Translational research Frontal-subcortical circuitry and behavior Raphael M Bonelli, MD, DMedSc; Jeffrey L. Cummings, MD Neurophysiologists used to view the basal gan- glia mainly as structures for regulating voluntary move- ment.The recent neuroanatomical, neuropsychological, and functional imaging literature, however, has made it increasingly clear that these subcortical structures are also intimately involved in regulating higher cerebral processes that control cognition, decision-making, the planning of complex behavioral strategies, and neu- ropsychiatric symptoms.1,2 The frontal-subcortical cir- cuitry provides a unifying framework for understanding The neuropsychiatric manifestations of neurodegenera- the behavioral changes that accompany neurodegener- tive diseases are closely linked to neurocircuitry defects. ative disorders.3 In the past three decades, a number of Frontal-subcortical circuits, in particular, are effector mech- significant advances have been made in our under- anisms that allow the organism to act on its environment. standing, not only of the neuroanatomy, but also of the In this paper, we present the three main frontal-subcorti- neurophysiology and chemoarchitecture, of the frontal- cal circuits: the dorsolateral prefrontal circuit allows the subcortical circuits.4 Parallelling this new understanding, organization of information to facilitate a response; the an increasingly broad spectrum of neuropsychiatric phe- anterior cingulate circuit is required for motivated behav- nomenology is recognized as being interpretable in the ior; and the orbitofrontal circuit allows the integration of context of frontal-subcortical circuit dysfunction. A limbic and emotional information into behavioral series of parallel segregated frontal-subcortical circuits responses. Impaired executive functions, apathy, and are now known to link specific regions of the frontal cor- impulsivity are hallmarks of frontal-subcortical circuit dys- tex to the striatum, the globus pallidus (GP) and sub- function. A variety of other neuropsychiatric disorders, stantia nigra (SN), and the thalamus, constituting an such as Tourette’s syndrome, Huntington's disease, obses- important effector mechanism that allows the organism sive-compulsive disorder, attention-deficit/hyperactivity to interact adaptively with its environment.5 Impaired disorder, schizophrenia, and mood disorders may result executive functions, apathy, and impulsivity are hall- from disturbances that have a direct or indirect impact on marks of frontal-subcortical circuit dysfunction. In a the integrity or functioning of these loops. recent event-related functional MRI (fMRI) study, for © 2007, LLS SAS Dialogues Clin Neurosci. 2007;9:141-151. instance, the authors concluded that the caudate nucleus and the putamen are particularly important, respectively, Keywords: frontal-subcortical circuit; dorsolateral prefrontal cortex; anterior cin- gulate; orbitofrontal cortex; dysexecutive syndrome in the planning and the execution of a self-generated Author affiliations: Department of Psychiatry, Graz Medical University, Graz, Address for correspondence: Raphael M. Bonelli, Department of Psychiatry, Austria (Raphael M. Bonelli); Department of Neurology, David Geffen School Graz Medical University, Auenbruggerplatz 31, 8036 Graz, Austria of Medicine at UCLA, Los Angeles, Calif, USA (Jeffrey L. Cummings) (e-mail: [email protected]) Copyright © 2007 LLS SAS. All rights reserved 141 www.dialogues-cns.org Translational research Selected abbreviations and acronyms motor response, make this region and its subcortical con- 5-HT serotonin nections critically important to an understanding of both GP globus pallidus normal and disordered psychomotor functions. GPe globus pallidus externa The architectonic organization of the prefrontal cortex is GPi ventrolateral globus pallidus interna reflected in the pattern of prefrontostriatal projections.15,16 SN substantia nigra The dorsal architectonic trend, which originates in the SNr substantia nigra, pars reticulata rostral cingulate gyrus and culminates in the dorsal por- STN subthalamic nucleus tion of the frontal eye field, maps onto the dorsal caudate nucleus. In contrast, the ventral architectonic trend, which novel action.6 A variety of neuropsychiatric disorders originates in the ventral orbital region and culminates in may result from disturbances that have a direct or indi- the ventral portion of the frontal eye field, maps onto the rect impact on the integrity or functioning of frontal- ventromedial portion of the caudate and the adjacent subcortical circuits. portion of the nucleus accumbens. Cortical areas that are closely connected functionally appear to send converg- Background ing projections into adjacent regions of the striatum.17-20 Information derived from the cortex is recombined at the Alexander et al5,7-9 proposed that the basal ganglia and striatal level to form small, functionally specialized thalamus participate in five parallel segregated circuits domains. Evidence from 2-deoxyclucose metabolic stud- with selected cortical areas in the frontal lobe. Two of ies of neuronal activation within the striatum is consis- these circuits are related to motor function, and influence tent with the concept that discrete regions of the striatum skeletomotor and oculomotor areas of cortex. The support specific functional properties.21 remaining three loops are connected with nonmotor Evidence for the role of a frontostriatal system in cogni- areas in the frontal lobe, including the dorsolateral pre- tion and behavior was first suggested by a series of exper- frontal cortex, the lateral orbitofrontal cortex, and the imental observations.22 Specifically, lesions of electrical anterior cingulate/medial orbitofrontal cortices. These stimulation of the dorsolateral prefrontal cortex or of the frontal regions are known to be involved in aspects of anterodorsal head of the caudate nucleus, to which this planning, working memory, rule-based learning, atten- region projects, were found to produce deficits in the tion, and emotional regulation such as the decision same behavioral domain—namely, delayed-response and threshold in reaction time tasks or in the control of auto- delayed-alternation tasks.23 Similarly, lesions or electrical matic visuospatial attention.10-12 Basal ganglia functional stimulation, either of the orbitofrontal cortex or of the connectivity, based on a recent meta-analysis of 126 ventrolateral head of the caudate, resulted in compara- positron emission tomography (PET) and fMRI imaging ble deficits in object alternation or response inhibition publications, showed that patterns of functional connec- paradigms.14 Accordingly, disruption to cognitive tivity between the cortex and the striatal nuclei are processes following striatal injury was interpreted as the broadly consistent with the predictions of this classical “downstream” interruption of anatomically congruent parallel loop model.13 outflow from the frontal cortex.24,25 The frontal lobe may be viewed as comprising two dis- tinct anatomical and functional systems, reflecting its dual Basic circuit structure developmental origin.14 The sequential processing of sen- sory, spatially related, and motivational information is The five major frontal-subcortical circuits suggested by mediated by a dorsal system, which involves dorsolateral Alexander et al5,7-9 are now generally accepted. These and medial portions of the frontal lobes, interconnected include a motor circuit that originates in the supplemen- with the posterior parietal lobe and cingulate gyrus. tary motor area, and an oculomotor circuit originating in Emotional tone is mediated by a second, ventral system, the frontal eye field. The motor circuit originates from which involves the orbital surface of the frontal lobes. neurons in the supplementary motor area, premotor cor- The function of the frontal lobes as an integrator of infor- tex, motor cortex, and somatosensory cortex, recently mation, related both to the external sensory and internal confirmed by fMRI findings.26 These areas project prin- limbic worlds and its role in motivation and appropriate cipally to the putamen in a somatotopic distribution.The 142 Frontal-subcortical circuitry and behavior - Bonelli and Cummings Dialogues in Clinical Neuroscience - Vol 9 . No. 2 . 2007 putamen in turn projects to ventrolateral globus pallidus orbitofrontal circuit allows integration of visceral-amyg- interna (GPi), globus pallidus externa (GPe), and cau- dalar functions with the internal state of the organism, dolateral SN. The globus pallidus (GP) connects to the while the lateral portion is involved with integration of ventrolateral, ventral anterior, and centromedianum limbic and emotional information into contextually nuclei of the thalamus, whose major efferents are to the appropriate behavioral responses. Middleton and Strick29 supplementary motor area, premotor cortex, and motor designate the lateral and medial portions of the cortex, completing the circuit. Thalamic nuclei have rec- orbitofrontal circuit as two separate circuit categories and iprocal connections with the putamen and cerebral cor- an inferotemporal/posterior parietal circuit as an addi- tex, in addition to the connections contained within the tional frontal-subcortical circuit in their revised scheme. circuit. Throughout the circuit, the discrete somatotopic Common to all circuits is an origin in the frontal lobes organization of movement-related neurons is main- with