Frontal-Subcortical Circuits and Human Behavior Jeffrey L. Cummings, MD \s=b\Objective.\p=m-\This synthetic review was performed to dromes. Recently, a series of parallel frontal-subcortical demonstrate the utility of frontal-subcortical circuits in the circuits have been described that link regions of the fron¬ explanation of a wide range of human behavioral disorders. tal lobes to subcortical structures.5"7 The circuits provide a Data Sources.\p=m-\Reportsof patients with degenerative unifying framework for understanding the similarity of disorders or focal lesions involving frontal lobe or linked behavioral changes associated with diverse anatomic le¬ subcortical structures were chosen from the English litera- sions. A wide range of behavioral alterations, including ture. Individual case reports and group investigations from disorders of executive function, personality changes, mood peer-reviewed journals were evaluated. disturbances, and obsessive-compulsive disorder (OCD), Study Selection.\p=m-\Studieswere included if they described can be linked to dysfunction of frontal-subcortical circuits. patient behavior in detail or reported pertinent neuropsy- In the synthesis presented herein, the anatomy of the cir¬ chological findings and had compelling evidence of a disor- cuits is reviewed; studies of patients with degenerative der affecting frontal-subcortical circuits. neurologic diseases or informative focal lesions involving Data Extraction.\p=m-\Informationwas used if the report circuit structures are then used to demonstrate the value of from which it was taken met study selection criteria. frontal-subcortical circuits as an interpretive model for Data Synthesis.\p=m-\Fiveparallel segregated circuits link the understanding human behavioral disorders. frontal lobe and subcortical structures. Clinical syndromes observed with frontal lobe injury are recapitulated with le- FRONTAL-SUBCORTICAL CIRCUITS sions of subcortical member structures of the circuits. Each Five circuits are a motor circuit circuit has a behavioral ex- currently recognized: prefrontal signature syndrome: in the motor an oculomo¬ ecutive function deficits occur with lesions of the dorsolat- originating supplementary area, tor circuit with in the frontal fields, and three eral circuit, disinhibition with lesions of the or- origins eye prefrontal circuits in cortex (dorsolateral bitofrontal and with to the anterior originating prefrontal pre¬ circuit, apathy injury frontal lateral orbital and anterior circuit. mania, and obsessive- cortex, cortex, cingulate cingulate Depression, The structure of all circuits is an or¬ disorder also be mediated cortex).5"7 prototypic compulsive may by frontal- in the frontal striatal subcortical circuits. Movement disorders involve- igin lobes, projection to structures identify (caudate, putamen, and ventral striatum), connections ment of the basal ganglia component of frontal-subcortical striatum and circuits. from to globus pallidus substantia nigra, from these two circuits mediate projections structures to specific thalamic Conclusions.\p=m-\Frontal-subcortical many and a final link back to the of human behavior. nuclei, frontal lobe (Fig 1). aspects Within of the circuits are a (Arch Neurol. 1993;50:873-880) each there two pathways: (1) direct pathway linking the striatum and the globus palli¬ dus interna/substantia nigra complex and (2) an indirect frontal a critical role in human lobes play behavior, pathway projecting from striatum to and some of the dramatic neurobehavioral globus pallidus The most syn¬ externa, then to subthalamic nucleus, and back to the glo¬ dromes are associated with frontal lobe dysfunction. bus interna/substantia Both direct and in¬ within pallidus nigra.7 Regional specialization the frontal lobe is recog¬ direct circuits to the thalamus. All circuits share with of project nized, injury prefrontal convexity, orbitofrontal, common structures—frontal lobe, striatum, and medial frontal cortex distinctive globus palli¬ producing syn¬ dus, substantia nigra, and thalamus—and are contiguous dromes.1 Similar behavioral changes, however, have been but remain in with in other brain anatomically segregated throughout. Projec¬ observed patients lesions regions,2"4 tions are focused onto a smaller number of the anatomic of "frontal lobe" progressively challenging specificity syn- neurons as they pass from cortical to subcortical structures, but circuit segregation is maintained. There are open and Accepted for publication January 7, 1993. closed aspects to the circuits; structures receive From projections the Departments of Neurology and Psychiatry and Biobehavior- from noncircuit cortical areas, thalamus, or UCLA amygdaloid al Sciences, School of Medicine, Los Angeles, Calif, and the Be- nuclei and to outside the circuits. Structures havioral Neuroscience Section, West Los Angeles Veterans Affairs Med- project regions ical Center. projecting to or receiving projections from specific circuits are and Reprint requests to Neurobehavior Unit, Bldg 256B (691 B/116AF), anatomically functionally related.8-9 The circuits West Los Angeles VAMC, 11301 Wilshire Blvd, Los Angeles, CA 90073 focus input on restricted cortical targets; several cortical (Dr Cummings). regions project to the striatum, where the output is tromedial substantia nigra, medial to the area receiving pro¬ jections from the dorsolateral caudate. The indirect pathway Frontal Cortex includes the globus pallidus externa and subthalamic nucleus receiving connections from the caudate and projecting to glo¬ bus pallidus interna/substantia nigra. Pallidum and nigra connect to medial portions of the ventral anterior and medial dorsal thalamic nuclei that project back to the orbitofrontal Striatum cortex. The anterior cingulate circuit begins in the cortex of the anterior cingulate gyrus (Brodmann's area 24) and projects to the ventral striatum (also known as the limbic striatum), including nucleus accumbens, olfactory tubercle, and the Globus Pallidus/ ventromedial portions of the caudate and putamen (Fig Substantia Nigra 2).6-7-9 Neurons from related limbic structures, including hippocampus, amygdala, and entorhinal and perirhinal cortices, also project to the ventral striatum. Ventral stria¬ tum has efferent connections with ventral and rostrolater- al substantia Thalamus globus pallidus and rostrodorsal nigra. The ventral pallidum is not clearly divided into internal and external segments giving rise to direct and indirect path¬ ways, but reciprocal connections of the ventral striatum Fig 1.—General organization of the frontal-subcortical circuits. with the subthalamic nucleus have been identified, and the existence of direct and indirect pathways is likely.7 Pallidal funneled through sequential circuit structures to limited and nigral efferents project to paramedian portions of the frontal lobe areas. medial dorsal nucleus of the thalamus as well as to the The motor circuit originates from neurons in the supple¬ ventral tegmental area, habenula, hypothalamus, and mentary motor area, premotor cortex, motor cortex, and amygdala. Medial dorsal thalamic neurons complete the somatosensory cortex.6-7 These areas project principally to circuit by projecting to the anterior cingulate cortex. the putamen in a somatotopic distribution. The putamen Several transmitters and modulators are involved in the in turn projects to ventrolateral globus pallidus interna, frontal-subcortical circuits; these include glutamine, globus pallidus externa, and caudolateral substantia nigra. -aminobutyric acid, glutamate, dopamine, acetylcholine, The globus pallidus connects to ventral lateral, ventral an¬ substance P, and enkephalin.5-7-9-10 The cortical-striatal pro¬ terior, and centromedianum nuclei of the thalamus, whose jections use excitatory glutamatergic neurons; -y-amino- major efferents are to the supplementary motor area, pre¬ butyric acid is the inhibitory transmitter of neurons orig¬ motor cortex, and motor cortex, completing the circuit. inating in the striatum and projecting to the globus Thalamic nuclei have reciprocal connections with the pallidus. The direct pathway also contains substance P, putamen and cerebral cortex. Throughout the circuit, the while the indirect pathway uses enkephalin. Output from discrete somatotopic organization of movement-related the globus pallidus and substantia nigra reticulata to the neurons is maintained. Information processing in the cir¬ subthalamic nucleus and thalamus is • -aminobutyric acid- cuits is not strictly sequential; neurophysiologic investiga¬ ergic. Glutamate is the transmitter of projections from the tions of movement demonstrate preparatory premove- subthalamic nucleus to globus pallidus interna and exter¬ ment activity, serial processing of movements initiated in na. Intrinsic excitatory cholinergic neurons are present the cortex, and concurrent parallel processing in the struc¬ within the striatum. Projections from substantia nigra tures of the circuit.5 compacta to striatal structures use dopamine. The ascend¬ The oculomotor circuit originates in the frontal eye fields ing dopamine system originating in the ventral tegmental (Brodmann's area 8) as well as prefrontal and posterior area projects to several circuit-related structures, including parietal cortex and connects sequentially the central body the septal area, amygdala, medial frontal cortex, and ante¬ of the caudate nucleus, dorsomedial globus pallidus and rior cingulate cortex.11 ventrolateral substantia ventral anterior and medial nigra, FRONTAL-SUBCORTICAL