Frontal-Subcortical Circuits and Neuropsychiatric Disorders

Transcription

1 Frontal-Subcortical Circuits and Neuropsychiatric Disorders Michael S. Mega, M.D. Jeffrey L. Cummings, M.D. Five parallel anatomic circuits link regions of the frontal cortex to the striatum, globus pallidus/ substantia nigra, and thalamus. The circuits originate in the supplementary motor area, frontal eye fields, dorsolateral prefrontal region, lateral orbitofrontal area, and anterior cingulate cortex. Open loop structures that provide input to or receive output from specific circuits share functions, cytoarchitectural features, and phylogenetic histories with the relevant circuits. The circuits mediate motor and oculomotor function as well as executive functions, socially responsive behavior, and motivation. Neuro psychiatric disorders of frontal-subcortical circuits include impaired executive function, disinhibition, and apathy; indicative mood disorders include depression, mania, and lability. Transmitters, modulators, receptor subtypes, and second messengers within the circults provide a chemoarchitecture that can inform pharmacotherapy. (The Journal of Neuropsychiatry and Clinical Neurosciences 1994; 6: ) F rontal-subcortical circuits form one of the principal organizational networks of the brain and are central to brain-behavior relationships. These circuits unite specific regions of the frontal cortex with the basal ganglia and the thalamus in circuits that mediate motor activity, eye movements, and behavior) Disruption of the circuits originating in the prefrontal cortex results in a variety of cognitive and neuropsychiatric disorders.2 The circuits have been the subject of intensive study, and information is available concerning their precise anatomy as well as their chemoarchitecture. In this review, we outline progress in understanding the anatomy and biochemistry of the circuits and describe the relevance of the circuits to neuropsychiatric disorders. We first discuss circuit anatomy, then connections of other brain regions to each circuit, and finally the circuits neurochemical organization. The three frontal-subcortical circuits most involved in mediating behavior and implicated in a number of neuropsychiatric syndromes are emphasized. OVERVIEW OF FRONTAL-SUBCORTICAL CIRCUITS Five circuits have been identified, and they are named according to their function or cortical site of origin. The From the Departments of Neurology and Psychiatry/Biobehavioral Science, UCLA School of Medicine, and the Behavioral Neuroscience Section, Psychiatry Service, West Los Angeles Veterans Affairs Medical Center, Los Angeles, California. Address correspondence to Dr. Curnmings, Neurobehavior Unit (II6AF, Bldg. 256B), West Los Angeles VAMC, Wilshire Boulevard, Los Angeles, CA Copyright 1994 American Psychiatric Press, Inc. 358 VOLUME 6 #{149} NUMBER 4 #{149} FALL 1994

2 MEGA AND CUMMINGS motor circuit, originating in the supplementary motor area, and the oculomotor circuit, originating in the frontal eye fields, are dedicated to motor function. The dorsolateral prefrontal, lateral orbitofrontal, and anterior cingulate circuits subserve executive cognitive functions, personality, and motivation, respectively. Each of the five circuits has the same member structures, including the frontal lobe, striatum, globus pallidus, substantia nigra, and thalamus. In addition, each circuit uses the same transmitters at each anatomic site. The relative anatomic positions of the circuits are preserved in each circuit structure; thus, the dorsolateral prefrontal cortex projects to the dorsolateral region of the caudate nucleus, the lateral orbitofrontal region projects to the ventral caudate area, and the anterior cingulate cortex connects to the medial striatal/nucleus accumbens region. Similar anatomic arrangements are maintained in the globus pallidus and thalamus. There is progressive spatial constraint of the circuits at subcortical levels, with a reduction in the volume occupied by the circuits in subcortical compared with cortical regions. The basic anatomic organization shared by all of the circuits is an origin in the frontal lobes with excitatory glutaminergic fibers that terminate in the striatum (caudate, putamen, and ventral striatum). These striatal cells then project inhibitory y-aminobutyric acid (GABA) fibers both to neurons in the globus pallidus interna/substantia nigra pars reticulata (direct loop connection) and the globus pallidus externa (indirect loop connection). In the indirect loop, the external globus pallidus projects to the subthalamic nucleus via inhibitory GABA fibers; the subthalamic nucleus then connects with the globus pallidus interna/substantia nigra pars reticulata through excitatory glutaminergic fibers.3 4 The direct pathway utilizes substance P with its GABA projection to the pallidum and expresses dopamine D1 receptors, whereas the indirect loop combines enkephalin with GABA and receives its dopaminergic influence via D2 receptors.5 The globus pallidus interna/substantia nigra pars reticulata then project inhibitory GABA fibers to specific thalamic targets that complete the circuit by sending a final excitatory connection to the cortical site of the circuit s origin in the frontal lobe (Figure 1). Each circuit comprises a closed loop; dedicated neurons remain anatomically segregated from the parallel chains of neurons in the other circuits. There are, however, open elements in each circuit. Input from regions outside the loops modulate the circuits activity. The circuits also project to areas outside the closed loop. The open afferent and efferent components of the circuits are regions that share functions with each specific circuit. Circuits mediating limbic functions have connections to other limbic areas of the brain, whereas those involved with executive functions interact with brain regions intimately involved with cognition. Thus, the circuits integrate information from anatomically disparate but functionally related brain regions. The observation that each of the circuits is anatomically discrete supports the concept of circuit-specific behaviors, with each of the circuits mediating a defined set of related behaviors. The dorsolateral prefrontal-subcortical circuit mediates executive function; the lateral orbitofrontal-subcortical circuit mediates socially critical restraint and empathy; and the anterior cingulate-subcortical circuit mediates motivation. Executive dysfunction, disinhibition, and apathy are the respective marker behaviors for dysfunction in these circuits. Mood disorders and obsessive-compulsive disorder (OCD) are also observed with disorders affecting the frontal-subcortical circuits. The numerous structures and the many transmitters, receptors, and modulators involved in these circuits account for the observation that lesions in different brain regions may have similar behavioral effects and FIGURE 1. The direct and indirect frontal subcortical loops (red arrows Indicate excitatory connections; blue arrows indicate inhibitory connections). 1. Excitatory glutaminergic corticostriatal fibers. 2. Direct loop s inhibitory GABA/substance P fibers (associated with D1 receptors) from the striatum to the globus pallidus interna/substantia nigra pars reticulata. 3. Indirect loop s inhibitory GABA/enkephalin fibers (associated with D2 receptors) from the striatum to the globus pallidus externa. 4. Indirect loop s inhibitory GABA fibers from the globus pallidus externa to the subthalamic nucleus. 5. Indirect loop s excitatory glutaminergic fibers from the subthalamic nucleus to the globus pallidus interna/substantia nigra pars reticulata. 6. Basal ganglia inhibitory outflow via GABA fibers from the globus pallidus interna/substantia nigra pars reticulata to specific thalamic sites. 7. Thalamic excitatory fibers returning to cortex (shown in contralateral hemisphere for convenience). JOURNAL OF NEUROPSYCHIATRY 359

3 CIRCUITS AND NEUROPSYCHIATRIC DISORDERS that a variety of pharmacologic interventions may have caudate nucleus.6 Fibers from this region of the caudate similar effects on behavioral disturbances. project to the lateral aspect of the mediodorsal globus paffidus interna and rostrolateral substantia nigra pars Dorsolateral Prefrontal Circuit reticulata via the direct pathway.7 The indirect pathway The dorsolateral prefrontal-subcortical circuit originates sends fibers to the dorsal globus pallidus externa, which in Brodmann areas 9 and 10 on the lateral surface of the in turn projects to the lateral subthalamic nucleus;8 fibers anterior frontal lobe (Figure 2, top left image). Neurons from the lateral subthalamic nucleus then terminate in in these regions project to the dorsolateral head of the the globus pallidus interna and substantia nigra pars FIGURE 2. Origins of three frontal-subcortical circuits. Top left Dorsolateral circuit. Brodmann areas 9 and 10 are colored blue on the superior and inferior dorsolateral prefrontal cortex. Bottom left Anterior cingulate circuit. The anterior portion of Brodmann area 24 is colored red on the medial frontal cortex. Right Lateral orbitofrontal circuit. Brodmann areas 10 and 11 are colored green on the medial and inferior orbitofrontal cortex. 360 VOLUME 6 #{149} NUMBER 4 #{149} FALL 1994

4 MEGA AND CUMMINGS reticulata. Output from these two structures terminates in the parvocellular portions of the ventral anterior and mediodorsal thalamus, respectively.9 10 The mediodorsal thalamus closes the circuit by projecting back to the circuit s origin in areas 9 and 10 of the dorsolateral frontal lobe The segregated anatomy of the dorsolateral prefrontal-subcortical circuit is illustrated in Figure 3. Functionally, the dorsolateral prefrontal circuit subserves executive function. 2 Executive functions include the ability to organize a behavioral response to solve a complex problem (including learning new information, copying complicated figures, and systematically searching memory), activation of remote memories, self- direction and independence from environmental contingencies, shifting and maintaining behavioral sets appropriately, generating motor programs, and using verbal skills to guide behavior (Table 1). Damage to the dorsolateral frontal lobe produces deficits in these executive functions. Not all executive skills are reduced with all lesions; a spectrum of severity, as well as variation in the specific abilities that are compromised, is evident among patients with dorsolateral prefrontal dysfunction. Successful performance of the Wisconsin Card Sorting Test (WCST) requires several of the functions mediated by this brain region, including set shifting and maintenance, strategy generation, and organization of information.13 FIGURE 3. The segregated anatomy of the frontal-subcortical circuits: dorsolateral (blue), lateral orbitofrontal (green), and anterior cingulate (red) circuits in the striatum (top), pallidum (center), and mediodorsal thalamus (bottom). FIGURE 4. Major open afferents and effereuts of the dorsolateral circuit. Top: Major open afferents. Brodmann areas 46 and 7a are ouflined in yellow on the dorsolateral prefrontal and caudal superior parietal lobes. Bottom: Major open efferents. Brodmann area 46 and the anterior portion of area 8 are outlined in yellow on the middle and superior prefrontal lobe. JOURNAL OF NEUROPSYCHIATRY 361

5 CIRCUITS AND NEUROPSYCHIATRIC DISORDERS The WCST has proved to be particularly sensitive to dorsolateral prefrontal abnormalities. Reduced verbal and design fluency, poor organizational strategies in learning tasks, and impoverished strategies on constructional tests are also observed Impairment of sequential motor tasks, such as alternating and reciprocal sequences, is characteristic of dorsolateral prefrontal dysfunction. 6 Executive function requires the integration of prefrontal and subcortical activity. Thus, similar behavioral changes are noted with lesions of the prefrontal cortex and the subcortical structures linked to this region in the dorsolateral prefrontal-subcortical circuit. Neuropsychiatric disturbances associated with dorsolateral prefrontal-subcortical circuit dysfunction include depression and anxiety with dorsolateral prefrontal strokes17 8 and depression with caudate dysfunction in stroke and basal ganglia disorders.17 9 TABLE 1. Executive cognitive dysfunctions associated with disorders of the dorsolateral prefrontal cortex Classification Impaired Functions Poor organizational strategies Segmented drawings Impaired organization of material to be learned Poor wordlist generation Reduced design fluency Poor sorting behavior Poor memory search strategies Reduced wordlist generation Poor recall of remote information Poor recall of recently learned information Stimulus-bound environmental behavior/ dependency Impaired set shifting and maintenance Poor set shifting Concrete interpretation of abstract concepts and proverbs Pull toward high-stimulus objects Imitation behavior Utilization behavior Reduced design fluency Impaired reciprocal programs Poor go/no-go performance Poor response inhibition (Stroop Color Word Test) Impaired card sorting Poor alternation between concepts Perseveration on: Multiple loops Alternating programs Reciprocal programs Go/no-go test Luria serial hand sequences Verbal-manual dissociation Impaired Luria serial hand sequences Note: Items appear several times when they have multiple determinants. Lateral Orbitofrontal Circuit The lateral orbitofrontal circuit originates in Brodmann areas 10 and 11 (Figure 2, right image) and sends projections to the ventromedial caudate.6 This portion of the caudate projects directly to the most medial portion of the mediodorsal globus pallidus interna and to the rostromedial substantia nigra pars reticulata.2#{176} The yentromedial caudate also sends an indirect loop through the dorsal globus pallidus externa to the lateral subthalamic nucleus, which then projects to the globus pallidus interna and substantia nigra pars reticulata.8 Neurons are sent from the globus pallidus and substantia mgra to the medial section of the magnocellular division of the ventral anterior thalamus as well as an inferomedial sector of the magnocellular division of the mediodorsal thalamus.6 10 The circuit then closes with projections from this thalamic region to the lateral orbitofrontal cortex.1#{176}this anatomic segregation is illustrated in Figure 3. The orbitofrontal circuit mediates empathic, civil, and socially appropriate behavior; personality change is the hallmark of orbitofrontal dysfunction. Irritability, lability, tactlessness, and fatuous euphoria have been described in patients with lesions of this area.21 Patients do not respond appropriately to social cues, show undue familiarity, and are unable to empathize with the feelings of others. Irritability and lability-rapid shifts from one mood to another-are often prominent. Utilization behavior (inappropriate automatic use of tools and utensils in the patient s environment) and automatic imitation of the gestures and actions of others may occur with large lesions.24 Similar behavioral changes are evident in patients with dysfunction of the subcortical structures of the orbitofrontal-subcortical circuit, including patients with Huntington s disease (caudate abnormalities) and manganese intoxication (globus pallidus lesions).19 Obsessive-compulsive disorder, a condition characterized by increased behavioral control, overconcern about social behaviors and contamination, and excessive investment in social appropriateness, is characterized by increased metabolic activity in the orbitofrontal cortex and increased caudate metabolism.26 Lesions of the gbbus pallidus can also produce (by virtue of the resulting thalamic disinhibition) increased orbitofrontal and caudate activity and have also been associated with OCD.27 Mania has been observed in patients with orbitofrontal lesions, caudate dysfunction in basal ganglia disorders, and lesions of the thalamus.2#{176} Table 2 summarizes the principal abnormalities associated with dysfunction of the lateral orbitofrontal cortex. Anterior Cingulate Circuit Neurons of the anterior cingulate serve as the origin of the anterior cingulate-subcortical circuit (Figure 2, bot- 362 VOLUME 6 #{149} NUMBER 4 #{149} FALL 1994

6 MEGA AND CUMMINGS torn left image). From Brodrnann area 24, input is provided to the ventral striatum,6 which includes the ventromedial caudate, ventral putamen, nucleus accumbens, and olfactory tubercle. This area is termed the limbic striatum.3 Projections from the ventral striatum innervate the rostromedial gbobus pallidus interna and ventral pallidum (the region of the gbobus pallidus inferior to the anterior commissure) as well as the rostrodorsal substantia nigra.32 There may also be an indirect loop projecting from the ventral striatum to the rostral pole of the gbobus pallidus externa.32 The external pallidum in turn connects to the medial subthalamic nucleus, which returns projections to the ventral pallidum.8 The ventral pallidum provides some input to the magnocellular mediodorsal thalamus. The anterior cingulate circuit closes with projections from the dorsal portion of the magnocellular mediodorsal thalamus to the anterior cmgulate.12 The anatomy of this circuit is illustrated in Figure 3. The anterior cingulate-subcortical circuit mediates motivated behavior, and apathy is the marker behavior of damage to the structures of this circuit. Akinetic mutism occurs with bilateral lesions of the anterior cingulate. TABLE 2. Cognitive and behavioral abnormalities associated with disorders of the lateral orbital and anterior cingulate prefrontal cortex Classification Impaired Functions Lateral orbital prefrontal cortex Personality change Imtabffity Tactlessness Fatuous euphoria Impulsivity Undue familiarity Environmental Utilization Imitation Mood Labffity Mama disorders dependency behavior behavior Obsessive-compulsive disorder (with increased orbitofrontal and caudate metabolism) Anterior cingulate prefrontal Impaired motivation cortex Akinetic mutism Marked apathy Psychic emptiness Poverty of spontaneous speech Indifference to pain Poor response inhibition Impaired go/no-go test performance Patients are profoundly apathetic. Rarely moving, they are incontinent, eat and drink only when fed, and if speech occurs it is limited to monosyllabic responses to others questions. Displaying no emotions, even when in pain, patients show complete indifference to their circumstances.37 Transient akinetic mutism with similar features occurs with unilateral lesions. Failure of response inhibition on go/no-go tests is the major neuropsychological deficit in the patient with medial frontal damage.39 4#{176}Apathy is also prominent in patients with disorders affecting the subcortical links of the anterior cingulate circuit, including Parkinson s disease, Huntington s disease, and thalamic lesions.4 Table 2 summarizes the principal abnormalities associated with dysfunction of the anterior cingulate cortex. CIRCUIT CONNECTIONS The activity within each frontal-subcortical circuit constitutes a closed loop of neural processing dedicated to the specific functions subserved by that circuit. Neuronal activity in brain areas outside the member structures of a particular circuit may provide functionally relevant input to a circuit via their efferent connections to the prefrontal cortex, striatum, gbobus paffidus, substantia nigra, or thalamus. The circuits also send efferents outside the closed loop to functionally related brain areas. These noncircuit connections constitute the open aspects of circuits. An examination of the open aspects of each circuit facilitates understanding of how information processed in different brain regions can be integrated and synthesized in the processing cascade of the closed circuit. Open aspects of the circuits also serve to unify diverse brain regions into functional systems relevant to specific behaviors. The frontal-subcortical circuits provide the anatomic framework for the final effector mechanisms of these functional distributed systems. Open elements of the circuits relate systematically to other brain regions that both mediate related functions and have similar phybogenetic origins. Review of the evolutionary, development of cortical and subcortical structures makes these functional and phybogenetic alliances apparent. At the subcortical level, two ctyoarchitectonic divisions are evident. These are most apparent in the thalamus, where one is termed magnocellular because of the larger cell bodies of the neurons compared to the smaller sized cells of the parvocellular regions. The larger magnocellular neurons predominate in phybogenetically older regions of the thalamus and participate in more primitive functions mediated by the limbic system, whereas the JOURNAL OF NEUROPSYCHIATRY 363

7 CIRCUITS AND NEUROPSYCHIATRIC DISORDERS parvocellular regions have appeared more recently in phylogenetic development and participate in more recently acquired cognitive functions. The cerebral cortex has derived from two regions with distinct evolutionary origins that are reflected in their different architectural organization and contrasting functions. A dorsal or archicortical derivation occupies the dorsal prefrontal region. Within the dorsal areas there is a progressive differentiation in the cortical cell layers extending from the medial to the dorsal frontal lobe. Thus, the least differentiated regions are found most medially in the area of the origin of the anterior cingulate circuit, whereas the most differentiated regions occupy the dorsolateral prefrontal cortex serving the dorsolateral prefrontal circuit. A second progression in cortical differentiation stems from the orbitofrontal cortex and extends over the ventrolateral prefrontal region. This progressive differentiation is termed the ventral or paleocortical trend. Again, the least differentiated regions are in the orbitofrontal cortex and the most differentiated in the dorsolateral prefrontal cortex. The highly differentiated dorsolateral region mediates executive function; the medial frontal/anterior cingulate and the orbitofrontal regions are composed of paralimbic cortex and mediate motivational and emotional aspects of behavior, respectively. The parvocellular and magnocellular regions of the dorsomedial thalamus project to the most differentiated and least differentiated prefrontal cortical areas, respectively. These prefrontal areas also have connections with other cortical areas that serve as open inputs to the circuits. In each case, the circuit connections share phybogenetic, cytoarchitectonic, and functional features. Dorsolateral Prefrontal Circuit: Afferents and Efferents In addition to Brodmann areas 9 and 10, which serve as the frontal origin of the closed loop for the circuit, Brodmann prefrontal area 466 and area 7a of the caudal superior parietal bobe serve as major open contributors to the dorsolateral prefrontal-subcortical circuit (Figure 4, p.361, top image; extrapolated from Walker s areas in nonhuman primates to their homologous Brodmann areas on a human brain). Minor open aspects (not shown in Figure 4) are listed in Table 3. These include the dorsal parafascicular thalamus, which terminates in the dorsolateral caudate, the medial pars compacta of the substantia nigra, the dorsal raphe, and the central midbrain tegmentum.47 Parietal area 7a subserves attention to significant visual stimuli, visually guided reaching, and planning of visuospatial strategies. There are rich interconnections between area 7a and frontal areas 9, 10, and 46. The minor open aspects of the executive circuit provide ascending thalamic, nigral, and brainstem input to the dorsolateral caudate. The parafascicular thalamus receives input primarily from the supplementary frontal eye fields, superior colliculus, and prefrontal cortex.47 The entire substantia nigra pars compacta receives significant input from the ventral pallidum, which allows limbic influence to reach the striatum via dopaminergic projections from the substantia nigra pars compada. Serotonergic and noradrenergic modulatory influences reach the dorsolateral circuit from the dorsal raphe and central midbrain tegmentum. The efferent projections of the dorsolateral circuit, emanating from the parvocellular ventral anterior and mediodorsal thalamus, close the circuit by terminating in areas 9 and 10 of the dorsolateral frontal lobe. Major open targets from these thalamic areas also include dorsolateral prefrontal area 46 and anterior frontal area 8 (Figure 4, bottom image), and the minor target is the anterior supplementary motor cortex of area 6.12 These open efferent targets are within the same dorsal architectonic derivation as the open afferent aspects of the circuit. The phybogenetically similar regions also connect with the parvocellular division of the thalamus dedicated to the dorsolateral prefrontal circuit. Orbitofrontal Circuit: Afferents and Efferents The major cortical afferent connections with the orbitofrontal circuit (in addition to Brodmann areas 10 and 11, the frontal origin for the closed loop of the circuit) are area 22 in the superior temporal lobe6 and area 12 in the orbital frontal lobe49 (Figure 5, left image). Minor open inputs (not shown in Figure 5) are listed in Table 3. These originate in the entorhinal cortex,5#{176}rostromedial parafascicular thalamus,47 amygdala,5 medial substantia nigra pars compacta, dorsal raphe, and central midbrain tegmentum. The paleocortical ventral cortical elements that serve as the closed afferent origin for the lateral orbitofrontal circuit (areas 10 and 11) have rich connections with the superior temporal area, which provides open input to this circuit. Diencephalic connections of the orbitofrontal-subcortical circuit are distinguished from the dorsolateral circuit by their termination in the magnocellular mediodorsal thalamus; the parvocellular mediodorsal thalamus is dedicated to the dorsolateral circuit. The minor afferent input of the orbitofrontal circuit is similar to the minor input to the executive circuit except for the additional limbic input from the amygdala and entorhinal cortex. Major open efferent targets of the orbitofrontal circuit (Figure 5, right image) receiving projections from the 364 VOLUME 6 #{149} NUMBER 4 #{149} FALL 1994

8 MEGA AND CUMMINGS TABLE 3. Afferents and efferents of the dorsolateral, lateral orbitofrontal, and anterior cingulate Circuits Category Dorsolateral Circuit Lateral Orbitofrontal Circuit Anterior Cingulate Circuit Closed afferents Dorsofrontal area 9 Orbitofrontal area 10 Anterior cingulate area 24 Dorsofrontal area 10 Orbitofrontal area 11 Closed efferents Dorsofrontal area 9 Dorsofrontal area 10 Major open afferents Dorsofrontal area 46 Parietal area 7a Major open efferents Dorsofrontal area 46 Anterior frontal area 8 Minor open afferents Dorsal parafascicular thalamus Medial pars compacta of substantia mgra Dorsal raphe Central midbrain tegmentum Orbitofrontal area 10 Orbitofrontal area 11 Superior temporal area 22 Orbitofrontal area 12 Orbitofrontal area 12 Mediofrontal area 25 Mediofrontal area 32 Entorhinal cortex Rostromedial parafascicular thalamus Amygdala Medial pars compacta of substantia nigra Dorsal raphe Central midbrain tegmentum Anterior cingulate area 24 Hippocampus Entorhinal area 28 Perirhiflal area 35 Pars compacta of substantia mgra Medial subthalamic nucleus Lateral hypothalamus Orbitofrontal area 12 Amygdala Subparafasdcular thalamus Dorsal raphe Central midbrain tegmentum Minor open efferents Anterior frontal area 6 Mediofrontal area 9 Anterior dngulate area 33 Anterior insula Temporal pole of area 38 Midline thalamic nuclei Dorsal globus pallidus interna/ externa Lateral habenula Central gray Tegmenti pedunculopontine nudeus magnocellular ventral anterior and mediodorsal thalamus are areas 12, encompassing gyrus rectus and paraolfactory gyri in the medial orbital frontal region; a portion of area 25 in the medial posterior frontal region; and area 32 in the inferorostral cingulate gyms. Minor open efferents (not shown in Figure 5) are the medial extension of area 9, the anterior portion of area 33, and the anterior insular cortex, as well as a portion of the temporal pole in area 38#{149}12,M The majority of the open efferents of the orbitofrontal circuit correspond to an olfactory-centered paralimbic belt.52 The paralimbic belt is a transitional cortical zone from less differentiated paleocortex or archicortex to the more differentiated isocortex, and it has two functional centers: the olfactory piriform paleocortex, which unites the orbitofrontal, insular, and temporopolar regions, and the hippocampus, which provides the nidus for the archicortical system spreading into the cingulate and parahippocampal components of the paralimbic cortical regions. Anterior Cingulate Circuit: Afferents and Efferents Brodmann area 28 in the entorhinal cortex, area 35 in the perirhinal area, and the hippocampus are the major open loop contributors to the ventral striatum (Figure 6; hippocampus not shown).32 Minor open afferent sources (not shown in Figure 6) are listed in Table 3 and include Brodmann area 12 in the orbitofrontal lobe, the amygdala, the subparafascicular thalamus, the dorsal raphe, and the central midbrain tegmentum.47 The major afferent input to the anterior cingulate circuit represents the second center of the paralimbic belt originating in the hippocampus.52 This hippocampalcentered system contains the cingulate and parahippocampal components of the paralimbic cortex. The archicortical anterior cingulate circuit is differentiated from the paleocortical orbitofrontal circuit within the paralimbic belt by the separate anatomical focus each circuit has within this cortical transition zone. Both are limbic circuits, but each reflects different phybogenetic organizations within the limbic system. The older orbitofrontal centered belt is involved with the internal state of the organism. The more recent hippocampal-centered belt is the externally directed arm of the limbic system. Both work in concert. Processing in the anterior cingulate circuit enables the intentional selection of environmental stimuli based on the internal relevance those stimuli have for the organism. Input about that internal relevance is provided by the activity of the orbitofrontal circuit. JOURNAL OF NEUROPSYCHIATRY 365

9 CIRCUITS AND NEUROPSYCHIATRIC DISORDERS The projections from the dorsal portion of the magnocellular mediodorsal thalamus close the anterior cmgulate circuit by terminating in area 24 of the anterior cingulate.12 Major open targets for the anterior cingulate circuit from the ventral pallidum are the entire mediolateral range of the substantia nigra pars compacta, the medial subthalamic nucleus, and its extension into the lateral hypothalamus.33 Minor open ventropallidal efferent targets include the midline nuclei of the thalamus, which have a major projection to the anterior ciiigulate, the dorsal portion of both the gbobus pallidus interna and gbobus paffidus externa, the lateral habenula, the central gray regions of the midbrain, and the tegmenti pedunculopontine nucleus? Open input from orbitofrontal and entorhinal areas provides the anterior cingulate circuit with information from the internal and external environment, respectively. From this input, the organism is able to initiate motor activity that is based on the emotional relevance of external stimuli. Damage to this circuit would disrupt the integration of emotional information with motivational mechanisms and produce unmotivated, apathetic behavior. NEUROCHEMICAL ORGANIZATION The striatum has two distinct organizational systems, the striosomes and the matrix. These two components are differentiated by their chemical, ontobogical, and connectional properties. The acetylcholine-poor neurons of the striosomes mature earlier than the acetylcholine-rich cells of the matrix. Striosomes also have lower concentrations of dopamine and serotonin than the matrix cells.55 Striosomes have high concentrations of limbic-associated membrane protein and receive dense orbitofrontal and insular input. In contrast, input to the matrix originates predominantly from the sensorimotor cortex. Dopaminergic input to striosomes is derived from the ventral tier of the substantia nigra pars compacta, in contrast to the more dorsal tier nigral input to the matrix. GABAergic output from the striosomes is to the medial portion of the pars compacta of the substantia nigra, dedicated to the orbitofrontal circuit, whereas the GABAergic output of the matrix is to the external and internal globus pallidus and pars reticulata portion of the substantia nigra. The effect of transmitter dysfunction within the circuits has been most extensively studied in Parkinson s disease. The loss of striatal dopamine decreases thalamocortical activation by decreasing the inhibitory outflow of the direct loop (Figure 1) and increasing activity in the indirect boop. The direct loop s D1 receptors, which stimulate the second messenger adenylate cyclase, are excitatory and thus release more GABA to inhibit the gbobus pallidus interna/substantia nigra pars reticulata. The 1)2 receptors of the indirect loop inhibit adenylate cyclase, causing decreased GABAergic inhibition of the globus pallidus externa. This results in an increased GABAergic inhibition of the excitatory outflow from the subthalamic nucleus to the gbobus pallidus intenna/substantia nigra pars reticulata. The direct loop s inhibition and indirect loop s excitation imposed on the outflow of the basal ganglia are normally balanced by the differential effect nigral dopamine has on the stniatum. Pallidal outflow inhibits thalamocortical excitation. Parkinson s disease, by decreasing direct loop inhibition and increasing indirect loop excitation on pallidal outflow, attenuates the normal thalamocortical activation. Although the direct and indirect loops are reiterated in each of the frontal-subcortical circuits, the dopaminergic balance in each circuit may differ in degenerative disease. Patients with Parkinson s disease associated with depression and dementia have more degeneration in the ventral tegmentum than do patients without dementia or depression. The ventral tegmentum provides dopaminergic input to the anterior cingulate circuit by terminating in the ventral striatum. For these demented Parkinson s patients, more thalamocortical deactivation occurs in the anterior cingulate circuit than occurs in the nondemented patients, an effect that may contribute to apathy and anhedoma. Dopaminergic projections from the pars compacta of the substantia nigra innervate the entire striatum and thus may influence each of the frontal-subcortical circuits. The pars compacta of the substantia nigra receives diffuse input from the anterior cingulate circuit and thus provides a means for limbic motivational input to influence motor activity and cognition. This anatomic arrangement provides an important convergence of limbic activation within the otherwise segregated frontalsubcortical circuits. Dopaminergic modulation of all three prefrontal-subcortical circuits provides an anatomic basis for the multifaceted effects of dopaminergic agents, including improved motor function in Parkinson s disease, enhanced motivation in akinetic mutism, and hallucinations and delusions.606 The cholinergic system also has a differential input to the frontal-subcortical circuits. Acetyicholine facilitates thalamic activation of the cortex. Most thalamic cholinergic input originates in the pedunculopontine and laterodorsal tegmentum; however, portions of the mediodorsal, ventroanterior, and reticular nuclei that participate in the cognitive and behavioral prefrontalsubcortical circuits receive input from the nucleus basalis of Meynert in the basal forebrain.62 The brainstem cho- 366 VOLUME 6 #{149} NUMBER 4 #{149} FALL 1994

10 MEGA AND CUMMINGS linergic nuclei are affected in progressive supranuclear Serotonun (5-hydroxytryptamine; 5-HT) receptors are palsy but not in Alzheimer s disease, which preferen- differentially distributed in the frontal-subcortical cirtially affects the nucleus basalis. Thus, the cognitive cuits. The serotonin 5-HT1 receptor is the most abundant differences between these two degenerative disorders serotonin receptor in the basal ganglia. The ventral may, in part, have a basis in the specific disruption each striatum, the principal striatal structure of the anterior has in restricted portions of the frontal-subcortical cir- cingulate subcortical circuit, is the exception in that the cuits. 5-HT3 receptor predominates there.55 This finding mir- FIGURE 5. Major open afferents and efferents of the lateral othitofrontal circuit. Right Major open afferents. Bmdmann areas 22 and 12 are outlined in yellow on the superior temporal and orbitofrontal lobes. Left Major open efferents. Brodmann areas 12, 25, and 32 are outlined in yellow on the orbitofrontal, posteriomedial, and inferiorostral frontal lobe, respectively. JOURNAL OF NEUROPSYCHIATRY 367

11 CIRCUITS AND NEUROPSYCHIATRIC DISORDERS FIGURE 6. Major open afferents of the anterior cingulate circuit. Brodmann areas 28,35 are outlined in yellow on the superior and inferior entorhinal cortex of the medial temporal lobe. The other major afferent for the anterior cingulate circuit, the hippocampus, is not shown. rors the distribution of 5-HT3 receptors in other areas functionally related to the anterior cingulate circuithippocampus, septum, and amygdala. Immunohistochemical markers of the second messenger systems (phosphoinositide, adenylate cyclase) in nonhuman primates appear to reflect the segregated anatomy of the frontal-subcortical circuits. The phosphounositide system is selectively concentrated in striosomes of the medial and ventral striatum, whereas the matrix selectively stains for adenylate cyclase.tm The phosphoinositide system has been hypothesized to play a prominent role in the mechanism of action of lithium s mood-stabilizing effect. The association of this second messenger system with the limbic striatum may provide insight into how lithium exerts its effects on mood and suggests that frontal-subcortical circuits may provide an anatomic basis for these effects. The complexity created by the multiple neurotransmitter systems, the specific distribution of their various receptor subtypes, the presence of several neuromodulators, and actions of second messengers within the frontal-subcortical circuits is daunting. This complexity makes predicting drug effects difficult and offers exciting possibilities for understanding the pharmacoanatomy of drug interventions as they relate to frontal-subcortical circuits. COMMENT Frontal-subcortical circuits are effector mechanisms that allow the organism to act on the environment. The dorsolateral prefrontal-subcortical circuit mediates the organization of information to facilitate a response; the anterior cingulate subcortical circuit is required for motivated behavior; and the lateral orbitofrontal circuit allows the integration of limbic and emotional information into contextually appropriate behavioral responses. Neuropsychiatric disorders observed with dysfunction of the frontal-subcortical circuits are disorders of action rather than of perception or of stimulus integration. Thus, impaired executive functions, apathy, and impulsivity are hallmarks of frontal-subcortical circuit dysfunction. Obsessive-compulsive behavior occurs when orbitofrontal structures are hyperactive. The mood disorders associated with frontal-subcortical circuit dysfunction include mania, depression, and lability. Mania has many effector elements (hyperactivity, pressured speech, increased sexual drive, exaggerated appetite), and depression also has effector aspects (anhedonia, psychomotor retardation, anorexia). Circuit-specific behaviors reveal an underlying organizational principle of neuropsychiatric disorders. Neurobehavioral disorders such as aphasia arise from lesions of the cortex and have signature syndromes, such as Wernicke s aphasia or Broca s aphasia, that indicate a specific anatomic lesion. By contrast, neuropsychiatric disorders reflect circuit dysfunction, and the same syndrome can be seen with involvement of several structures of the circuit. Neurobehavioral disorders associated with signature syndromes have proved to be treatment resistant, whereas circuit-mediated behaviors such as reduced motivation and mood abnormalities are more amenable to pharmacotherapy. The circuits involve a number of transmitters, receptor subtypes, and second messengers that can be manipulated pharmacologically. As the chemoarchitecture of the circuits is revealed, there will be an increased opportunity to construct a pharmacoanatomy that will guide circuit-specific intervention. This project was supported by the Department of Veterans Affairs and by National Institute on Aging Alzheimer s Disease Core Center Grant AGIIOI2-3. References 1. Alexander GE, DeLong MR. Stick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986; 9: Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol 1993; 50: Albin RL, Young AB, Penney JB: The functional anatomy of basal ganglia disorders. Trends Neurosci 1989; 12: Alexander GE, Crutcher MD: Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990; 13: Groenewegen HJ, Roeling TAP, Voorn P. et al: The parallel arrangement of basal ganglia-thalamocortical circuits: a neuronal substrate 368 VOLUME 6 #{149} NUMBER 4 #{149} FALL 1994

12 MEGA AND CUMMINGS for the role of dopamine in motor and cognitive functions? in Mental Dysfunction in Parkinson Disease, edited by Wolters EC, Scheltens P. Amsterdam, Vrije Universiteit, 1993, pp Selemon LD, Goldman-Rakic PS: Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J Neurosci 1985; 5: Parent A, Bouchard C, Smith Y: The striatopaffidal and striatonigral projections: two distinct fiber systems in primate. Brain Res 1984; 303: Smith Y, Hazrati L-N, Parent A: Efferent projections of the subthalamic nucleus in the squirrel monkey as studied by the PHA-L anterograde tracing method. J Comp Neurol 1990; 294: Kim R, Nakano K, Jayaraman A, et al: Projections of the globus pallidus and adjacent structures: an autoradiographic study in the monkey. J Comp Neurol 1976; 169: flinsky IA, Jouandet ML, Goldman-Rakic PS: Organization of the mgrothalamocortical system in the rhesus monkey. J Comp Neurol 1985; 236: Kievit J, Kuypers HGJM: Organization of the thalamo-cortical connexions to the frontal lobe in the rhesus monkey. Exp Brain Res 1977; 29: Giguere M, Goldman-Rakic PS: Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkey. J Comp Neurol 1988; 277: Milner B: Effects of different brain lesions on card sorting. Arch Neurol 1963; 9: Benton AL: Differential behavioral effects in frontal lobe disease. Neuropsychologia 1968; 6: Jones-Gotman M, Milner B: Design fluency: the invention of nonsense drawings after focal cortical lesions. Neuropsychologia 1977; 15: Cummings JL: Clinical Neuropsychiatry. New York, Grune and Stratton, Robinson RG, Starkstein SE: Current research in affective disorders following stroke. J Neuropsychiatry Clin Neurosci 1990; 2: Starkstein SE, Cohen BS, Federoff F, et a!: Relationship between anxiety disorders and depressive disorders in patients with cerebrovascular injury. Arch Gen Psychiatry 1990; 47: Folstein SE: Huntington s Disease: A Disorder of Families. Baltimore, Johns Hopkins University Press, Johnson TN, Rosvold HE: Topographic projections on the globus pallidus and substantia nigra of selectively placed lesions in the precommissural caudate nucleus and putamen in the monkey. Exp Neurol 1971; 33: Logue V, Durward M, Pratt RTC, et al: The quality of survival after an anterior cerebral aneurysm. Br J Psychiatry 1968; 114: Hunter R, Blackwood W, Bull J: Three cases of frontal meningiomas presenting psychiatrically. British Medical Journal 1968; 3: BogousslavskyJ, Regli F: Anterior cerebral artery territory infarction in the Lausanne stroke registry. Arch Neurol 1990; 47: Lhermitte F, Pillon B, Serdaru M: Human autonomy and the frontal lobes, I: imitation and utilization behavior, a neuropsychological study of 75 patients. Ann Neurol 1986; 19: Mena I, Mann 0, Fuenzalida 5, et al: Chronic manganese poisoning. Neurology 1967; 17: Baxter LR Jr. Phelps ME, Mazziotta JC, et al: Local cerebral glucose metabolic rates in obsessive-compulsive disorder. Arch Gen Psychiatry 1987; 44: Cummings JL, Cunningham K: Obsessive-compulsive disorder in Huntington s disease. Biol Psychiatry 1992; 31: Bogousslavsky J, Ferrazzini M, Regli F, et al: Manic delirium and frontal-likesyndrome with paramedian infarction of the right thalamus. J Neurol Neurosurg Psychiatry 1988; 51: Jorge RE, Robinson RG, Starkstein SE, et a!: Secondary mania following traumatic brain injury. Am J Psychiatry 1993; 150: Starkstein SE, Pearlson GD, Boston J, et a!: Mania after brain injury: a controlled study of causative factors.arch Neurol 1987; 44: Heimer L: The olfactory cortex and the ventral striatum, in Limbic Mechanisms, edited by Livingston KE, Hornykiewisz 0. New York, Plenum, 1978, pp Haber SN, Lynd E, Klein C, et al: Topographic organization of the ventral striatal efferent projections in the rhesus monkey: an anterograde tracing study. J Comp Neurol 1990; 293: Haber SN, Lynd-Balta E, Mitchell SJ: The organization of the descending ventral pallidal projections in the monkey. J Comp Neurol 1993; 329: Goldman-Rakic PS, Porrino U: The primate mediodorsal (MD) nucleus and its projection to the frontal lobe. J Comp Neurol 1985; 242: Barns RW, Schuman FIR: Bilateralanterior cingulate gyrus lesions. Neurology 1953; 3: Fesenmeier JT, Kuzniecky R, Garcia il-i: Akinetic mutism caused by bilateral anterior cerebral tuberculous obliterative arteritis. Neurology 1990; 30: Nielsen JM, Jacobs LL: Bilateral lesions of the anterior cingulate gyri. Bulletin of the Los Angeles Neurolological Society 1951; 16: Damasio H, Damasio AR: Lesion Analysis in Neuropsychology. New York, Oxford University Press, Drewe EA: Go-no go learning after frontal lobe lesions in humans. Cortex 1975; 11: Leimkuhlen ME, Mesulam M-M: Reversible go-no go deficits in a case of frontal lobe tumor. Ann Neurol 1985; 18: Burns A, Foistein 5, BrandtJ, et al: Clinical assessment of irritability, aggression, and apathy in Huntington and Alzheimer disease. J Nerv Ment Dis 1990; 178: Starkstein SE, Mayberg HS, Preziosi TJ, et al: Reliability, validity, and clinical correlates of apathy in Parkinson s disease. J Neuropsychiatry Clin Neurosci 1992; 4: Stuss DT, Guberman A, Nelson R, et al: The neuropsychology of paramedian thalamic infarction. Brain Cogn 1988; 8: Yakovlev P1: Development of the nuclei of the dorsal thalamus and the cerebral cortex. Morphogenetic and tectogenetic correlation, in Modern Neurology, edited by Locke S. Boston, Little, Brown, 1969, ppl Sanides F: Comparative architectonics of the neocortex of mammals and their evolutionary interpretation. Ann NY Acad Sd 1969; 167: Yeterian EH, Pandya DN: Striatal connections of the parietal association cortices in rhesus monkeys. J Comp Neurol 1993; 332: Sadikot AF, Parent A, Francois C: Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: a PHA-L study of subcortical projections. J Comp Neurol 1992; 315: Parent A, Mackey A, De Bellefeuille L: The subcortical afferents to caudate nucleus and putamen in primate: a fluorescence retrograde double labeling study. Neuroscience 1983; 10: Yeterian EH, Pandya DN: Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys. J Comp Neurol 1991; 312: HedreenJC, DeLongMR: Organization of striatopaffidal, striatomgral, and nigrostriatal projections in the macaque. J Comp Neurol 1991; 304: Russchen Fr, Bakst I, Amaral DG, et al: The amygdalostniatal projectionsin the monkey: an anterograde tracing study. Brain Res 1985; 329: Mesulam M-M: Patterns in behavioral neuroanatomy: association areas, the limbic system, and hemispheric specialization, in Behavioral Neurology, edited by Mesulam M-M. Philadelphia, FA Davis, 1985, pp Vogt BA, Pandya DN, Rosene DL: Cingulate cortex of the rhesus monkey, I: cytoarchitecture and thalamic afferents. J Comp Neurol JOURNAL OF NEUROPSYCHIATRY 369

13 CIRCUITS AND NEUROPSYCHIATRIC DISORDERS 1987; 262: Graybiel AM: Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci 1990; 13: Lavoie B, Parent A: Immunohistochemical study of the serotoninergic innervation of the basal ganglia in the squirrel monkey. J Comp Neunol 1990; 299: Chesselet M-F, Gonzales C, Levitt P: Heterogeneous distribution of the limbic system-associated membrane protein in the caudate nudeus and substantia nigra of the cat. Neuroscience 1991; 40: GibbWRG: Melanin, tyrosinehydroxylase, calbindin and substance Pin the human midbrain and substantia nigra in relation to nignostriatal projections and differential neuronal susceptibility in Parkinson s disease. Brain Res 1992; 581: Stoof JC, Drukarch B, Vermeulen RJ: Dopamine and glutamate receptor subtypes as (potential) targets for the pharmacotherapy of Parkinson s disease, in Mental Dysfunction in Parkinson Disease, edited by Wolters EC, Scheltens P. Amsterdam, Vrije Umversiteit, 1993, pp Torack RM, Morris JC: The association of ventral tegmental area histopathology with adult dementia. Arch Neurol 1988; 45: Cummings JL: Behavioral complications of drug treatment of Parkinson s disease. JAm Geriatn Soc 1991; 39: Ross ED, Stewart RM: Akinetic mutism from hypothalamic damage: successful treatment with dopamine agonists. Neurology 1981; 31: Parent A, Pare D, Smith Y, et a!: Basal forebrain cholinergic and noncholinergic projections to the thalamus and brainstem in cats and monkeys. J Comp Neurol 1988; 277: Brandel JP, Hirsch EC, Malessa 5, et al: Differential vulnerability of cholinergic projections to the mediodorsal nucleus of the thalamus in senile dementia of Alzheimen type and progressive supranudear palsy. Neuroscience 1991; 41: Fotuhi M, Dawson TM, Sharp AH, et al: Phosphoinositide second messenger system is enriched in striosomes: immunohistochemical demonstration of inositol 1,4,5-triphosphate receptors and phospholipase C and gamma in primate basal ganglia. J Neurosci 1993; 13: Snyder SH: Second messengers and affective illness. focus on the phosphinositide cycle. Pharmacopsychiatry 1992; 25: VOLUME 6 #{149} NUMBER 4 #{149} FALL 1994