Using diffusion MRI data acquired with ultra-high gradient strength to improve tractography in routine-quality data.

The development of scanners with ultra-high gradient strength, spearheaded by the Human Connectome Project, has led to dramatic improvements in the spatial, angular, and diffusion resolution that is feasible for in vivo diffusion MRI acquisitions. The improved quality of the data can be exploited to achieve higher accuracy in the inference of both microstructural and macrostructural anatomy. However, such high-quality data can only be acquired on a handful of Connectom MRI scanners worldwide, while remaining prohibitive in clinical settings because of the constraints imposed by hardware and scanning time. In this study, we first update the classical protocols for tractography-based, manual annotation of major white-matter pathways, to adapt them to the much greater volume and variability of the streamlines that can be produced from today's state-of-the-art diffusion MRI data. We then use these protocols to annotate 42 major pathways manually in data from a Connectom scanner. Finally, we show that, when we use these manually annotated pathways as training data for global probabilistic tractography with anatomical neighborhood priors, we can perform highly accurate, automated reconstruction of the same pathways in much lower-quality, more widely available diffusion MRI data. The outcomes of this work include both a new, comprehensive atlas of WM pathways from Connectom data, and an updated version of our tractography toolbox, TRActs Constrained by UnderLying Anatomy (TRACULA), which is trained on data from this atlas. Both the atlas and TRACULA are distributed publicly as part of FreeSurfer. We present the first comprehensive comparison of TRACULA to the more conventional, multi-region-of-interest approach to automated tractography, and the first demonstration of training TRACULA on high-quality, Connectom data to benefit studies that use more modest acquisition protocols.

The place of dopamine in the cortico-basal ganglia circuit.

The midbrain dopamine (DA) neurons play a central role in developing appropriate goal-directed behaviors, including the motivation and cognition to develop appropriate actions to obtain a specific outcome. Indeed, subpopulations of DA neurons have been associated with these different functions: the mesolimbic, mesocortical, and nigrostriatal pathways. The mesolimbic and nigrostriatal pathways are an integral part of the basal ganglia through its reciprocal connections to the ventral and dorsal striatum respectively. This chapter reviews the connections of the midbrain DA cells and their role in integrating information across limbic, cognitive and motor functions. Emphasis is placed on the interface between these functional domains within the striatum through corticostriatal connections, through the striato-nigro-striatal connection, and through the lateral habenula projection to the midbrain.

Panic and fear induced by deep brain stimulation.

BACKGROUND: Mood, cognitive, and behavioural changes have been reported with deep brain stimulation (DBS) in the thalamus, globus pallidus interna, and anterior limb of the internal capsule/nucleus accumbens region. OBJECTIVE: To investigate panic and fear resulting from DBS. METHODS: Intraoperative DBS in the region of the right and then left anterior limb of the internal capsule and nucleus accumbens region was undertaken to treat a 52 year old man with treatment refractory obsessive-compulsive disorder (OCD). Mood, anxiety, OCD, alertness, heart rate, and subjective feelings were recorded during intraoperative test stimulation and at follow up programming sessions. RESULTS: DBS at the distal (0) contact (cathode 0-, anode 2+, pulse width 210 ms, rate 135 Hz, at 6 volts) elicited a panic attack (only seen at the (0) contact). The patient felt flushed, hot, fearful, and described himself as having a "panic attack." His heart rate increased from 53 to 111. The effect (present with either device) was witnessed immediately after turning the device on, and abruptly ceased in the off condition CONCLUSIONS: DBS of the anterior limb of the internal capsule and nucleus accumbens region caused severe "panic." This response may result from activation of limbic and autonomic networks.

Restricted daily consumption of a highly palatable food (chocolate Ensure(R)) alters striatal enkephalin gene expression.

Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake. Opioid peptides within the ventral striatum are thought to play a key role in the latter function, regulating the affective response to highly palatable, energy-dense foods such as those containing fat and sugar. It has been shown previously that stimulation of mu opiate receptors within the ventral striatum increases intake of palatable food. In the present study, we examined enkephalin peptide gene expression within the striatum in rats that had been given restricted daily access to an energy-dense, palatable liquid food, chocolate Ensure(R). Rats maintained on an ad libitum diet of rat chow and water were given 3-h access to Ensure(R) daily for two weeks. One day following the end of this period, preproenkephalin gene expression was measured with quantitative in situ hybridization. Compared with control animals, rats that had been exposed to Ensure(R) had significantly reduced enkephalin gene expression in several striatal regions including the ventral striatum (nucleus accumbens), a finding that was confirmed in a different group with Northern blot analysis. Rats fed this regimen of Ensure(R) did not differ in weight from controls. In contrast to chronic Ensure(R), acute ingestion of Ensure(R) did not appear to affect enkephalin peptide gene expression. These results suggest that repeated consumption of a highly rewarding, energy-dense food induces neuroadaptations in cognitive-motivational circuits.

Microglial response is poorly correlated with neurodegeneration following chronic, low-dose MPTP administration in monkeys.

Many investigators have reported extensive microglial activation in the mouse substantia nigra and striatum following acute, high-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Our previous work demonstrated tyrosine hydroxylase (TH)-positive fiber sprouting in the striatum in monkeys that had received a partial dopaminergic lesion using a low-dose, chronic MPTP administration paradigm. To characterize the microglial response, we utilized HLA-DR (LN3) to immunolabel the class II major histocompatibility complex (MHC II). In MPTP-treated monkeys, there was an intense microglial response in the substantia nigra, nigrostriatal tract, and in both segments of the globus pallidus. This response was morphologically heterogeneous, with commingled ramified, activated, and multicellular morphologies throughout the extent of these basal ganglia structures. Surprisingly, there was little evidence of microglial reactivity in the striatum despite evidence of neurodegeneration-by silver labeling and by loss of TH immunolabeling. Moreover, this pattern of microglial reactivity was the same in all animals that had received MPTP and seemed to be independent of the degree of neurotoxin-induced neurodegeneration. Thus, we conclude that microglial reactivity, per se, is not consistently associated with neurodegeneration, but depends on regional differences.

Opioid modulation of taste hedonics within the ventral striatum.

There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity.

Amygdaloid projections to ventromedial striatal subterritories in the primate.

The ventral striatum is the part of the striatum associated with reward and goal-directed behaviors, which are mediated in part by inputs from the amygdala. The ventral striatum is divided into 'shell' and 'core' subterritories which have different connectional, histochemical and pharmacological properties. Behavioral studies also indicate that subterritories of the ventral striatum are differentially involved in specific goal-directed behaviors. The amygdala is a heterogeneous structure which has multiple nuclei involved in processing emotional information. While the existence of an amygdalostriatal pathway has long been established, the relationship between amygdaloid afferents and specific subterritories of the ventral striatum is not known. In this study we operationally defined the ventromedial striatum as the region receiving cortical inputs primarily from the orbital and medial prefrontal cortex. We placed retrograde tracer injections into subregions of the ventromedial striatum of macaques monkeys to determine the relative contribution of specific amygdaloid inputs to each region. Calbindin-D28k immunostaining was used to further define the shell subterritory of the ventromedial striatum. Based on these definitions, the amygdala innervates the entire ventromedial striatum, and has few to no inputs to the central striatum. The basal and accessory basal nuclei are the major source of input to the ventromedial striatum, innervating both the shell and ventromedial striatum outside the shell. However, a restricted portion of the dorsomedial shell receives few basal nucleus inputs. Afferent inputs from the basal nucleus subdivisions are arranged such that the parvicellular subdivision projects mainly to the ventral shell and core, and the magnocellular subdivision targets the ventral shell and ventromedial putamen. In contrast, the intermediate subdivision of the basal nucleus projects broadly across the ventromedial striatum avoiding only the dorsomedial shell. The shell has a specific set of connections derived from the medial part of the central nucleus and periamygdaloid cortex. Within the shell, the dorsomedial region is distinguished by additional inputs from the medial nucleus. The ventromedial caudate nucleus forms a unique transition zone with the shell, based on inputs from the periamygdaloid cortex. Together, these results indicate that subterritories of the ventromedial striatum are differentially modulated by amygdaloid nuclei which play roles in processing olfactory, visual/gustatory, multimodal sensory, and 'drive'-related stimuli.

Bed nucleus of the stria terminalis and extended amygdala inputs to dopamine subpopulations in primates.

The 'extended amygdala', a forebrain continuum implicated in complex motivational responses, is comprised of the bed nucleus of the stria terminalis and its sublenticular extension into the centromedial amygdala. Dopamine is also involved in motivated behavior, and is increased in several brain regions by emotionally relevant stimuli. To examine how the extended amygdala influences the dopamine cells, we determined the organization of inputs from subdivisions of the bed nucleus of the stria terminalis and sublenticular extended amygdala to the dopamine subpopulations in monkeys. Inputs from the bed nucleus of the stria terminalis and corresponding regions of the sublenticular extended amygdala are differentially organized. The medial bed nucleus of the stria terminalis and its medial sublenticular extension have a mediolateral organization with the densest inputs to the medial substantia nigra, pars compacta, and relatively few inputs to the central and lateral substantia nigra. In contrast, the lateral bed nucleus of the stria terminalis (and its continuation into the sublenticular extended amygdala) projects across the mediolateral extent of the substantia nigra. The subnuclei of the lateral bed nucleus of the stria terminalis also have differential projections to the dopamine cells. While the central core of the lateral bed nucleus of the stria terminalis has restricted inputs, the surrounding dorsolateral, capsular and juxtacapsular subdivisions project strongly to the dorsal tier dopamine neurons. The posterior subdivision of the lateral bed nucleus of the stria terminalis and its continuation into the central sublenticular extended amygdala project more broadly to both the dorsal tier and densocellular region of the ventral tier. From these results we suggest that specific subdivisions of the bed nucleus of the stria terminalis have differential influences on the dopamine subpopulations, influencing dopamine responses in diverse brain regions.

Organization of thalamostriatal terminals from the ventral motor nuclei in the macaque.

This study examines the organization of thalamostriatal projections from ventral tier nuclei that relay basal ganglia output to the frontal cortex. Although previous thalamostriatal studies emphasize projections from the intralaminar nuclei, studies in primates show a substantial projection from the ventral anterior (VA) and ventral lateral (VL) nuclei. These nuclei make up the main efferent projection from the basal ganglia to frontal cortical areas, including primary motor, supplementary, premotor, and cingulate motor areas. Functionally related motor areas of the frontal cortex and VA/VL have convergent projections to specific regions of the dorsal striatum. The distribution of VA/VL terminals within the striatum is crucial to understanding their relationship to motor cortical afferents. We placed anterograde tracer injections into discrete VA/VL thalamic areas. VA/VL thalamostriatal projections terminate in broad, rostrocaudal regions of the dorsal striatum, corresponding to regions innervated by functionally related cortical motor areas. The pars oralis division of VL projects primarily to the dorsolateral, postcommissural putamen, whereas the parvicellular VA targets more medial and rostral putamen regions, and the magnocellular division of VA targets the dorsal head of the caudate nucleus. Whereas these results demonstrate a general functional topography, specific VA/VL projections overlap extensively, suggesting that functionally distinct VA/VL projections may also converge in dorsal striatal areas. Within striatal territories, VA/VL projections terminate in a patchy, nonhomogeneous manner, indicating another level of complexity. Moreover, terminal fields contain both terminal clusters and scattered, long, unbranched fibers with many varicosities. These fiber morphologies resemble those from the cortex and raise the possibility that VA/VL thalamostriatal projections neurons have divergent connectional features.

The central nucleus of the amygdala projection to dopamine subpopulations in primates.

The dopamine system plays a major role in responses to potentially rewarding stimuli. An important input to the dopamine neurons is derived from the central nucleus of the amygdala. The central nucleus is a complex structure consisting of several subdivisions with distinct histochemical, morphologic, and connectional features. The central nucleus subdivisions are therefore likely to have specific inputs to the dopamine neurons. The midbrain dopamine cells are divided into dorsal and ventral subpopulations. We determined the organization of inputs from the central nucleus subdivisions to the dopamine subpopulations in monkeys. The dorsal tier neurons receive relatively greater central nucleus input compared to the ventral tier. Within the ventral tier, the central nucleus projects to the densocellular region, but not the cell columns. Furthermore, the midbrain subpopulations receive a differential projection from specific central nucleus subterritories. The medial subdivision of the central nucleus has the greatest input to the dopamine system, and projects throughout the dorsal tier and densocellular regions. This indicates that the medial subdivision influences not only the ventral striatum but also more dorsal striatal areas, through its inputs to these dopamine subpopulations. In contrast, the capsular subdivision of the lateral central nucleus and the amygdalostriatal area project preferentially to the dorsal tier, which selectively modulates the ventral striatum and cortex. The central core of the lateral central nucleus is unique in its restricted projection to the lateral substantia nigra in the region of the nigrotectal pathway. Taken as a whole, the central nucleus-nigral pathway provides a route for affectively significant stimuli to modulate the DA system, influencing the initiation of behavioral responses.

Striatal responses to partial dopaminergic lesion: evidence for compensatory sprouting.

Dopaminergic lesions result in the acute loss of striatal dopamine content, the loss of tyrosine hydroxylase-immunoreactive fibers, upregulation of preproenkephalin mRNA expression, and compensatory changes in the synthesis and metabolism of dopamine. Despite the severe loss of fine tyrosine hydroxylase-immunoreactive fibers, larger fibers persist. We found that some tyrosine hydroxylase fiber types increase their branching and become thicker after partial lesion. To determine whether the remaining tyrosine hydroxylase fibers were degenerative or part of a compensatory response, we morphologically characterized striatal tyrosine hydroxylase fibers and compared them to silver-stained degenerative structures. Branched and large tyrosine hydroxylase fiber types were nondegenerative. Furthermore, normal preproenkephalin mRNA expression was maintained despite severe overall loss of tyrosine hydroxylase fibers in striatal regions with abundant branching, whereas preproenkephalin mRNA expression increased in severely depleted regions that lacked branched fibers, indicating that branching or sprouting was involved in the compensation for dopamine depletion and the maintenance of normal preproenkephalin expression. In support of compensatory sprouting by tyrosine hydroxylase fibers, mRNA for growth associated protein-43 was upregulated in dopaminergic midbrain cells. We conclude that an important compensatory response to partial dopaminergic depletion is the formation of new branches or sprouting.

Convergent inputs from thalamic motor nuclei and frontal cortical areas to the dorsal striatum in the primate.

Current models of basal ganglia circuitry primarily associate the ventral thalamic nuclei with relaying basal ganglia output to the frontal cortex. However, some studies have demonstrated projections from the ventral anterior (VA) and ventral lateral (VL) thalamic nuclei to the striatum, suggesting that these nuclei directly modulate the striatum. VA/VL nuclei have specific connections with primary, supplementary, premotor, and cingulate motor cortices indicating their involvement in motor function. These areas mediate different aspects of motor control such as movement execution, motor learning, and sensorimotor integration. Increasing evidence indicates that functionally related motor areas have convergent projections to the dorsal striatum, suggesting that integration of different aspects of motor control occur at the level of the striatum. This study examines the organization of VA/VL thalamic inputs to the dorsal "motor" striatum to determine how this afferent projection is organized with respect to corticostriatal afferents from motor, premotor, and cingulate motor areas. Motor cortical projections to specific dorsal striatal regions arose from multiple areas, including components from primary motor, premotor, supplementary, and cingulate motor areas. Diverse motor cortical projections to a given dorsal striatal region indicated convergence of functionally related corticostriatal motor pathways. Most dorsal striatal sites received dense thalamic inputs from the VL pars oralis nucleus. Additional thalamostriatal projections arose from VA, VL pars caudalis, and ventral posterior lateral pars oralis nuclei and Olszewski's Area X. Our results provide evidence for convergent striatal projections from interconnected ventral thalamic and cortical motor areas, suggesting that these afferents modulate the same striatal output circuits.

Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum.

Clinical manifestations in diseases affecting the dopamine system include deficits in emotional, cognitive, and motor function. Although the parallel organization of specific corticostriatal pathways is well documented, mechanisms by which dopamine might integrate information across different cortical/basal ganglia circuits are less well understood. We analyzed a collection of retrograde and anterograde tracing studies to understand how the striatonigrostriatal (SNS) subcircuit directs information flow between ventromedial (limbic), central (associative), and dorsolateral (motor) striatal regions. When viewed as a whole, the ventromedial striatum projects to a wide range of the dopamine cells and receives a relatively small dopamine input. In contrast, the dorsolateral striatum (DLS) receives input from a broad expanse of dopamine cells and has a confined input to the substantia nigra (SN). The central striatum (CS) receives input from and projects to a relatively wide range of the SN. The SNS projection from each striatal region contains three substantia nigra components: a dorsal group of nigrostriatal projecting cells, a central region containing both nigrostriatal projecting cells and its reciprocal striatonigral terminal fields, and a ventral region that receives a specific striatonigral projection but does not contain its reciprocal nigrostriatal projection. Examination of results from multiple tracing experiments simultaneously demonstrates an interface between different striatal regions via the midbrain dopamine cells that forms an ascending spiral between regions. The shell influences the core, the core influences the central striatum, and the central striatum influences the dorsolateral striatum. This anatomical arrangement creates a hierarchy of information flow and provides an anatomical basis for the limbic/cognitive/motor interface via the ventral midbrain.

The concept of the ventral striatum in nonhuman primates.

The concept of the ventral striatum was first put forth by Heimer and Wilson to describe the extension of basal ganglia elements into the olfactory tubercle. The ventral striatum includes the conventional nucleus accumbens, which has been closely associated with reward and motivation. This paper uses the afferent connections to the ventral striatum to define this region in monkeys. Furthermore the shell and core subterritories are discussed with respect to their histochemistry and specific connections.

The distribution of dynorphinergic terminals in striatal target regions in comparison to the distribution of substance P-containing and enkephalinergic terminals in monkeys and humans.

Single- and double-label immunohistochemical techniques using several different highly specific antisera against dynorphin peptides were used to examine the distribution of dynorphinergic terminals in globus pallidus and substantia nigra in rhesus monkeys and humans in comparison to substance P-containing and enkephalinergic terminals in these same regions. Similar results were observed in monkey and human tissue. Dynorphinergic fibers were very abundant in the medial half of the internal pallidal segment, but scarce in the external pallidal segment and the lateral half of the internal pallidal segment. In substantia nigra, dynorphinergic fibers were present in both the pars compacta and reticulata. Labeling of adjacent sections for enkephalin or substance P showed that the dynorphinergic terminals overlapped those for substance P in the medial half of the internal pallidal segment, but showed only slight overlap with enkephalinergic terminals in the external pallidal segment. The substance P-containing fibers were moderately abundant along the borders of the external pallidal segment, and enkephalinergic fibers were moderately abundant in parts of the internal pallidal segment. Dynorphinergic and substance P-containing terminals overlapped extensively in the nigra, and both extensively overlapped enkephalinergic fibers in medial nigra. Immunofluorescence double-labeling studies revealed that dynorphin co-localized extensively with substance P in individual fibers and terminals in the medial half of the internal pallidal segment and in substantia nigra. Thus, as has been found in non-primates, dynorphin within the striatum and its projection systems appears to be extensively localized to substance P-containing striatopallidal and striatonigral projection neurons. Nonetheless, our results also raise the possibility that a population of substance P-containing neurons that projects to the internal pallidal segment and does not contain dynorphin is present in primate striatum. Our results also suggest the possible existence of populations of striatopallidal and striatonigral projection neurons in which substance P and enkephalin or dynorphin and enkephalin, or all three, are co-localized. Thus, striatal projection neurons in primates may not consist of merely two types, one containing substance P and dynorphin and the other enkephalin.

Considering the role of the amygdala in psychotic illness: a clinicopathological correlation.

For many years, the structures of the medial temporal lobe have been implicated in the pathogenesis of schizophrenia. Recent hypotheses, based on data from MRI and functional imaging, propose that disruption of frontotemporal neural networks may be an anatomical substrate of schizophrenia. Many studies have focused on possible abnormalities of the hippocampus within this network. However, the role of the amygdala has been little studied because of the relative complexity of its structure and the paucity of patients with confined amygdaloid lesions. The authors present a case of chronic psychosis in which postmortem findings reveal lesions in and adjacent to the left amygdala. They use this case to review what is known of the functional anatomy of the amygdala and its possible role in some psychoses.

Dopamine neurons make glutamatergic synapses in vitro.

Interactions between dopamine and glutamate play prominent roles in memory, addiction, and schizophrenia. Several lines of evidence have suggested that the ventral midbrain dopamine neurons that give rise to the major CNS dopaminergic projections may also be glutamatergic. To examine this possibility, we double immunostained ventral midbrain sections from rat and monkey for the dopamine-synthetic enzyme tyrosine hydroxylase and for glutamate; we found that most dopamine neurons immunostained for glutamate, both in rat and monkey. We then used postnatal cell culture to examine individual dopamine neurons. Again, most dopamine neurons immunostained for glutamate; they were also immunoreactive for phosphate-activated glutaminase, the major source of neurotransmitter glutamate. Inhibition of glutaminase reduced glutamate staining. In single-cell microculture, dopamine neurons gave rise to varicosities immunoreactive for both tyrosine hydroxylase and glutamate and others immunoreactive mainly for glutamate, which were found near the cell body. At the ultrastructural level, dopamine neurons formed occasional dopaminergic varicosities with symmetric synaptic specializations, but they more commonly formed nondopaminergic varicosities with asymmetric synaptic specializations. Stimulation of individual dopamine neurons evoked a fast glutamatergic autaptic EPSC that showed presynaptic inhibition caused by concomitant dopamine release. Thus, dopamine neurons may exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, the present results suggest that glutamatergic cotransmission may be the rule for central monoaminergic neurons.

The accumbens: beyond the core-shell dichotomy.

This article highlights recent discoveries related to the accumbens and closely associated structures, with special reference to their importance in neuropsychiatry. The development of "striatal patches" in the accumbens is reviewed in a series of pictures. Neuronal ensembles are discussed as potentially important functional-anatomical units. Attention is also drawn to recent discoveries related to the neuronal circuits that the primate accumbens establishes with the mesencephalic dopamine system. On the basis of histological and neurochemical differences, the accumbens has been divided into core and shell compartments. In the context of this article, the shell, which is an especially diversified part of the accumbens, is the subject of special attention because of its close relation to the extended amygdala and distinctive response to antipsychotic and psychoactive drugs.

The primate substantia nigra and VTA: integrative circuitry and function.

A substantial amount of research has focused on the midbrain dopamine system and its role in mediating a wide range of behaviors. In diseases in which dopamine function is compromised, patients exhibit a constellation of symptoms suggesting that the dopamine system plays an important role in the integration of several functions. We have shown that there are subgroups of dopamine neurons that receive information from limbic and association areas and project widely throughout cortex and striatum, including motor areas. A dorsal tier of dopamine neurons receive input from the ventral (limbic) striatum and the amygdala and project widely throughout cortex. A more ventrally located group of dopamine cells receives input from both the limbic and association areas of striatum and project widely throughout the striatum including the sensorimotor regions. Through these projections the dopamine system can effect a wide range of behaviors. For the most part, structures of the basal ganglia are thought to be organized in parallel pathways. However, the behaviors affected by basal ganglia disorders can be in part explained by the integrative nature of the dopamine system and its links to motor, limbic, and association areas of the striatum and cortex.

The interface between dopamine neurons and the amygdala: implications for schizophrenia.

A substantial amount of research has focused on the midbrain dopamine system and its role in emotional and motivational behaviors. In diseases in which dopamine function is compromised, patients exhibit a constellation of symptoms, suggesting that the dopamine system plays an important role in the integration of several functions. Subgroups of dopamine neurons receive information from limbic and association areas and project widely throughout cortex and striatum, including motor areas. A dorsal tier of dopamine neurons receive input from the ventral (limbic-related) striatum and from the amygdala and project widely throughout cortex. A more ventrally located group of dopamine cells receives input from both the limbic and association areas of striatum and projects widely throughout the striatum, including the sensorimotor regions. Through these projections, the limbic system has an enormous influence on dopamine output and can therefore affect the emotional and motivational "coloring" of a wide range of behaviors.