhemispheric functional connectivity in humans

Resting state functional connectivity is defined in terms of temporal correlations between physiologic signals, most commonly studied using functional magnetic resonance imaging. Major features of functional connectivity correspond to structural (axonal) connectivity. However, this relation is not one-to-one. Interhemispheric functional connectivity in relation to the corpus callosum presents a case in point. Specifically, several reports have documented nearly intact interhemispheric functional connectivity in individuals in whom the corpus callosum (the major commissure between the hemispheres) never develops. To investigate this question, we assessed functional connectivity before and after surgical section of the corpus callosum in 22 patients with medically refractory epilepsy. Section of the corpus callosum markedly reduced interhemispheric functional connectivity. This effect was more profound in multimodal associative areas in the frontal and parietal lobe than primary regions of sensorimotor and visual function. Moreover, no evidence of recovery was observed in a limited sample in which multiyear, longitudinal follow-up was obtained. Comparison of partial vs. complete callosotomy revealed several effects implying the existence of polysynaptic functional connectivity between remote brain regions. Thus, our results demonstrate that callosal as well as extracallosal anatomical connections play a role in the maintenance of interhemispheric functional connectivity.

Thermal Stimulation Alters Cervical Spinal Cord Functional Connectivity in Humans

The spinal cord has an active role in the modulation and transmission of the neural signals traveling between the body and the brain. Recent advancements in functional magnetic resonance imaging (fMRI) have made the in vivo examination of spinal cord function in humans now possible. This technology has been recently extended to the investigation of resting state functional networks in the spinal cord, leading to the identification of distinct patterns of spinal cord functional connectivity. In this study, we expand on the previous work and further investigate resting state cervical spinal cord functional connectivity in healthy participants (n = 15) using high resolution imaging coupled with both seed-based functional connectivity analyses and graph theory-based metrics. Within spinal cord segment functional connectivity was present between the left and right ventral horns (bilateral motor network), left and right dorsal horns (bilateral sensory network), and the ipsilateral ventral and dorsal horns (unilateral sensory-motor network). Functional connectivity between the spinal cord segments was less apparent with the connectivity centered at the region of interest and spanning <20 mm along the superior-inferior axis. In a subset of participants (n = 10), the cervical spinal cord functional network was demonstrated to be state-dependent as thermal stimulation of the right ventrolateral forearm resulted in significant disruption of the bilateral sensory network, increased network global efficiency, and decreased network modularity.

Transcranial Direct Current Stimulation Facilitates Associative Learning and Alters Functional Connectivity in the Primate Brain

There has been growing interest in transcranial direct current stimulation (tDCS), a non-invasive technique purported to modulate neural activity via weak, externally applied electric fields. Although some promising preliminary data have been reported for applications ranging from stroke rehabilitation to cognitive enhancement, little is known about how tDCS affects the human brain, and some studies have concluded that it may have no effect at all. Here, we describe a macaque model of tDCS that allows us to simultaneously examine the effects of tDCS on brain activity and behavior. We find that applying tDCS to right prefrontal cortex improves monkeys' performance on an associative learning task. While firing rates do not change within the targeted area, tDCS does induce large low-frequency oscillations in the underlying tissue. These oscillations alter functional connectivity, both locally and between distant brain areas, and these long-range changes correlate with tDCS's effects on behavior. Together, these results are consistent with the idea that tDCS leads to widespread changes in brain activity and suggest that it may be a valuable method for cheaply and non-invasively altering functional connectivity in humans.

The Power of Connecting Dots: Advanced Techniques to Evaluate Brain Functional Connectivity in Humans.

Brain functional connectivity estimation allows us to depict patterns of cerebral activity not understandable otherwise with the standard brain imaging techniques such as functional magnetic resonance imaging (fMRI) as well as electro or magnetoencephalography (hr-EEG, MEG). This special issue of the IEEE Transactions on Biomedical Engineering reports a range of methodological innovations toward the estimation of functional connectivity from brain activity data, with emphasis on neuroelectric and hemodynamic imaging modalities. Functional connectivity methodologies enable "connecting of the dots" derived from brain activity observations over multiple distributed sites, as depicted by such fMRI and hr-EEG/MEG devices.

Hypothesizing that, A Pro-Dopamine Regulator (KB220Z) Should Optimize, but Not Hyper-Activate the Activity of Trace Amine-Associated Receptor 1 (TAAR-1) and Induce Anti-Craving of Psychostimulants in the Long-Term.

Unlike other drugs of abuse such as alcohol, nicotine, opiates/opioids, the FDA has not approved any agent to treat psychostimulant dependence. Certainly, it is widely acceptable that dopaminergic signaling is a key factor in both the initiation and continued motivation to abuse this class of stimulant substances. It is also well accepted that psychostimulants such as cocaine affect not only the release of neuronal dopamine at the nucleus accumbens (NAc), but also has powerful inhibitory actions on the dopamine transporter system. Understandably, certain individuals are at high risk and very vulnerable to abuse this class of substances. Trace-amine-associated receptor 1 (TAAR1) is a G -protein coupled receptor activated by trace amines. The encoded protein responds little or not at all to dopamine, serotonin, epinephrine, or histamine, but responds well to beta-phenylethylamine, p-tyramine, octopamine, and tryptamine. This gene is thought to be intronless. TAAR1 agonists reduce the neurochemical effects of cocaine and amphetamines as well as attenuate addiction and abuse associated with these two psychostimulants. The mechanism involves blocking the firing rate of dopamine in the limbic system thereby decreasing a hyperdopaminergic trait/state, whereby the opposite is true for TAAR1 antagonists. Based on many studies, it is accepted that in Reward Deficiency Syndrome (RDS), there is weakened tonic and improved phasic dopamine discharge leading to a hypodopaminergic/glutamatergic trait. The dopamine pro-complex mixture KB220, following many clinical trials including neuroimaging studies, has been shown to enhance resting state functional connectivity in humans (abstinent heroin addicts), naïve rodent models, and regulates extensive theta action in the cingulate gyrus of abstinent psychostimulant abusers. In this article, we are hypothesizing that KB220 may induce its action on resting state functional connectivity, for example, by actually balancing (optimizing) the effects of TAAR1 on the glutamatergic system allowing for optimization of this system. This will lead to a normalized and homeostatic release of NAc dopamine. This proposed optimization, and not enhanced activation of TAAR1, should lead to well-being of the individual. Hyper-activation instead of optimizing the TAAR1 system unfortunately will lead to a prolonged hypodopaminergic state and as such, will cause enhanced craving for not only psychoactive substances, but also other drug-related and even non-drug related RDS behaviors. This hypothesis will require extensive research, which seems warranted based on the global epidemic of drug and behavioral addictions.

Multimodal imaging of dynamic functional connectivity.

The study of large-scale functional interactions in the human brain with functional magnetic resonance imaging (fMRI) extends almost to the first applications of this technology. Due to historical reasons and preconceptions about the limitations of this brain imaging method, most studies have focused on assessing connectivity over extended periods of time. It is now clear that fMRI can resolve the temporal dynamics of functional connectivity, like other faster imaging techniques such as electroencephalography and magnetoencephalography (albeit on a different temporal scale). However, the indirect nature of fMRI measurements can hinder the interpretability of the results. After briefly summarizing recent advances in the field, we discuss how the simultaneous combination of fMRI with electrophysiological activity measurements can contribute to a better understanding of dynamic functional connectivity in humans both during rest and task, wakefulness, and other brain states.

Multiphasic modification of intrinsic functional connectivity of the rat brain during increasing levels of propofol

The dose-dependent effects of anesthetics on brain functional connectivity are incompletely understood. Resting-state functional magnetic resonance imaging (rsfMRI) is widely used to assess the functional connectivity in humans and animals. Propofol is an anesthetic agent with desirable characteristics for functional neuroimaging in animals but its dose-dependent effects on rsfMRI functional connectivity have not been determined. Here we tested the hypothesis that brain functional connectivity undergoes specific changes in distinct neural networks at anesthetic depths associated with loss of consciousness. We acquired spontaneous blood oxygen level-dependent (BOLD) signals simultaneously with electroencephalographic (EEG) signals from rats under steady-state, intravenously administered propofol at increasing doses from light sedation to deep anesthesia (20, 40, 60, 80, and 100mg/kg/h IV). Power spectra and burst suppression ratio were calculated from the EEG to verify anesthetic depth. Functional connectivity was determined from the whole brain correlation of BOLD data in regions of interest followed by a segmentation of the correlation maps into anatomically defined regional connectivity. We found that propofol produced multiphasic, dose dependent changes in functional connectivity of various cortical and subcortical networks. Cluster analysis predicted segregation of connectivity into two cortical and two subcortical clusters. In one cortical cluster (somatosensory and parietal), the early reduction in connectivity was followed by transient reversal; in the other cluster (sensory, motor and cingulate/retrosplenial), this rebound was absent. The connectivity of the subcortical cluster (brainstem, hippocampal and caudate) was strongly reduced, whereas that of another (hypothalamus, medial thalamus and n. basalis) did not. Subcortical connectivity increased again in deep anesthesia associated with EEG burst suppression. Regional correlation analysis confirmed the breakdown of connectivity within and between specific cortical and subcortical networks with deepening propofol anesthesia. Cortical connectivity was suppressed before subcortical connectivity at a critical propofol dose associated with loss of consciousness.

Correction: Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans

Correction: Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans

Dynamics of large-scale neuronal networks of the human cortex functional connectivity

Spatio-temporally organized low-frequency fluctuations (<0.1 Hz) of blood-oxygen-level-dependent (BOLD) fMRI signal have been intensively investigated as a measure of functional connectivity (FC) between region pairs in the whole brain [1]. Resting state FC is commonly assumed to be shaped by the underlying anatomical connectivity (AC). Furthermore, it has been suggested that the strength, persistence, and spatial properties of FC are constrained by the large-scale anatomical structure of the cortex [2]. However, strong resting state FC is often observed between pairs of remote cortical regions, even without apparent direct anatomical connections [3]. Mechanisms generating resting state FC are largely unknown, and it has been contended that indirect connections, interregional distance, and collective effects governed by network properties of the cortex play significant role. In addition, some theoretical studies on large-scale brain networks demonstrated the importance of time delays in networks dynamics for the generation of resting state FC fluctuations [4,5]. To address these questions we investigate large-scale neural network model of human cortex FC. Our model is based on an empirically derived resting state FC network consisting of 64 region of interest (ROIs) (network nodes), which are chosen from all over the cortex. The ROIs are adapted from a study of functional segmentation of the brain cortex using high-model-order independent component analysis (ICA) [6]. There are 30 pairs of inter-hemispheric homologues, and 4 additional ROIs are chosen along the midline. The activity of each node is described by FitzHugh-Nagumo neurons. Network dynamics is modelled with different parameters for each node and different time delays to account for the finite signal propagation times between the nodes.

Ongoing Cortical Activity at Rest: Criticality, Multistability, and Ghost Attractors

The ongoing activity of the brain at rest, i.e., under no stimulation and in absence of any task, is astonishingly highly structured into spatiotemporal patterns. These spatiotemporal patterns, called resting state networks, display low-frequency characteristics (<0.1 Hz) observed typically in the BOLD-fMRI signal of human subjects. We aim here to understand the origins of resting state activity through modeling via a global spiking attractor network of the brain. This approach offers a realistic mechanistic model at the level of each single brain area based on spiking neurons and realistic AMPA, NMDA, and GABA synapses. Integrating the biologically realistic diffusion tensor imaging/diffusion spectrum imaging-based neuroanatomical connectivity into the brain model, the resultant emerging resting state functional connectivity of the brain network fits quantitatively best the experimentally observed functional connectivity in humans when the brain network operates at the edge of instability. Under these conditions, the slow fluctuating (<0.1 Hz) resting state networks emerge as structured noise fluctuations around a stable low firing activity equilibrium state in the presence of latent "ghost" multistable attractors. The multistable attractor landscape defines a functionally meaningful dynamic repertoire of the brain network that is inherently present in the neuroanatomical connectivity.

Dynamic BOLD functional connectivity in humans and its electrophysiological correlates

Neural oscillations subserve many human perceptual and cognitive operations. Accordingly, brain functional connectivity is not static in time, but fluctuates dynamically following the synchronization and desynchronization of neural populations. This dynamic functional connectivity has recently been demonstrated in spontaneous fluctuations of the Blood Oxygen Level-Dependent (BOLD) signal, measured with functional Magnetic Resonance Imaging (fMRI). We analyzed temporal fluctuations in BOLD connectivity and their electrophysiological correlates, by means of long (≈50 min) joint electroencephalographic (EEG) and fMRI recordings obtained from two populations: 15 awake subjects and 13 subjects undergoing vigilance transitions. We identified positive and negative correlations between EEG spectral power (extracted from electrodes covering different scalp regions) and fMRI BOLD connectivity in a network of 90 cortical and subcortical regions (with millimeter spatial resolution). In particular, increased alpha (8–12 Hz) and beta (15–30 Hz) power were related to decreased functional connectivity, whereas gamma (30–60 Hz) power correlated positively with BOLD connectivity between specific brain regions. These patterns were altered for subjects undergoing vigilance changes, with slower oscillations being correlated with functional connectivity increases. Dynamic BOLD functional connectivity was reflected in the fluctuations of graph theoretical indices of network structure, with changes in frontal and central alpha power correlating with average path length. Our results strongly suggest that fluctuations of BOLD functional connectivity have a neurophysiological origin. Positive correlations with gamma can be interpreted as facilitating increased BOLD connectivity needed to integrate brain regions for cognitive performance. Negative correlations with alpha suggest a temporary functional weakening of local and long-range connectivity, associated with an idling state.

Motivational salience modulates hippocampal repetition suppression and functional connectivity in humans

Repetition suppression (RS) is a rapid decrease of stimulus-related neuronal responses upon repeated presentation of a stimulus. Previous studies have demonstrated that negative emotional salience of stimuli enhances RS. It is, however, unclear how motivational salience of stimuli, such as reward-predicting value, influences RS for complex visual stimuli, and which brain regions might show differences in RS for reward-predicting and neutral stimuli. Here we investigated the influence of motivational salience on RS of complex scenes using event-related functional magnetic resonance imaging. Thirty young healthy volunteers performed a monetary incentive delay task with complex scenes (indoor vs. outdoor) serving as neutral or reward-predicting cue pictures. Each cue picture was presented three times. In line with previous findings, reward anticipation was associated with activations in the ventral striatum, midbrain, and orbitofrontal cortex (OFC). Stimulus repetition was associated with pronounced RS in ventral visual stream areas like the parahippocampal place area (PPA). An interaction of reward anticipation and RS was specifically observed in the anterior hippocampus, where a response decrease across repetitions was observed for the reward-predicting scenes only. Functional connectivity analysis further revealed specific activity-dependent connectivity increases of the hippocampus and the PPA and OFC. Our results suggest that hippocampal RS is sensitive to reward-predicting properties of stimuli and might therefore reflect a rapid, adaptive neural response mechanism for motivationally salient information.

Connections to and from Broca’s region successfully predict functional connectivity in humans: a new perspective on ‘language’ networks? (Commentary on Kelly et al.)

Brain Behavior and Cognition Program and Program In Neurosciences Boston University, 64 Cummington St., Boston 02215, MA,USAIn this issue of EJN, Kelly et al. succeeded in demonstrating that autoradiographic anatomical tracing studies in the macaque monkey predictedpatterns of connectivity into and out of Broca’s ‘language’ region in man. Resting state connectivity during functional magnetic resonanceimaging was measured in humans, as anatomical tracing cannot be done and diffusion tensor imaging cannot delineate the exact cortical originsand terminations of pathways.The Kelly et al. (2010) study was executed with great rigor. The human regions of interest were mapped on the basis of individuals’ uniquesulcal and gyral morphology, which were precisely defined and translated from the monkey into human cytoarchitectural nomenclature. Thisindividualized method was then followed by a seed-based analysis and a data-driven spectral clustering analysis. Great methodologicaltransparency was provided (e.g. by illustrating how the number of clusters designated to be found (e.g. 2 vs. 4) affected the structure of thefindings).The monkey target regions were BA 44 and 45 (traditionally considered Broca’s Area) and BA 6 (which subserves orofacial movements).However, recent research suggest that BA 47 (pars orbitalis) should now be included in ‘Broca’s Complex’ (Hagoort et al., 2004; Hagoort, 2005)as it is activated during both semantic processing (Bookheimer, 2002) and in the extraction of structural order or ‘syntax’ from oral (Friedericiet al., 2006) and signed (Petitto et al., 2000) speech.Many of the projections from Broca’s area (Kelly et al., 2010) and from Broca’s complex (Xiang et al., 2010) are not with regions traditionallyconsidered linguistic. Indeed, BA 47 has been implicated in the extraction of temporal coherence from music (Levitin & Menon, 2003). Takentogether these findings may help to liberate Broca’s complex from being primarily a language-specific node. Instead, consistent with the cognitiveneuroscience perspective, regions inside of and outside of Broca’s complex participate in variety of functional networks beyond just ‘language’.In terms of future research, it would be good to validate the relationship between anatomical tracing and resting state functional connectivity ofBroca’s Complex within at least one species of monkey. To my knowledge this has not been done even though resting state activity in man andmonkey have been compared (Rilling et al., 2007).After that, it would be interesting to compare the hypothesis–driven findings guided by the new anatomical tracings of ‘Broca’s complex’ in themonkey to a recent resting state functional connectivity analysis of ‘Broca’s complex’ in man. This would help to assess the extent to which data-driven predictions from the monkey affect data analysis in the human.Another suggestion may be to move away from just measuring connectivity of the default brain at rest and, instead, examine resting stateconnectivity during the immediate period before a trial has begun but while the individual is preparing for a specific cognitive task (such as wordrhyming). Frye et al. (2008, 2010) have performed such a connectivity analysis with magnetoencephalographic data analyzed by means ofGranger Causality. This method computes not only the strength of connectivity between regions but also the strength of the direction of activity inor out of a specific cortical area.

Basal Ganglia Functional Connectivity Based on a Meta-Analysis of 126 Positron Emission Tomography and Functional Magnetic Resonance Imaging Publications

The striatum receives projections from the entire cerebral cortex. Different, but not mutually exclusive, models of corticostriatal connectivity have been proposed, including connectivity based on proximity, parallel loops, and a model of a tripartite division of the striatum into motor, associative, and limbic areas. All these models were largely based on studies of anatomic connectivity in nonhuman mammals and lesion studies in animals and humans. Functional neuroimaging has the potential to discern patterns of functional connectivity in humans in vivo. We analyzed the functional connectivity between the cortex and the striatum in a meta-analysis of 126 published functional neuroimaging studies. We mapped the peak activations listed in each publication into stereotaxic space and used standard functional imaging statistical methods to determine which cortical areas were most likely to coactivate with different parts of the striatum. The patterns of functional connectivity between the cortex and the different striatal nuclei are broadly consistent with the predictions of the parallel loop model. The rostrocaudal and dorsoventral patterns of corticostriatal functional connectivity are consistent with the tripartite division of the striatum into motor, associative, and limbic zones.