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 CIRCUIT SYNDROMES dorsal thalamic nuclei, and frontal eye fields.6-7 Frontal Lobe The dorsolateral prefrontal circuit originates in the con¬ Syndromes vexity of the frontal lobe (Brodmann's areas 9 and 10) and Three distinct frontal lobe neurobehavioral syndromes projects primarily to the dorsolateral head of the caudate are recognized, and each corresponds to a region of origin nucleus (Fig 2).6-7 This caudate region connects to the dor¬ of one of the three prefrontal-subcortical circuits. The dor¬ somedial globus pallidus interna and rostral substantia solateral prefrontal syndrome is characterized primarily by nigra through the direct pathway and through the globus "executive function" deficits and motor programming ab¬ pallidus externa to subthalamic nucleus, then to globus normalities. Patients with restricted cortical lesions in this pallidus interna and substantia nigra through the indirect area are unable to generate hypotheses and flexibly main¬ pathway. Pallidal and nigral neurons of the circuit project tain or shift sets as required by changing task demands on to the ventral anterior and medial dorsal thalamic nuclei such tests as the Wisconsin Card Sort Test.12 They also ex¬ that in turn connect with the dorsolateral prefrontal region. hibit reduced verbal and design fluency, poor organiza¬ The lateral orbitofrontal circuit begins in the inferolateral pre¬ tional strategies for learning tasks, and poor construction¬ frontal cortex (Brodmann's area 10) and projects to ventrome- al strategies for copying complex designs.1314 Motor dial caudate nucleus (Fig 2).6-7 This caudate region projects via programming disturbances are evident in alternating and the direct pathway to the dorsomedial pallidum and the ros- reciprocal motor tasks and sequential motor tests.1 The orbitofrontal syndrome features marked changes in the behavioral consequences of focal striatal lesions, but In a of 79 survivors of of ante¬ Méndez and coworkers2 observed contrasting behavioral personality. study rupture caudate lesions. Pa¬ rior communicating artery aneurysms with orbitofrontal consequences of dorsal and ventral injury, Logue and colleagues15 found personality alter¬ tients with dorsal lesions were more confused and disin¬ ations in 75 of were terested, whereas patients with ventral lesions were disin- percent. Thirty-three percent patients and These more 32% worried less, 27% were more irrita¬ hibited, euphoric, inappropriate. two outspoken, dorsal ble, 19% had an elevated mood, and 8% were more tactless. syndromes recapitulate the corresponding and All on Forty-six percent had alterations in interest, initiative, or ventral frontal lobe syndromes. patients had deficits conscientiousness. Similar syndromes have been described tests of memory, attention, and executive function, includ¬ in with orbitofrontal tumors16 and inferior frontal ing the Wisconsin Card Sort Test. patients disease the best-known disorder affect¬ lobe infarction.17 Irritability, lability, and a fatuous eupho¬ Huntington's is the caudate nuclei. The ria may be present. Lhermitte and colleagues18 described ing primarily degeneration begins two additional behavioral syndromes in patients with in the medial caudate region and progresses to affect more large bilateral anterior orbitofrontal lobe lesions—imita¬ lateral areas.26 Behavioral and neuropsychological abnor¬ tion and utilization. These behaviors reflect an enslave¬ malities are marked in Huntington's disease. Among 186 ment to environmental cues with automatic imitation of patients with Huntington's disease described by Folstein,27 37% a 30% had the gestures and actions of others or enforced utilization of had mood disorder, irritability and explo¬ objects in the environment. Unlike individuals with dor¬ sive disorder, and 6% were diagnosed as having antisocial solateral prefrontal lesions, patients with orbitofrontal personality disorder. Apathy was also common. Obses¬ dysfunction have been found to perform card-sorting tasks sive-compulsive disorder has also been linked to Hunting- ton's disease,28 and all patients with Huntington's disease normally.19 Patients with The anterior cingulate syndrome has been studied less ex¬ evidence cognitive abnormalities. Hunting- tensively. The most dramatic examples of anterior cingulate ton's disease manifest deficits on the Wisconsin Card Sort are cases of akinetic mutism associated with bilateral Test,29 decreased verbal fluency, and poor recall of recent¬ injury learned information abnormalities noted lesions. The are profoundly apathetic. They typical¬ ly similar to the patients in with Be¬ have their eyes open, do not speak spontaneously, and an¬ patients dorsolateral prefrontal dysfunction.30 ly abnormalities in correlate swer in if at all. move little, are havioral Huntington's disease questions monosyllables They of metabolic the and incontinent, and eat and drink only if fed. They display no with the severity changes in caudate are when cortical is normal.31 in emotion even when in pain and are indifferent to their dire present metabolism Thus, circumstances.20"22 Unilateral lesions produce transient aki¬ Huntington's disease, cognitive and behavioral alterations netic mutism.23 The major neuropsychological deficit dem¬ corresponding to dysfunction of all three behaviorally rel¬ onstrated in with medial frontal lobe lesions is fail¬ evant frontal-caudate circuit projections are evident. The patients of alterations in ure of response inhibition on go-no go tests.24-25 early appearance personality Hunting- ton's disease corresponds to the involvement of the medi¬ al caudate regions receiving projections from the orbito¬ Striatal Syndromes frontal and anterior cingulate circuits mediating limbic The dorsolateral prefrontal cortex projects to the dorso¬ system function.26 The cognitive deficits of Huntington's lateral caudate nucleus, the orbitofrontal cortex projects to disease reflect involvement of the head of the caudate nu¬ the ventromedial region of the caudate, and the anterior cleus receiving lateral prefrontal-striatal projections. cingulate gyrus projects to the ventral striatum and nucle¬ Observations of patients with neuroacanthocytosis, a us accumbens. There have been relatively few reports of rare degenerative disorder affecting primarily the caudate

Dorsolateral Lateral Orbital Anterior Cingulate Prefrontal Cortex Cortex Cortex

Caudate Caudate Nucleus (Dorsolateral) (Ventromedial) Accumbens

Globus Pallidus Globus Pallidus Globus Pallidus (Lateral Dorsomedial) (Medial Dorsomedial) (Rostrolateral)

Thalamus Thalamus Thalamus (VA and MD) (VA and MD) (MD)

Flg 2.—Organization of the three frontal-subcortical circuits in which lesions produce alterations of cognition and emotion. VA indicates ventral an¬ terior; MD, medial dorsal. The indirect circuits and connections of the substantia nigra and the subthalamic nucleus are not shown. Table 1.—Neuropsychiatrie Alterations Associated cular disease. Strub4 described a patient with bilateral glo¬ With Abnormalities of Specific Frontal-Subcortical bus pallidus hemorrhages and noted the marked similar¬ Circuit Structures* ity of the behavior of the patient to that of patients with frontal lobe The manifested a Structure Mood OCD dysfunction. patient marked Personality change in personality with prominent apathy, withdraw¬ Prefrontal dorsolateral Depression UD No al, and loss of interest. Neuropsychological testing re¬ cortex vealed normal intelligence, poor memory, and severely Orbitofrontal cortex Mania Disinhibition, Yes impaired performance on the Wisconsin Card Sort Test. irritability Laplane et al37 described three patients with bilateral Anterior cingulate No Apathy Yes globus pallidus lesions after anoxic insult or carbon mon¬ cortex oxide intoxication. After recovery from the acute phase of Caudate Depression (L, B), Disinhibition, Yes the disorder, all patients exhibited "psychic akinesia" with mania (R, B) irritability reduced spontaneous activity, impaired initiative, and di¬ Nucleus accumbens No Apathy No minished ability to conceive new thoughts. Neuropsycho¬ logical assessment revealed normal language, reasoning, Globus pallidus UD Apathy, Yes and mental control with irritability intact impaired memory. Manganese toxicity has a disproportionate effect on the Thalamus Mania (R) Apathy, No and behavioral irritability globus pallidus, abnormalities commonly *OCD accompany manganese-induced parkinsonism. Irritability indicates obsessive-compulsive disorder; UD, undetermined; was in all 13 of the studied Mena et al38: and B, bilateral. present patients by seven had compulsions and six were depressed. Of the 15 patients described by Schuler et al,39 seven were apathetic, nuclei, also support a relationship between caudate dys¬ six were irritable, and three were withdrawn. (The total function and behavioral and intellectual alterations resem¬ does not add up because some patients had more than one bling those observed in patients with frontal lobe lesions. symptom.) The patients have intellectual deficits and personality Three discrete syndromes equivalent to the frontal lobe alterations with irritability and disinhibited behavior.32 symptom complexes cannot be identified in patients de¬ Behavioral changes resulting from lesions of the ventro¬ scribed with globus pallidus lesions. Nevertheless, mix¬ medial striatum-nucleus accumbens area have not been tures of apathy and irritability similar to the symptoms of fully documented, and potential similarities between be¬ frontal lobe dysfunction and neuropsychological deficits haviors associated with anterior cingulate lesions and in¬ affecting memory and executive function resembling those jury to the nucleus accumbens require further investiga¬ of patients with frontal lobe lesions are present in patients tion. A few pertinent observations have been reported. with lesions confined to this structure. Given the progres¬ Phillips et al33 noted apathy, withdrawal, and loss of ini¬ sive spatial restriction of the parallel circuits at this tiative similar to the symptoms of akinetic mutism in a pa¬ anatomic level, focal lesions may involve several circuits tient with rupture of a posteriorly located anterior com¬ simultaneously, resulting in mixed behavioral syndromes. municating artery aneurysm. Neuropsychological Thalamic assessment revealed that the patient performed normally Syndromes on tests of intelligence, constructions, verbal fluency, and Frontal-subcortical circuit projections continue from the set shifting (including the Wisconsin Card Sort Test). His globus pallidus and substantia nigra to the nuclei of the memory was defective, and confabulation was evident. At thalamus. The dorsolateral prefrontal and lateral orbito- autopsy, the patient had bilateral lesions confined to the region of the rostroventral globus pallidus, nucleus ac¬ cumbens, septal gray matter, and nucleus of the diagonal band of Broca. Akinetic mutism has also been described Dorsolateral with craniopharyngiomas, obstructive hydrocephalus, Prefrontal Cortex and tumors in the region of the third ventricle3436— conditions involving ventral striatum, ventral globus pal¬ lidus, and medial thalamus. Together these observations support the hypothesis that the behavioral syndromes observed with frontal lobe Caudate lesions are recapitulated with striatal dysfunction and that there are recognizable circuit-specific behaviors. Dorsal caudate lesions produce executive function deficits (ie, on the Wisconsin Card Sort impaired performance Test), Globus Pallidus/ ventral caudate lesions are associated with disinhibition Substantia Nigra and inappropriate behavior, and nucleus accumbens le¬ sions produce apathy and lack of initiative. Globus Pallidus Syndromes Thalamus The striatal structures of the frontal-subcortical circuits Hypothalamus Hippocampus project to subregions of the globus pallidus and substantia nigra. Focal insults of the globus pallidus are rare but have been reported after carbon monoxide poisoning and man¬ Fig 3.—Intersection of the dorsolateral prefrontal-subcortical circuit and ganese intoxication and occasionally in the course of vas- the hippocampal-medial limbic circuit in the thalamus. Table 2.—Behavioral Abnormalities Associated With Basal Ganglia Disorders* Personality Subcortical Disease Change Mania Depression OCD Dementia Parkinson's disease Yes No Yes No Yes Progressive supranuclear palsy UD No Yes UD Yes Huntington's disease Yes Yes Yes Yes Yes Wilson's disease Yes Yes Yes No Yes Neuroacanthocytosis Yes Yes Yes Yes Yes Fahr's disease UD Yes Yes No Yes Gilles de la Tourette's syndrome No No Yes Yes No *OCD indicates obsessive-compulsive disorder; UD, undetermined. frontal circuits project primarily to regions of the ventral dus, discrete syndromes corresponding to the the three anterior and medial dorsal nuclei; the anterior cingulate frontal syndromes have not been established at the tha¬ circuit incorporates primarily subregions of the medial lamic level, and disorders with mixed features are the dorsal nuclei.6 Lesions of the medial dorsal nuclei produce rule. neuropsychological deficits and behavioral disturbances. Behaviors Gentilini et al40 studied eight patients with bilateral para- Circuit-Specific median thalamic infarctions and noted that several were Three frontal lobe symptom complexes are recognizable: dysphoric and irritable, one alternated between fretfulness a dorsolateral prefrontal syndrome with neuropsycholog¬ and silly cheerfulness, and one was disinhibited and inap¬ ical deficits, including decreased verbal and design fluen¬ propriate. Six of the seven testable patients had marked cy, abnormal motor programming, impaired set shifting, memory deficits. Eslinger et al41 also described a patient reduced learning and memory retrieval, and poor problem with bilateral medial thalamic infarction. They observed solving; an orbitofrontal syndrome with prominent disin- disinhibition, apathetic irritability, utilization behavior, hibition and irritability; and a medial frontal-anterior cin¬ and distractibility. Neurobehavioral examination re¬ gulate syndrome with apathy and diminished initiative. vealed decreased mental control, normal language, poor Similar behavioral syndromes have been observed with memory, and reduced verbal fluency. The similarity of disorders of subcortical structures of the three frontal- the patient's clinical syndrome to that observed with subcortical circuits. These observations support the exist¬ frontal lobe dysfunction was noted. Stuss and col¬ ence of circuit-specific behavioral syndromes with exe¬ leagues42 studied three patients with paramedian tha¬ cutive function deficits marking dysfunction of the dorso¬ lamic infarction: one with bilateral symmetric lesions, lateral prefrontal circuit, irritability and disinhibition one with bilateral asymmetric lesions (more severe on implicating involvement of the orbitofrontal circuit, and the right), and one with unilateral left-sided infarction. apathy indicating disturbances of the anterior cingulate Memory impairment was present in all three; it was circuit. most severe in the patient with bilateral symmetric le¬ sions, involved primarily nonverbal information in the COMMENT patient with predominantly right-sided damage, and af¬ Frontal-subcortical circuits have implications for under¬ fected verbal memory more severely in the patient with standing several neuropsychiatrie disorders, the syndrome left-sided injury. The patient with bilateral lesions and of subcortical dementia, and the occurrence of behavioral the individual with a large left-sided lesion performed disturbances and neuropsychological deficits in patients poorly on the Wisconsin Card Sort Test. The patient with movement disorders. with bilateral lesions had marked persistent apathy, whereas the patients with more limited lesions exhib¬ Neuropsychiatrie Disorders ited transient passivity with at least partial recovery of and Frontal-Subcortical Circuits motivation. Sandson et al3 described a patient with an In addition to personality alterations (eg, apathy and infarction involving primarily the left medial dorsal tha¬ disinhibition), mood changes and obsessive-compulsive lamic nucleus. The patient was apathetic and exhibited behaviors are also associated with focal brain lesions neuropsychological abnormalities on tests of recent affecting frontal-subcortical circuits. Depression occurs memory and of executive function, including serial mo¬ with lesions of the dorsolateral prefrontal cortex and cau¬ tor behavior, set shifting, and word list generation. The date nucleus, particularly when the left hemisphere is disorder was observed to have many similarities to affected.4547 Positron emission tomographic studies in frontal lobe syndromes. Huntington's disease and Parkinson's disease reveal di¬ Thalamic degenerative diseases produce behaviors sim¬ minished metabolism in the orbitofrontal cortex in de¬ ilar to those observed with thalamic infarction. Severe pressed compared with nondepressed patients,48-49 and memory abnormalities and impaired insight are charac¬ positron emission tomography in patients with idiopathic teristic, and both apathetic and disinhibited behaviors unipolar depression shows diminished glucose metabo¬ have been described.43-44 lism in the prefrontal cortex and the caudate nuclei.50 These These observations in vascular and degenerative dis¬ investigations suggest that dysfunction of the dorsolateral orders affecting the thalamus reveal that typical "frontal or orbitofrontal circuits may serve as a common anatomic lobe"-type behaviors can be observed with lesions of substrate for idiopathic and acquired mood disorders. the thalamus. As noted with lesions of the globus palli- Secondary mania has a contrasting set of anatomic cor- relates, but the lesions also involve primarily nuclei and mus. Memory deficits associated with lesions of the connections of frontal-subcortical circuits. Mania has been dorsolateral prefrontal cortex and caudate nucleus are observed with lesions of the medial orbitofrontal cortex, characterized by poor recall with relative preservation diseases of the caudate nuclei, such as Huntington' disease, of recognition abilities,65 whereas thalamic lesions pro¬ and injury to the right thalamus.28-51"53 Thus, orbitofrontal duce amnesia with impairment of both recall and recog¬ cortex, caudate nuclei, and thalamic nuclei, all members of nition.42 The thalamus is poised at the interface of the the orbitofrontal circuit, participate in the mediation of medial temporal-limbic circuit (incorporating the hip¬ manic behavior. pocampus, fornix, hypothalamus, and thalamus) and Both idiopathic and acquired OCD have been related to the frontal-subcortical circuits (Fig 3). The medial dysfunction of frontal-subcortical circuits. Obsessive- temporal-thalamic circuit mediates memory storage, and compulsive behavior has been observed in patients with lesions produce an amnestic syndrome; the frontal- caudate dysfunction in Huntington's disease and after Sy- subcortical circuits mediate memory activation and denham's chorea28-54 and with globus pallidus lesions in search functions, and lesions produce deficits of infor¬ postencephalitic parkinsonism, progressive supranuclear mation retrieval with relatively preserved recognition. palsy, and manganese-induced parkinsonism and after Thalamic lesions combine the amnesia of medial limbic anoxic injury.28-38-55-56 Obsessive-compulsive disorder oc¬ dysfunction with features typical of subcortical demen¬ curs in many patients with Gilles de la Tourette's syn¬ tia and frontal-subcortical circuit dysfunction.41"43 drome,57 a disorder associated with hyperdopaminergic activity of the putamen and caudate.58 idiopathic OCD has Movement Disorders and been associated with increased glucose metabolism in the Frontal-Subcortical Circuits orbitofrontal region and caudate nuclei59 and with in¬ Basal ganglia dysfunction has traditionally been associ¬ creased blood flow in the medial frontal area.60 These ated with disturbances of movement. In addition to motor studies indicate that frontal-subcortical circuit structures dysfunction, however, patients with basal ganglia dis¬ are involved in the mediation of both idiopathic and eases have alterations in intellectual function, personality, acquired OCD. and mood. Subcortical dementia is present in Huntington's Participation of specific neurotransmitters in frontal- disease, neuroacanthocytosis, Parkinson's disease, pro¬ subcortical circuits may allow an integration of behavioral gressive supranuclear palsy, Wilson's disease, and other neuroanatomy and behavioral pharmacology. For exam¬ subcortical disorders.63-64 Executive function deficits in ple, dopamine projections originating in the midbrain these disorders reflect involvement of the dorsolateral project to the nucleus accumbens and the medial frontal prefrontal circuit as it projects through the basal ganglia. cortex.61 These structures are members of the anterior cin¬ Depression is present in most of these diseases, and mania gulate circuit. Apathy is the behavioral syndrome associ¬ has been reported in patients with Huntington's disease, ated with dysfunction of this circuit, and dopaminergic Fahr's disease, and neuroacanthocytosis.27'32'48'49,66"68 Mood agents have been successfully used to treat akinetic mut¬ disorders are associated with dysfunction of the prefron¬ ism, the extreme version of the apathetic state.62 Antide- tal cortex (dorsolateral and orbitofrontal) and the caudate pressants, antimanic agents, and serotoninergic agents nuclei. Personality changes—apathy, irritability, and used in the treatment of OCD may exert their effects on disinhibition—are prominent in Huntington's disease and circuit function. have also been described in neuroacanthocytosis, Wilson's Table 1 summarizes the neuropsychiatrie syndromes disease, and Parkinson's disease.27-32-68-69 Basal ganglionic associated with lesions involving the structures of the dysfunction with disturbances of the anterior cingulate frontal-subcortical circuits. and orbitofrontal circuits are implicated as the anatomic substrate of these behavioral alterations. Obsessive- Frontal-Subcortical Circuits and the Syndrome compulsive disorder has been associated with Hunting- of Subcortical Dementia ton's disease, Sydenham's chorea, Gilles de la Tourette's The cardinal features of subcortical dementia are mem¬ syndrome, postencephalitic parkinsonism, manganese- ory deficits, executive function abnormalities, slowed induced parkinsonism, and progressive supranuclear information processing, and mood and personality palsy.28-38-54"57 Involvement of the orbitofrontal or anterior changes.63-64 Similarities between the characteristics of cingulate circuits as they project through the basal ganglia subcortical dementia and those of frontal lobe dysfunc¬ correlate with the occurrence of OCD. Table 2 summarizes tion were noted in the first contemporary descriptions the relationship of neuropsychiatrie syndromes to basal of subcortical dementia.63 Neuropsychological deficits ganglia disorders. occurring with dorsolateral prefrontal lesions and with The nature and severity of behavioral changes observed damage in other structures of the dorsal-prefrontal cir¬ in basal ganglia diseases reflect the extent of involvement cuit are compatible with definitions of subcortical de¬ of the behaviorally relevant structures in frontal- mentia. The anatomic basis of the subcortical dementia subcortical circuits. The putamen is involved primarily in syndrome can be expanded to include the restricted the motor circuit, whereas the caudate nucleus is a critical regions of the dorsolateral prefrontal cortex that project structure of the prefrontal circuits, mediating executive to the head of the caudate as well as the basal gangli- and emotional function; diseases affecting primarily the onic and thalamic structures constituting the dorsolat¬ putamen, such as Parkinson's disease and Wilson's dis¬ eral prefrontal-subcortical circuit.64 This system mediates ease, exhibit less marked intellectual and emotional alter¬ executive function and motor programming. ations than diseases affecting primarily the caudate, such An important exception to the similarity between as Huntington's disease and neuroacanthocytosis. In Par¬ frontal lobe deficits and neuropsychological abnormali¬ kinson's disease, dementia is present when there is in¬ ties observed with subcortical disorders is the occur¬ volvement of the medial substantia nigra projecting to rence of an amnestic disorder with lesions of the thala- caudate nucleus and medial frontal cortex and not when changes are confined to the lateral nigral neurons project¬ frontal-subcortical circuit dysfunction. The model is ap¬ ing to the putamen.70 plicable to neuropsychiatrie as well as neurobehavioral The high frequency of neuropsychological alterations, disorders and offers insights into the pathophysiology of the notable occurrence of personality and mood distur¬ a variety of human behavioral syndromes. bances, and the similarity between behaviors of patients with basal ganglia diseases and patients with frontal This project was supported by the Department of Veterans Affairs, lobe injury are attributable to dysfunction of multiple a National Institute on Aging Alzheimer's Disease Core Center grant, frontal-subcortical circuits in basal ganglia disorders. In and a grant from the Marv and Mildred Conney Family. this framework, movement disorders are markers of dys¬ References function of caudate nucleus, putamen, globus pallidus, 1. Cummings JL. Clinical Neuropsychiatry. New York, NY: Grune & Strat- and subthalamic nucleus within the frontal-subcortical ton Inc; 1985. 2. Mendez MF, Adams NL, Lewandowski KS. Neurobehavioral changes circuitry. associated with caudate lesions. Neurology. 1989;39:349-354. 3. Sandson TA, Daffner KR, Carvalho PA, et al. Frontal lobe dysfunction CONCLUSIONS following infarction of the left-sided medial thalamus. Arch Neurol. 1991; This of information allows several axioms 48:1300-1303. synthesis 4. Strub RL. Frontal lobe syndrome in a patient with bilateral globus pal- governing the relationship of behavioral disturbances to lidus lesions. Arch Neurol. 1989;46:1024-1027. frontal-subcortical circuit function to be posited. First, 5. Alexander GE, Crutcher MD. Functional architecture of basal ganglia frontal-subcortical circuits are implicated in mediating circuits: neural substrates of parallel processing. Trends Neurosci. 1990;13: when lesions in several circuit- 266-271. behavioral alterations (1) 6. Alexander GE, DeLong MR, Strick PL. Parallel organization of func- related structures produce a similar behavioral disorder, tionally segregated circuits linking basal ganglia and cortex. Ann Rev Neu- (2) the behavioral syndrome is not commonly seen with rosci. 1986;9:357-381. lesions in other brain and (3) simultaneous le¬ 7. Alexander GE, Crutcher MD, DeLong MR. Basal ganglia- regions, thalamocortical circuits: parallel substrates for motor, oculomotor, 'prefron- sions in several circuit structures produce analogous tal' and 'limbic' functions. Prog Brain Res. 1990;85:119-146. rather than additive effects. Second, behavioral 8. Groenewegen HJ, Berendse HW, Wolters JG, et al. The anatomical re- changes of the cortex with the the thala- associated with subcortical lesions resemble those occur¬ lationship prefrontal striatopallidal system, mus and the amygdala: evidence for a parallel organization. Prog Brain Res. ring with frontal lobe dysfunction because these ana¬ 1990;85:95-116. tomic structures are linked in discrete, parallel frontal- 9. Parent A. Extrinsic connections of the basal ganglia. Trends Neurosci. subcortical circuits. there are identifiable circuit- 1990;13:254-258. Third, 10. Gabriel AM. Neurotransmitters and neuromodulators in the basal specific behavioral markers for the prefrontal-subcortical ganglia. Trends Neurosci. 1990;13:244-254. circuits. They are (1) executive dysfunction and motor 11. Moore RY. Catecholamine neuron systems in brain. Ann Neurol. deficits for the dorsolateral cir¬ 1982;12:321-327. programming prefrontal 12. Milner B. Effects of different brain lesions on card sorting. Arch Neu- cuit, (2) irritability and disinhibition for the orbitofrontal rol. 1963;9:90-100. circuit, and (3) apathy for the anterior cingulate circuit. 13. Benton AL. Differential behavioral effects in frontal lobe disease. Fourth, with mixed behavioral manifesta¬ Neuropsychologia. 1968;6:53-60. syndromes 14. Jones-Gotman M, Milner B. Design the invention of nonsense tions involvement of several circuits are fluency: indicating fre¬ drawings after focal cortical lesions. Neuropsychologia. 1977;15:653-674. quent with subcortical lesions and degenerative pro¬ 15. Logue V, Durward M, Pratt RTC, et al. The quality of survival after an cesses. Fifth, the precise anatomic correlates of mood anterior cerebral aneurysm. Br J Psychiatry. 1968;114:137-160. disturbances and ÒCD further but dorso¬ 16. Hunter R, Blackwood W, Bull J. Three cases of frontal meningiomas require study, presenting psychiatrically. BMJ. 1968;3:9-16. lateral prefrontal or orbitofrontal-subcortical circuits are 17. Bogousslavsky J, Regli F. Anterior cerebral artery territory infarction in candidates for the mediation of and orbito¬ the Lausanne Stroke Registry. Arch Neurol. 1990;47:144-150. depression, 18. Lhermitte Pillon Serdaru M. Human and the frontal frontal or anterior circuits are F, B, autonomy cingulate currently impli¬ lobes, part I: imitation and utilization behavior: a neuropsychological study cated in the mediation of OCD. Sixth, classic movement of 75 patients. Ann Neurol. 1986;19:326-334. disorders (parkinsonism, chorea) are markers for in¬ 19. Laiacona M, De Santis A, Barbarotto R, et al. Neuropsychological volvement of the frontal-subcortical circuits at the level follow-up of patients operated for aneurysms of anterior communicating ar- tery. Cortex. 1989;25:261-273. of the basal of a circuit ganglia. Seventh, dysfunction 20. Barris RW, Schuman HR. Bilateral anterior cingulate gyrus lesions. structure may its effects Neurology. 1953;3:44-52. produce symptoms by altering caused on distant structures within the circuit. Disinhibition of 21. Fesenmeier JT, Kuzniecky R, Garcia JH. Akinetic mutism by bilateral anterior cerebral tuberculous obliterative arteritis. Neurology. the subthalamic nucleus by caudate dysfunction pro¬ 1990;30:1005-1006. duces chorea,71 and disinhibition of thalamocortical con¬ 22. Nielsen JM, Jacobs LL. Bilateral lesions of the anterior cingulate gyri. Bull Neurol nections may be the common Los Angeles Soc. 1951;16:231-234. physiologic abnormality 23. Damasio H, Damasio AR. Lesion in New both OCD OCD cau¬ Analysis Neuropsychology. in idiopathic and associated with York, NY: Oxford University Press; 1989. date and globus pallidus lesions.28 Eighth, circuit struc¬ 24. Drewe EA. Go-no go learning after frontal lobe lesions in humans. tures may have connections with noncircuit anatomic Cortex. 1975;11:8-16. and in non-circuit-related 25. Leimkuhler ME, Mesulam M-M. Reversible go-no go deficits in a case regions may participate be¬ of frontal lobe tumor. Ann Neurol. 1985;18:617-619. havioral syndromes. For example, amnesia is associated 26. Vonsattel J-P, Myers RH, Stevens TJ, et al. Neuropathological classi- with thalamic lesions, and delusions occur with caudate fication of Huntington's disease. J Neuropathol Exp Neurol. 1985;44:559\x=req-\ 577. but these conditions are not seen with other dysfunction 27. Folstein SE. Huntington's Disease:A Disorder of Families. Baltimore, frontal-subcortical circuit lesions. These axioms can be Md: Johns Hopkins University Press; 1989. verified or disconfirmed and observa¬ 28. Cummings JL, Cunningham K. Obsessive-compulsive disorder in by experiment disease. Biol tions; can a research the Huntington's Psychiatry. 1992;31:263-270. they guide agenda exploring 29. Weinberger DR, Berman KF, Ladorola M, et al. Prefrontal cortical putative relationship between behavioral disorders and blood flow and cognitive function in Huntington's disease. J Neurol Neuro- frontal-subcortical circuits. surg Psychiatry. 1988;51:94-104. Advances in the anatomic be¬ 30. Butters N, Sax D, Montgomery K, et al. Comparison of the neuropsy- defining relationships chological deficits associated with early and advanced Huntington's disease. tween the frontal lobe and subcortical structures provide Arch Neurol. 1978;35:585-589. a framework for linking behavioral alterations with 31. Mazziotta JC. PET and Huntington's disease. In: Martin WRW, ed. Functional Imaging in Movement Disorders. New Boca Raton, Fla: CRC cular lesions. Am J Psychiatry. 1984;141:1084-1087. Press; 1990:177-192. 53. Starkstein SE, Boston JD, Robinson RG. Mechanisms of mania after 32. Wyszynski B, Merriam A, Medalia A, et al. Choreoacanthocytosis: re- brain injury: 12 case reports and review of the literature. J Nerv Ment Dis. port of a case with psychiatric features. Neuropsychiatry Neuropsychol Be- 1988;176:87-100. hav Neurol. 1989;2:137-144. 54. Swedo SE, Rapoport JL, Cheslow DL, et al. High prevalence of 33. Phillips S, Sangalang V, Stern G. Basal forebrain infarction: a clinico- obsessive-compulsive symptoms in patients with Sydenham's chorea. Am J pathologic correlation. Arch Neurol. 1987;44:1134-1138. Psychiatry. 1989;146:246-249. 34. Klee A. Akinetic mutism: review of the literature and report of a case. 55. Laplane D, Levasseur M, Pillon B, et al. Obsessive-compulsive and J Nerv Ment Dis. 1961;133:536-553. other behavioral changes with bilateral basal ganglia lesions. Brain. 1989; 35. Lavy S. Akinetic mutism in a case of craniopharyngioma. Psychiatr 112:699-725. Neurol. 1959;138:369-374. 56. Schilder P. The organic background of obsessions and compulsions. 36. Messert B, Henke TK, Langheim W. Syndrome of akinetic mutism as- Am J Psychiatry. 1938;94:1397-1416. sociated with obstructive hydrocephalus. Neurology. 1966;16:635-649. 57. Frankel M, Cummings JL, Robertson MM, et al. Obsessions and com- 37. Laplane D, Baulac M, Widlocher D, et al. Pure psychic akinesia with pulsions in Gilles de la Tourette's syndrome. Neurology. 1986;36:378-382. bilateral lesions of basal ganglia. J Neurol Neurosurg Psychiatry. 1984;47: 58. Singer HS, Hahn I-H, Moran TH. Abnormal dopamine uptakes sites in 377-385. postmortem striatum from patients with Tourette's syndrome. Ann Neurol. 38. Mena I, Marin O, Fuenzalida S, et al. Chronic manganese poisoning. 1991;30:558-562. Neurology. 1967;17:128-136. 59. Baxter LR, Phelps ME, Mazziotta JC, et al. Local cerebral glucose met- 39. Schuler P, Oyanguren H, Maturana V, et al. Manganese poisoning. Ind abolic rates in obsessive-compulsive disorder. Arch Gen Psychiatry. 1987; Med Surg. 1957;26:167-173. 44:211-218. 40. Gentilini M, De Renzi E, Crisi G. Bilateral paramedian thalamic artery 60. Machlin SR, Harris GJ, Pearlson GD, et al. Elevated medial-frontal ce- infarcts: report of eight cases. J Neurol Neurosurg Psychiatry. 1987;50:900\x=req-\ rebral blood flow in obsessive-compulsive patients: a SPECT study. Am J 909. Psychiatry. 1991;148:1240-1242.;148:1240-1242. 41. Eslinger PJ, Warner GC, Grattan LM, et al. 'Frontal lobe' utilization 61. Nieuwenhuys R. The Chemoarchitecture of the Brain. New York, NY: behavior associated with paramedian thalamic infarction. Neurology. 1991; Springer-Verlag NY Inc; 1985. 41:450-452. 62. Ross ED, Stewart RM. Akinetic mutism from hypothalamic damage: 42. Stuss DT, Guberman A, Nelson R, et al. The neuropsychology of successful treatment with dopamine agonists. Neurology. 1981 ;31:1435- paramedian thalamic infarction. Brain Cogn. 1988;8:348-378. 1439. 43. Deymeer F, Smith TW, DeGirolami U, et al. Thalamic dementia and 63. Albert ML, Feldman RG, Willis AL. The 'subcortical dementia' of pro- motor neuron disease. Neurology. 1989;39:58-61. gressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 1974;37:121\x=req-\ 44. Moossy I, Martinez J, Hamin I, et al. Thalamic and subcortical gliosis 130. with dementia. Arch Neurol. 1987;44:510-513. 64. Cummings JL. Introduction. In: Cummings JL, ed. SubcorticalDemen- 45. Robinson RG, Kubos KL, Starr LB, et al. Mood disorders in stroke pa- tia. New York, NY: Oxford University Press; 1990:3-16. tients: importance of location of lesion. Brain. 1984;107:81-93. 65. Butters N, Wolfe J, Granholm E, et al. An assessment of verbal recall, 46. Starkstein SE, Robinson RG, Price TR. Comparison of cortical and recognition and fluency abilities in patients with Huntington's disease. Cor- subcortical lesions in the production of post-stroke mood disorders. Brain. tex. 1986;22:11-32. 1987;110:1045-1059. 66. Cummings JL. Depression and Parkinson's disease: a review. Am J 47. Starkstein SE, Robinson RG, Berthier ML, et al. Differential mood Psychiatry. 1992;149:443-454. changes following basal ganglia vs thalamic lesions. Arch Neurol. 1988;45: 67. Trautner RJ, Cummings JL, Read SL, et al. Idiopathic basal ganglia cal- 725-730. cification and organic mood disorder. Am J Psychiatry. 1988;145:350\x=req-\ 48. Mayberg HS, Starkstein SE, Peyser CE, et al. Paralimbic frontal lobe 353. hypometabolism in depression associated with Huntington's disease. Neu- 68. Akil M, Schwartz JA, Yuzbasiyan-Gurkan V, et al. The psychiatric rology. 1992;42:1791-1797. presentations of Wilson's disease. J Neuropsychiatry Clin Neurosci. 1991 ;3: 49. Mayberg HS, Starkstein SE, Sadzot B, et al. Selective hypometabolism 377-382. in the inferior frontal lobe in depressed patients with Parkinson's disease. Ann 69. Starkstein SE, Mayberg HS, Preziosi TJ, et al. Reliability, validity, and Neurol. 1990;28:57-64. clinical correlates of apathy in Parkinson's disease. J Neuropsychiatry Clin 50. Baxter LR, Phelps ME, Mazziotta JC, et al. Cerebral metabolic rates for Neurosci. 1992;4:134-139. glucose in mood disorders. Arch Gen Psychiatry. 1985;42:441-447. 70. Rinne JO, Rummukainen J, Paljarvi L, et al. Dementia in Parkinson's 51. Bogousslavsky J, Ferrazzini M, Regli F, et al. Manic delirium and fron- disease is related to neuronal loss in the medial substantia nigra. Ann Neu- tal lobe syndrome with paramedian infarction of the right thalamus. J Neurol rol. 1989;26:47-50. Neurosurg Psychiatry. 1988;51:116-119. 71. DeLong MR. Primate models of movement disorders of basal ganglia 52. Cummings JL, Mendez MF. Secondary mania with focal cerebrovas- origin. Trends Neurosci. 1990;13:281-285.