Section I Structural and Functional Neuroanatomy
Chapter
Frontal-subcortical circuits
5 David G. Lichter
A series of parallel segregated frontal-subcortical cir-
cuits (FSCs) connect speciic regions of the frontal cor-
tex (including paralimbic frontal areas) to the stria-
tum, the globus pallidus (GP) and substantia nigra
(SN), and the thalamus [1–3]. Together, these con-
stitute an important efector mechanism that allows
the individual to interact adaptively with the envi-
ronment. his chapter reviews the neuroanatomy and
neurochemistry of FSCs, and outlines the signature
syndromes of FSC circuit dysfunction. he similar-
ity of cognitive and behavioral changes that accom-
pany cortical and subcortical lesions is discussed
within this framework. Select neuropsychiatric disor-
ders that appear linked to FSC dysfunction are then
presented. Finally, we explore the manner in which
these insights may better inform clinical management
of patients with relevant neuropsychological, behav-
ioral, and neuropsychiatric disorders.
Frontostriatal systems
he frontal lobe may be viewed as comprising two
distinct anatomical/functional systems, which relect
its dual developmental origin [4]. he sequential
processing of sensory, spatially related, and motiva-
tional information is mediated by a dorsal system,
which comprises dorsolateral and medial portions of
the frontal lobes, interconnected with the posterior
parietal lobe and cingulate gyrus. Emotional tone is
mediated by a second, ventral system, which involves
the orbital surface of the frontal lobes. he architec-
tonic organization of the prefrontal cortex [5, 6] is
relected in the pattern of prefrontostriatal projections
[7]. hus, the dorsal architectonic trend, which orig-
inates in the rostral cingulate gyrus and culminates in
the dorsal portion of the frontal eye ield, maps onto
Behavioral Neurology & Neuropsychiatry, eds. David B. Arciniegas, C. Alan Anderson, and Christopher M. Filley.
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the dorsal caudate nucleus. In contrast, the ventral
architectonic trend, which originates in the ventral
orbital region and extends to the ventral portion of
the frontal eye ield, maps onto the ventro-medial
portion of the caudate and adjacent portion of nucleus
accumbens (NAc). Closely connected cortical areas
send converging projections into the striatum [8, 9].
Early experimental observations supported a
role for discrete dorsal and ventral frontostriatal
systems in cognition and behavior. hus, lesions or
electrical stimulation of the dorsolateral prefrontal
(DLPF) cortex or of the anterodorsal head of the
caudate nucleus, to which this region projects,
produce deicits in delayed response and delayed
alternation tasks [10, 11]. In contrast, lesions or
electrical stimulation of either the orbitofrontal (OF)
cortex or of the ventrolateral head of the caudate
result in deicits in object alternation or response
inhibition paradigms [12]. Disruption to discrete
cognitive processes following striatal injury can be
interpreted as the “downstream” interruption of
anatomically congruent outlow from the frontal
cortex [12–14].
Frontal-subcortical circuits:
shared anatomy
Basic circuit structure
he following principal circuits may now be recog-
nized: a motor circuit that originates in the supple-
mentary motor area (SMA), an oculomotor circuit
originating in the frontal eye ields, and three primary
circuits/circuit networks mediating cognitive, behav-
ioral, and afective functions [1–3]. Of these, the DLPF
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 Section I: Structural and Functional Neuroanatomy
Figure 5.1. The general structure shared by
Frontal cortex all frontal-subcortical circuits (direct
connections).
Striatum
Globus pallidus/
substantia nigra
Thalamus
circuit mediates “executive functions,” i.e., the organi-
zation of information to facilitate a response. he lat-
eral OF (LOF) circuit is involved with integration of
limbic and emotional information into goal-directed
and contextually appropriate behavioral responses.
Finally, the rostromedial limbic network consists of the
medial OF (MOF) circuit, which facilitates integration
of information pertaining to emotions, and the linked
anterior cingulate (AC) circuitry. he AC network is
involved primarily in motivational mechanisms but
also, through the activity of its subgenual portion, in
mood regulation.
All circuits share a basic anatomy, with an ori-
gin in the frontal lobes and sequential projections
to the striatum (caudate, putamen, or ventral stria-
tum), GP/SN, and then to speciic thalamic nuclei,
with a inal link back to the frontal lobe (Figure 5.1).
he circuits have two pathways: (1) a direct pathway,
featuring a monosynaptic link between the striatum
and GP interna (GPi)/SN pars reticulata (SNr) com-
plex, and (2) an indirect pathway that projects from
striatum to GP externa (GPe), linking to GPi/SNr
via the subthalamic nucleus [3] (Figure 5.2). Both
direct and indirect circuits project to the thalamus;
the direct pathway disinhibits the thalamus, whereas
the indirect pathway inhibits it. he relative inlu-
ence of the two pathways therefore determines the
inal output of the circuit. All circuits thus share com-
mon structures and are parallel and contiguous, but
remain largely segregated anatomically, despite the
progressive focusing of succeeding projections onto
smaller numbers of neurons. hus, the DLPF cor-
tex projects to the dorsolateral region of the cau-
date nucleus, the LOF cortex projects to the ventral
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Figure 5.2. The general anatomy of the direct and indirect
frontal-subcortical pathways. 1 – Excitatory cortico-striatal fibers. 2 –
Direct loop’s inhibitory striato-pallidal (GPi) fibers. 3 – Indirect loop’s
inhibitory striato-pallidal (GPe) fibers. 4 – Indirect loop’s inhibitory
GPe-subthalamic nucleus fibers. 5 – Indirect loop’s excitatory
subthalamic-GPi/SNr fibers. 6 – Inhibitory outflow from GPi/SNr to
specific thalamic regions. 7 – Excitatory fibers returning from
thalamus to cortex (shown for convenience in contralateral
hemisphere). Excitatory fibers are glutaminergic, inhibitory fibers
mediated via GABA. Note: these circuits are unilateral: each set of
projections from cortex to subcortical structures to cortex remains
within a single hemisphere. In this figure, projection from cortex to
subcortical structures as well as projections between subcortical
structures are illustrated on the left half of the figure whereas
projections from thalamus to cortex are illustrated on the right side
of the figure. This does not suggest that these circuits cross from
one hemisphere to the other; instead, they are diagrammed in this
manner here in order to preserve readability of the figure.
caudate area, and the MOF and AC circuitry connects
to the medial striatal/NAc region. Similar anatomic
arrangements are maintained in the GP and thalamus
(Figure 5.3).
Open-loop elements
While each circuit comprises a closed loop of anatom-
ically segregated dedicated neurons, open-loop ele-
ments support the functional connectivity of FSCs.
Circuit structures receive projections from non-circuit
cortical areas, thalamic and amygdaloid nuclei, and
also project to regions outside the circuits. Brain
regions linked by these aferent or eferent projec-
tions are functionally related [15, 16]. Circuits medi-
ating limbic functions, for example, have connections
to other limbic areas whereas those involved with
executive functions (EFs) interact with brain struc-
tures involved with cognition. In this manner, circuits
integrate information from anatomically disparate but

Figure 5.3. The segregated anatomy of the frontal-subcortical
circuits: dorsolateral prefrontal (horizontal stripes), lateral
orbitofrontal (stippling), and anterior cingulate/medial orbitofrontal
(cross-hatched) circuits in the striatum (top), pallidum (center), and
mediodorsal thalamus (bottom).
functionally related brain regions, the cascade of the
closed circuit constituting the eventual efector mech-
anism [17].
Organization of individual
frontal-subcortical circuits
The motor circuit
he motor circuit originates from neurons in the SMA,
premotor cortex, motor cortex, and somatosensory
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Chapter 5: Frontal-subcortical circuits
cortex [1, 3]. hese areas project principally to the
putamen and thence to ventrolateral GPi, GPe, and
caudolateral SNr. he GP connects to ventral lateral,
ventral anterior, and centromedian nuclei of the tha-
lamus whose major eferents are to the SMA, premo-
tor cortex, and motor cortex, completing the circuit.
hroughout the circuit, the discrete somatotopic orga-
nization of movement-related neurons is maintained,
although information processing in the circuits is not
strictly sequential [3].
The oculomotor circuit
he oculomotor circuit originates in the frontal eye
ield, Brodmann’s area (BA) 8, as well as prefrontal and
posterior parietal cortex and connects sequentially to
the central body of the caudate nucleus, dorsomedial
GPi and ventrolateral SNr, ventral anterior and medial
dorsal thalamic nuclei, and back to the frontal eye ield
[1–3].
The dorsolateral prefrontal circuit
Figure 5.4 illustrates the anatomy of the direct path-
ways of two of the behaviorally relevant FSCs. he
DLPF circuit originates in BA 9 and 10 (areas recip-
rocally connected with adjacent BA 46) on the lat-
eral surface of the anterior frontal lobe. Neurons in
these regions project to the dorsolateral head of the
caudate nucleus [18], thence to the lateral aspect of
the mediodorsal GPi and rostrolateral SNr via the
direct pathway [19]. he indirect pathway projects
sequentially to the dorsal GPe, lateral subthalamic
nucleus [20] and GPi/SNr. Output from the basal gan-
glia projects to the ventral anterior and mediodorsal
(parvocellular portion) thalamic nuclei [21–23]. he
circuit is closed by projections from these thalamic
regions back to the dorsolateral frontal lobe [24, 25].
The lateral orbitofrontal circuit
he LOF circuit originates in the lateral orbital gyrus
of BA 11 and the medial inferior frontal gyrus of
areas 10 and 47 [26]. Multiple sensory inputs, includ-
ing olfactory, gustatory, visceral, somatic, and visual
aferents converge on this region. Projections are to
the ventrolateral caudate and dorsal edge of the NAc
[27] with subsequent links to the most medial portion
of the mediodorsal GPi and to the dorsomedial SNr
[28]. he ventrolateral caudate also sends an indirect
loop through the dorsal GPe to the lateral subthalamic
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 Section I: Structural and Functional Neuroanatomy
Figure 5.4. The anatomy of the direct pathways of the
dorsolateral prefrontal and lateral orbitofrontal circuits. NAc, nucleus
accumbens; GPi, globus pallidus, internal segment; SNr, substantia
nigra, pars reticulata; VAmc, ventral anterior nucleus, magnocellular
portion; VApc, ventral anterior nucleus, parvocellular portion; MDpc,
mediodorsal nucleus, parvocellular portion; MDmc, mediodorsal
nucleus, magnocellular portion; MDpl, mediodorsal nucleus,
paralaminar portion.
nucleus, thence to GPi and SNr [20]. Neurons are sent
from the GPi and SNr to the medial section of the mag-
nocellular division of the ventral anterior thalamus as
well as the paralaminar portion and inferomedial sec-
tor of the magnocellular division of the mediodorsal
thalamus [18, 21, 29]. he circuit then closes with pro-
jections from these thalamic regions to the LOF cortex
(Figure 5.4).
The rostromedial limbic circuitry
Emotional, motivational, and afective information
processed by the basal ganglia is represented in the ros-
tromedial limbic circuitry arising from the orbital and
medial prefrontal cortex. Closely integrated anatom-
ically and functionally, this comprises AC circuitry
(including that related to the subgenual cingulate) and
the MOF circuit (Figure 5.5).
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The anterior cingulate and subgenual
cingulate circuits
here are two major subdivisions of the AC cortex,
which subserve distinct functions (Figure 5.6). he
dorsal cognitive division (BA 24, 24a’–b’ and 32’),
also referred to as the cognitive efector region [26],
is more developed in its cytoarchitecture than the
rostral-ventral division, and is part of a distributed
attentional network which has reciprocal interconnec-
tions with DLPF cortex (BA 46/9), parietal cortex (BA
7), and premotor and supplementary motor areas [30–
32]. his region is connected via the Muratof bundle
to dorsal and medial portions of the head and body of
the caudate nucleus [7, 18, 33], with succeeding pro-
jections to the GPi/SNr and thence to the parvocellu-
lar mediodorsal thalamus as well as the ventral ante-
rior and midline/intralaminar thalamic nuclei [25, 34].
hese thalamic regions then reconnect with the cogni-
tive division of AC via the inferior thalamic peduncle
and anterior internal capsule (Figure 5.5). Functions
of the cognitive efector region include modulation of
attention or executive functions by inluencing sensory
or response selection; monitoring competition, com-
plex motor control, motivation, novelty, error detec-
tion and working memory; and anticipation of cogni-
tively demanding tasks [35].
he rostral-ventral afective division of the AC
cortex comprises the subgenual cingulate (BA 25),
adjacent (caudal) portions of BA 32 (pregenual cingu-
late), area 33, and the rostral portions of AC cortex,
subcallosal areas 24a and 24b (Figure 5.6). hese
regions project to the medial part of the ventral stria-
tum [18, 36], which includes the ventromedial caudate,
ventral putamen [37], and core and shell of the NAc
(the shell region receiving projections especially from
the subgenual cingulate [38]). Projections from the
ventral striatum and NAc core innervate the rostrome-
dial GPi and ventral pallidum (VP, the portion of the
globus pallidus inferior to the anterior commissure)
as well as the rostromedial SNr and ventral tegmental
area (VTA) [39–41]. he NAc shell projects to the
VP, VTA and SNpc, allowing this region to inluence
dopaminergic inputs to other parts of the striatum
[41]. he VP and GPi then project to the dorsal portion
of the magnocellular mediodorsal thalamus, midline
and intralaminar (parafascicular) thalamic nuclei
[23, 40, 42–44], with closed-loop projections back
to the anterior and subgenual cingulate (Figure 5.5)
[25, 34].

While the OF cortex mediates information con-
cerning the internal environment, the AC circuitry
facilitates the intentional selection of environmental
stimuli based on their internal relevance [45], thereby
mediating motivated behavior. hrough both its dor-
sal and rostral-ventral divisions and their connec-
tions with motor pathways, lateral PFC, and aferents
from the midline thalamus and brainstem (includ-
ing arousal systems), the AC cortex is ideally posi-
tioned to participate in the willed control of behavior
[46].
he subgenual cingulate component of AC
circuitry (Figures 5.5 and 5.6) includes substan-
tial predominantly ipsilateral connections with
the amygdala [44], MOF cortex (see below), other
portions of both anterior and posterior cingulate,
anterior insula, medial temporal lobe, hypothalamus,
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Chapter 5: Frontal-subcortical circuits
Figure 5.5. The anatomy of the direct
pathways of the rostromedial limbic
circuits. VP, ventral pallidum; Pf,
parafascicular nucleus. Other
abbreviations follow Figure 5.4. The pale
arrows indicate open-loop connections
between engaged thalamic nuclei and the
lateral orbitofrontal and dorsolateral
prefrontal cortices.
periaqueductal gray and dorsal brainstem [47]. he
strong projections to the dorsal raphe suggest a role
in regulating the overall function of the serotonergic
system [44]. With its major outlow to autonomic,
visceromotor, and endocrine systems [30, 35, 48], this
circuit has been implicated in salience monitoring of
emotional and motivational information, mediation
of emotional and autonomic response to socially
signiicant or provocative stimuli, afective processing,
and inhibitory control [35, 49, 50].
The medial orbitofrontal circuit
Arising from the gyrus rectus (areas 14r, 14c) and
related areas on the medial orbital surface, includ-
ing BA 11m, 13a and 13b, the MOF cortex is
integrated anatomically and functionally with the
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 Section I: Structural and Functional Neuroanatomy
Figure 5.6. The medial surface of the right hemisphere (anterior
towards the left), showing a schematic representation of
cytoarchitectural areas of the anterior cingulate cortex. The areas
forming the dorsal cognitive division and the skeletomotor effector
region (striped) are outlined by solid lines, the rostro-ventral
affective division areas being outlined by dotted lines.
infracallosal AC and subgenual cingulate (“visceral
efector region”) [27, 51], with which it shares sub-
cortical projections (Figure 5.5). Sequentially, these
links are to the ventromedial caudate and NAc (core);
ventromedial pallidum and dorsomedial SNr; magno-
cellular portions of the ventral anterior and medial
mediodorsal thalamic nuclei, with a closed-loop pro-
jection back to the MOF cortex [18, 23, 38–40, 52,
53]. In addition to its connections with the infra-
callosal cingulate, the MOF cortex has strong recip-
rocal connections with the medial portion of the
basal and magnocellular division of the accessory
basal amygdala, as well as with the ventromedial tem-
poral pole and rostral (agranular) insula [51, 54–
57]. he subgenual cingulate provides motivational
input to gustatory, olfactory and alimentary infor-
mation from anterior insular processing converging
on the MOF cortex. Considering its robust connec-
tions with high-order sensory association cortices and
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Figure 5.7. The direct and indirect frontal-subcortical pathways.
Filled arrows represent inhibitory (GABAergic) pathways; open
arrows, excitatory (glutamatergic) pathways. Note that
dopaminergic input from the substantia nigra pars compacta and
ventral tegmental area is inhibitory, via D2 receptors, to
GABA/enkephalin neurons projecting to the indirect pathway, and
excitatory, via D1 receptors, to GABA/substance P neurons
projecting to the direct pathway.
specialized connections with the amygdala, the MOF
circuit may serve both as an integrator of visceral
drives as well as a sensor of information pertaining to
emotions [51, 58].
Neurochemical organization
Shared neurochemical organization
Common to all circuits is an origin in the frontal lobes
with excitatory glutamatergic ibers that terminate in
the striatum (caudate, putamen, and ventral striatum).
hese striatal cells then project inhibitory gamma-
aminobutyric acid (GABA) ibers both to neurons in
the GPi/SNr (direct loop connection) and to the GPe
(indirect loop connection). Via the indirect loop, the
GPe projects inhibitory GABA ibers to the subthala-
mic nucleus which then connects with the GPi/SNr
through excitatory glutamatergic ibers [2, 59]. he
direct pathway expresses dopamine (DA) D1 recep-
tors and utilizes substance P with its GABA projec-
tion to the pallidum while the indirect loop receives
its dopaminergic inluence via D2 receptors and com-
bines GABA with enkephalin [60]. he GPi/SNr then
project inhibitory GABA ibers to speciic thalamic
targets, which complete the circuit by sending a inal
excitatory connection to the cortical site of the circuit’s
origin in the frontal lobe (Figure 5.7).
 Chapter 5: Frontal-subcortical circuits

Circuit-discrete neurochemical organization retrorubral region (cell group A8) and the VTA (A10
cell group) innervate the entire striatum, thereby inlu-
he striatum is organized as two separate systems, the
encing each of the FSCs. his provides an anatomic
striosomes and the matrix. hese elements are dif-
basis for the multifaceted efects of dopaminergic
ferentiated by their distinct ontological, connectional,
agents on motor activity, motivation, thought, and
and chemical characteristics [61]. Relative to matrix
behavior. Relecting DA’s modulatory function, DA-
neurons, striosomal cells mature earlier, have lower
containing axon terminals synapse directly on stri-
concentrations of DA, serotonin and acetylcholine,
atal output neurons, many on the necks of dendritic
and have high concentrations of limbic-associated
spines. he VTA is the primary source of DA for the
membrane protein [62, 63]. Striosomes receive dense
ventral striatum, prefrontal cortex, and limbic targets.
orbitofrontal and insular input and have high levels
he nigra has inhibitory connections, via D1 receptors,
of D1 receptors, with dopaminergic projections from
with the indirect portions of the FSCs and excitatory
the ventral tier of the substantia nigra pars compacta
connections, via D2 receptors, with the direct circuits
(SNpc). In contradistinction, matrix cells receive afer-
(see Figure 5.2). Representing an important conver-
ents predominantly from the sensorimotor cortex and
gence within the otherwise segregated FSCs, the SNpc
express primarily D2 receptors, with dopaminergic
receives difuse input from the limbic circuits, provid-
input from the dorsal tier of the SNpc [64]. he matrix
ing a means for limbic emotional input to inluence
stains selectively for adenylate cyclase whereas the
both motor activity and cognition.
phosphoinositide system is selectively concentrated
in the striosomes of the medial and ventral striatum
[65]. GABAergic output from the striosomes is to the The cholinergic system
medial portion of the SNpc, dedicated to the OF cir-
Cholinergic input to the basal ganglia and most of
cuit, whereas the GABAergic output of the matrix is to
the thalamus is derived from the pedunculopontine
the GPe, GPi, and SNr.
nucleus and laterodorsal tegmentum of the brainstem.
Mirroring the circuit-discrete neurochemical orga-
Second, portions of the mediodorsal, ventroanterior,
nization of the striatum, the NAc region of the ventro-
and reticular nuclei of the thalamus, as well as lim-
medial striatum is also divided into two functionally
bic structures and neocortex, receive cholinergic input
distinct components with discrete histochemistries.
from the basal forebrain, which includes the septum,
hus, the core or dorsolateral portion of the NAc,
diagonal band of Broca, and the nucleus basalis of
which receives projections from the MOF and AC
Meynert [66]. Acetylcholine facilitates thalamic acti-
cortex, is distinguished by a lower concentration of
vation of the cortex and also assists in the septal hip-
mu opiate receptors and a higher concentration of
pocampal pathway supporting mnemonic function.
calcium-binding proteins. his region is virtually iden-
Within the striatum, there are important inter-
tical histologically to the ventromedial caudate. In dis-
actions between the cholinergic and dopaminergic
tinction, the shell or ventromedial portion of NAc,
systems. Activation of D2 DA receptors, located
which receives a segregated pool of projections from
on cholinergic interneurons, inhibits acetylcholine
the subgenual cingulate (BA 25) and pregenual cin-
release, whereas D1 receptor agonists enhance acetyl-
gulate (BA 32), is inversely devoid of calcium-binding
choline release. Conversely, acetylcholine enhances
proteins and replete with mu opiate receptors [38].
DA release via nicotinic and muscarinic receptors
located on presynaptic DA terminals [67].
Neurotransmitter systems inluencing
frontal-subcortical circuits The norepinephrine system
Processing of the detailed information contained in
Noradrenergic neurons from the locus coeruleus
the FSCs is modulated by input from dopaminergic,
project to the entire cortex and hippocampus as well
cholinergic, noradrenergic, and serotonergic systems.
as cerebellum and spinal cord. A ventral pathway orig-
inating below the locus coeruleus innervates the brain-
The dopamine system stem and hypothalamus. Beta 1 receptors are present in
Dopaminergic projections from the SNpc (primarily the cerebral cortex while beta 2 receptors predominate
cell group A9), the caudal extension of SNpc into the in the cerebellum. Electrophysiologic studies suggest

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 Section I: Structural and Functional Neuroanatomy
that a balance between norepinephrine and DA lev-
els may set the signal-to-noise ratio of the attentional
system [68, 69], which incorporates a distributed net-
work involving the cingulate, DLPF, and inferior pari-
etal cortices [70].
The serotonergic system
he serotonin 5-HT1 receptor is the most abundant
serotonin receptor in the basal ganglia. 5-HT1C recep-
tors are very dense in the globus pallidus and mod-
erately dense in the caudate, putamen, and accum-
bens regions, which also contain intermediate levels of
the 5-HT2 receptor. he highest densities of 5-HT1D
receptors are found in the basal ganglia and SN. 5-HT3
is enriched in the striatal matrix and is the most abun-
dant receptor in the ventral striatum [62, 71] and other
areas functionally related to the AC circuit, including
hippocampus, septum, and amygdala. his receptor is
linked to a ligand-gated cation channel that also mod-
ulates the release of acetylcholine and DA.
Mechanisms for interactions between
motor and behavioral circuits
Although the FSCs remain largely segregated through-
out their course, several mechanisms may allow for
complex interactions between motor and behavioral
systems [52]. At higher levels, thalamic relay nuclei
form not only reciprocal but also non-reciprocal corti-
cal connections, linking multiple frontal cortical areas,
allowing for information low between cortical cir-
cuits [23] (see Figure 5.5 as an example). At the level
of the striatum, striosomes interdigitate with the sur-
rounding matrix, so that matrix-striosome borders
may serve as interfaces where the sensorimotor sys-
tems of the matrix interact with the striosomal pro-
cessing of prefrontal and limbic inputs [72]. Linkage
between the sensorimotor and limbic related regions
of the striatum can also occur through corticonigral
inluences on the striatum and through the overlap-
ping eferent striatal projections to the SN. Whereas
the main output from the striatal matrix is to the GPi
and SNr, striosomes project primarily to the dopamin-
ergic SNpc. In this manner, the ventral striatum is able
to exert a global regulatory inluence on the dopamin-
ergic input to the entire striatum. his provides an
important mechanism for limbic “motivational” input
to modulate motor behavior and provides for the
“anchoring” or reinforcement of successful experience.
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A recent re-evaluation [41] supports the original
concept of the NAc part of the ventral striatum as
a functional interface between the limbic and motor
systems [73]. hus, its aferent connections position
this region as a site for integration of signals with
emotional content (amygdala); contextual information
(hippocampus); motivational signiicance (dopamin-
ergic inputs); information about the state of arousal
(midline thalamus); and executive/cognitive informa-
tion (prefrontal cortex) [41]. Outputs of the ventral
striatum include projections to the brainstem dorsal
raphe, the midbrain parabrachial region and to the
habenula, which may also play an important role in
integration of the motor and behavioral circuits [74].
he habenula, which receives input from the anterior
thalamic nuclei and GP, projects to the rostral mid-
brain with connections to the dopaminergic VTA and
to the serotonergic dorsal raphe. Both of these cell
groups project difusely to multiple tiers of the FSCs.
In particular, the limbic ventral striatal and habenular
input to the dorsal raphe suggests another important
mechanism for cross-talk between circuits and for lim-
bic modulation of motor function [75].
Also providing for circuit linkage between
limbic and motor systems are the cholinergic
interneurons of the caudate and putamen and somato-
statin/neuropeptide Y-containing interneurons that
ramify between compartments [76]. Diferences
in peptide cotransmitters and in monoaminergic,
GABAergic and glutamatergic synaptic receptor
expression at subcortical sites (see above) provide
other mechanisms for diferential response within
FSCs and for a complex interplay between these
circuits [75].
From a neurophysiologic perspective, integration
of the temporal coincidence of processing in FSCs,
occurring particularly at the level of the thalamus [74],
may also contribute importantly to linkage and synthe-
sis of information between FSCs.
Prototypical frontal-subcortical
circuit syndromes
hree principal frontal lobe symptom complexes are
recognizable: a medial frontal-AC syndrome with apa-
thy and diminished initiative; an OF syndrome with
prominent disinhibition and irritability; and a DLPF
syndrome, with neuropsychological deicits involving

EFs. Supporting the concept of circuit-speciic behav-
ioral syndromes, similar disorders have been observed
with lesions of subcortical structures of these circuits.
The anterior cingulate syndrome: akinetic
mutism and abulia
Akinetic mutism (AM) [77] represents a wakeful state
of profound apathy, with indiference to pain, thirst,
or hunger, and absence of motor or psychic initiative,
manifested by lack of spontaneous movement, absent
verbalization, and failure to respond to questions or
commands. he term abulia, derived from the Greek
boul, or will [78] refers to a similar but less severe psy-
chomotor syndrome, encompassing lack of spontane-
ity, apathy, and paucity of speech and movement.
Akinetic mutism has been described with AC
lesions, craniopharyngiomas, obstructive hydro-
cephalus, tumors in the region of the third ventricle,
and other conditions involving the ventral striatum
(NAc and ventromedial caudate), ventral GP, and
medial thalamus [79]. Although reports of the clinical
consequences of lesions restricted to limbic structures
of the basal ganglia are scarce [57], larger lesions that
include both ventral striatum and more dorsal areas of
the basal ganglia are associated with severe apathetic
states. In a review of patients with focal lesions of
the basal ganglia [80], abulia occurred in 18 of 64
(28%) small and large caudate lesions sparing the
lentiform nucleus, 15 of which were unilateral. Abulia
was also seen in six of 22 (27%) restricted GP lesions,
all bilateral, but did not accompany isolated lesions of
the putamen (a link in the motor circuit). Lesions of
the mediodorsal and anterior nuclei of the thalamus
may also result in apathy [81–83].
Unilateral lesions of the AC cortex produce
transient AM [84] while the most dramatic examples
of AM follow bilateral AC lesions [85], particularly
lesions that extend from the cognitive efector region
posteriorly into the skeletomotor efector division of
the cingulate [51], a region connected with primary
motor and SMA [29, 86]. here are non-overlapping
representations for hand movements and speech
within the AC cortex, relecting separate AC motor
channels [29]. While there are no published reports
of isolated speech deicits with restricted cingulate
lesions, bilateral lesions in monkeys to the rostral
AC cortex, located around the genu of the corpus
callosum, signiicantly impair spontaneous vocaliza-
tion whereas deicits involving limb movements in
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Chapter 5: Frontal-subcortical circuits
humans have been associated with lesions afecting
both rostral and caudal cingulate motor areas [46].
Relecting reciprocal connections between the AC
cortex and the MOF cortex [51], orbito-medial pre-
frontal cortical lesions may also result in severe forms
of apathy [46, 57]. Data suggest a functional contin-
uum along the rostral-caudal axis of medial frontal
lobe regions from cognitive and emotional functions
to motor functions devoted to self-initiation of action
and thought [57]. Relecting this continuum, a sim-
ilar disorder afecting the “drive” for willed move-
ment and speech (“motor neglect”) has been seen in
patients with lesions of the SMA [87–89]. Such patients
exhibit initial global akinesia and neglect, which then
lateralizes in unilateral cases. Primarily part of the
motor circuit, the SMA also receives reciprocal pro-
jections from the AC (area 24c’). Positron emission
tomography (PET) studies in humans have shown that
regional cerebral blood low in the rostral SMA and
adjacent mesial frontal cortex is associated with the
self-generation of motor actions but not with exter-
nally cued ones [90].
Conceptually distinct, DLPC circuit lesions
may produce a “cognitive” rather than “emotional-
afective” form of apathy, cognitive inertia resulting
from diiculties in elaborating the plan of actions
necessary for ongoing or forthcoming behavior [57].
his relects links between layer V of the dorsal
cingulate cortex and supericial layers of the DLPF
cortex (see Figure 5.5), a powerful avenue of commu-
nication between cognitive and motor systems [31].
hus, while the AC can be considered broadly as the
cortical gateway for limbic motivation to inluence
goal-directed behavior [26], subtypes of apathy may
be deined based on the connections of the cingulate
with other regions [30, 91].
The orbitofrontal syndrome: personality and
emotional changes
he OF cortex is the neocortical representation of the
limbic system [92] and is involved in the determination
of the appropriate time, place, and strategy for envi-
ronmentally elicited behavioral responses. Lesions in
this area disconnect frontal monitoring systems from
limbic input [93]. In particular, visceral sensory input
to OF cortex is normally used to provide informa-
tion about the internal milieu and guide bodily reac-
tions to that status (“somatic marker hypothesis”) [94].
Lesions of the LOF may then result in an “interoceptic
67
 Section I: Structural and Functional Neuroanatomy
agnosia,” which may provide the basis for the variety of
emotional and social deicits commonly observed with
such lesions.
Impulsivity and behavioral disinhibition are
the hallmark symptoms of OF lesions. Common
manifestations include lack of judgment and social
tact, improper sexual remarks or gestures and other
antisocial acts [95, 96]. Patients may exhibit inappro-
priate jocularity (witzelsucht) or emotional lability
and irritability, trivial stimuli oten resulting in abrupt
outbursts of anger [97]. Inattention, distractibility,
and increased motor activity may be seen, as well
as hypomania or mania. MOF lesions are associated
with abnormal autonomic responses to socially
meaningful behavior and diiculty extinguishing
unreinforced behavior, which correlate with antiso-
cial acts [98]. Large bilateral OF lobe lesions may
result in enslavement to environmental cues, with
automatic imitation of the gestures of others, or
enforced utilization of environmental objects [99].
Typically, however, patients with OF dysfunction
exhibit a dissociation between impairment of behav-
ior necessary for activities of daily living and normal
performance on psychological tests sensitive to frontal
lobe dysfunction, such as the Wisconsin Card-Sorting
Test (WCST) [93, 100, 101].
Although the OF syndrome usually follows bilat-
eral OF cortex injury [93, 101], unilateral lesions
may produce a similar disorder [102]. Patients with
ventral caudate lesions may also appear disinhibited,
euphoric, impulsive and inappropriate, reproducing
the corresponding OF lobe syndrome [103]. It is likely
that the early appearance of comparable personal-
ity alterations in Huntington’s disease (HD) relects
the involvement of medial caudate regions receiving
OF and AC circuit projections [104]. Similarly, mania
(see below) may result not only from injury to MOF
cortex and caudate nuclei but also from lesions to
the right thalamus [105–108]. Mixed behavioral syn-
dromes commonly accompany focal lesions of the GP
and thalamus, relecting the progressive spatial restric-
tion of the parallel circuits at these levels [109].
The dorsolateral prefrontal syndrome:
executive function deicits
Both experimental and clinical data link the DLPF cor-
tex and its subcortical connections with EFs. Exec-
utive functions incorporate anticipation, goal selec-
tion, planning, monitoring, and use of feedback to
68
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adjust task performance. Patients with restricted DLPF
cortex lesions have diiculty focusing and sustaining
attention, generating hypotheses, and maintaining or
shiting sets in response to changing task demands,
as required by the WCST [110]. Associated features
include reduced verbal and design luency, impair-
ment of memory search strategies and of organiza-
tional and constructional strategies on learning and
copying tasks, and motor programming disturbances.
Similar syndromes have been reported in patients
with lesions of subcortical structures of the DLPF
circuit [109]. hus, impairment on tests of memory
and EF, including the WCST, have been noted in
patients with dorsal caudate lesions [103], bilat-
eral GP hemorrhages [111] and bilateral or let
paramedian/medio-dorsal thalamic infarction [112,
113]. Executive functions deicits and other features of
“subcortical” dementia [114] in such conditions as HD,
Parkinson’s disease (PD), progressive supranuclear
palsy (PSP), Wilson’s disease, neuroacanthocytosis
and other subcortical disorders are believed to relect
involvement of the DLPF circuit as it projects through
the basal ganglia [109, 115–117].
Movement disorders and
frontal-subcortical circuits
Basal ganglia dysfunction frequently results not only
in disorders of movement, but also in alterations in
intellectual function, mood, personality, and behav-
ior. he nature and severity of such changes relect
the extent of involvement of the behaviorally relevant
FSC structures, which project through the caudate and
ventral striatum, rather than the motor circuit, which
projects to the putamen. Diseases afecting primar-
ily the putamen, such as PD, thus exhibit less strik-
ing intellectual and emotional alterations than dis-
eases that afect primarily the caudate, such as HD. In
PD, executive dysfunction and dementia is associated
with involvement of the medial substantia nigra and
VTA, which project to the caudate nucleus and medial
frontal cortex, and is not present when changes are
conined to the lateral nigral neurons, which project to
the putamen [118]. While patients with PSP, a hypoki-
netic disease, exhibit hypoactive behaviors such as
apathy, patients with HD, a hyperkinetic syndrome,
exhibit predominantly hyperactive behaviors, such as
agitation, irritation, euphoria, or anxiety. Such behav-
iors may result from an excitatory subcortical output
through the medial and OF cortical circuits [119].

Subcortical dementia and
amnestic syndromes
Subcortical dementia is generally characterized by
neuropsychological deicits typical of DLPF circuit
lesions [114, 120]. Such deicits may be combined with
amnesia, however, when subcortical lesions involve the
thalamus [109]. he thalamus is poised at the interface
of the FSCs and the medial temporal-limbic circuit
(incorporating the hippocampus, fornix, hypothala-
mus, and thalamus). While the FSCs mediate memory
activation and search functions, the medial temporal-
thalamic circuit mediates memory storage (both recall
and recognition) [113].
A related syndrome involving amnesia, luctuat-
ing inattention, apathy and psychomotor retardation,
may occur with capsular genu infarction. It has been
inferred that such lesions interrupt the inferior and
anterior thalamic peduncles, functionally deactivating
the ipsilateral frontal cortex [121]. he anterior thala-
mic peduncle conveys reciprocal connections between
the thalamic dorsomedial nucleus and the cingulate
gyrus, as well as the prefrontal and OF cortex; the infe-
rior thalamic peduncle carries ibers which connect
with the OF, insular and temporal cortices, and amyg-
dala. Injury to these tracts thus produces a thalamo-
cortical disconnection syndrome combining amnesia
with FSC circuit deicits.
Frontal-subcortical circuit dysfunction
associated with neuropsychiatric
disorders
Obsessive-compulsive disorder and
Tourette syndrome
Convergent data, including ethological and exper-
imental observations [122, 123], clinicopathologic
indings [124, 125], behavioral observations [126],
magnetic resonance imaging (MRI) [127–129] and
PET studies [130–133] have implicated the basal gan-
glia and related cortical and thalamic structures in
the pathobiology of both obsessive-compulsive dis-
order (OCD) and Gilles de la Tourette syndrome
(TS). he neurobiologic substrates for these disor-
ders include both corticostriatothalamocortical cir-
cuits and monoaminergic pathways that modulate the
activity of these circuits [134–139].
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Chapter 5: Frontal-subcortical circuits
In OCD, functional imaging studies have shown
increased glucose metabolism or blood low in the
medial and OF cortex and AC gyrus, in the cau-
date nucleus, and, to a lesser extent, in the thalamus.
his has suggested aberrant OF and limbic circuits as
pathophysiologic mechanisms in OCD [130, 140, 141].
he prevailing theory is that the observed cortical, stri-
atal, and thalamic overactivity in OCD results from a
relative imbalance favoring the direct versus indirect
pathways within this circuitry, leading to failed striato-
thalamic inhibition [140, 142, 143].
In TS, studies have suggested both anatomi-
cal and functional disturbances in basal ganglia-
thalamocortical circuits. Difusion-tensor (DT)-MRI
has shown smaller let caudate and bilateral thala-
mic volumes in TS children compared with con-
trols, tic severity being positively correlated with
group diferences in radial water perfusion in the
right thalamus [144]. Resting state luorodeoxyglucose
(FDG)–PET has suggested reduced activity in a limbic
basal ganglia-thalamocortical network, with covariate
decreases in caudate and thalamic metabolism asso-
ciated with smaller reductions in lentiform and hip-
pocampal activity. he expression of this metabolic
pattern correlated closely with ratings on the Tourette
Syndrome Global Scale [133]. Tic severity in TS has
also been correlated with hypoperfusion of the let
caudate and cingulate gyrus [145] and diferences in
D2 DA receptor binding in the head of the caudate
nucleus has predicted diferences in tic severity within
monozygotic twin pairs [146].
he preceding observations link tics to the “asso-
ciative” (non-motor) neural circuits in which the cau-
date nucleus (not the putamen) is a key node, and
has suggested that dopaminergic dysfunction in the
caudate may underlie the integrated ideational-motor
symptomatology of TS and the “compulsive” quality
of tics [146]. Other studies have supported the impor-
tance of sensory elements in tic pathophysiology. hus,
functional MRI (fMRI) has identiied a brain network
of paralimbic and sensory association areas which are
activated before tic onset, analogous to movements
triggered internally by unpleasant sensations, such as
itch and pain [147].
It has been hypothesized that discrete sets of stri-
atal neurons may become overactive in TS, and that
the production of simple tics (via motor circuit activa-
tion), complex tics (via activation of premotor areas,
SMAs, and cingulate motor areas), and compulsions
(with OF circuit involvement) might be determined
69
 Section I: Structural and Functional Neuroanatomy
by the speciic FSC that is impacted [148]. Consistent
with this hypothesis, increasing complexity of cogni-
tive and behavioral symptoms in TS has been associ-
ated with increasing, apparently dysfunctional synap-
tic activity within the medial, lateral, and caudal OF
cortices on FDG-PET scans [149].
PET data have also suggested an alteration of
cortical–subcortical interactions in TS, with increased
metabolic rates in frontal motor regions and decreases
in glucose utilization in paralimbic prefrontal cor-
tices and in the ventral striatum [131]. Ventral stri-
atal dysfunction has also been shown with PET using
[11C] dihydrotetrabenazine (DTBZ) to label the type
2 vesicular monoamine transporter, TS patients show-
ing increased DTBZ binding in the ventral striatum
relative to controls [150]. Pertinent to such indings,
and by analogy with animal models of stereotypy, it has
been postulated that the pathophysiology of TS may
be related to an imbalance between dorsal and ventral
striato-pallidal systems, perhaps arising from strioso-
mal dysfunction [148, 151, 152].
Attention-deicit hyperactivity disorder
Characterized by inattention, impulsivity and hyper-
activity, attention-deicit hyperactivity disorder
(ADHD) shares clinical features with other neu-
ropsychiatric conditions, including the OF and
DLPF syndromes. It has been hypothesized that the
neural substrates of ADHD involve disturbances in
frontal-subcortical interactions involving arousal and
reward systems [153] which are driven primarily by
dopaminergic activity and modulated by adrener-
gic and serotonergic mechanisms. Dysfunction of
fronto-striatal type in ADHD has been inferred from
neuropsychological studies [154–156], the pattern of
cognitive deicits resembling those found in “striatal”
disorders such as TS [157] and HD [158].
Both MRI and quantitative morphologic stud-
ies have shown smaller caudate volumes in ADHD
patients compared with controls [159, 160]. Xenon
inhalation and emission tomography have revealed
striatal hypoperfusion in childhood ADHD, partially
reversible by methylphenidate [161], and fMRI has
also shown diferences between ADHD children and
controls in frontal-striatal function and its mod-
ulation by methylphenidate [162]. Performance on
response inhibition tasks have correlated signiicantly
with fMRI measures of the prefrontal cortex and cau-
date nuclei, predominantly in the right hemisphere
70
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[163]. Comparable PET studies have shown caudate
hypofunction in response-inhibition paradigms [164].
he relevance of these indings may relate to the inte-
gration of the caudate nuclei not only in the DLPF
(executive function) circuit but also in the OF circuit,
which subserves delayed responding in primates.
Impaired signaling of delayed rewards is also inte-
gral to ADHD and has been linked to disturbances
in motivation processes. his implicates the AC cir-
cuit [165], which links the ventral striatum, espe-
cially NAc [166] to both AC and OF cortex [167].
Dysfunction in NAc in ADHD is consistent with the
observed variability in response to psychostimulant
therapy in afected children [168]. A dual pathway
hypothesis [169, 170] proposes that alterations within
the DLPF circuit, modulated by mesocortical DA,
and the AC/reward circuit, modulated by mesolim-
bic DA, constitute discrete neuropsychologic bases for
dissociable psychological processes in ADHD, lead-
ing to executive/inhibitory deicits and delay aversion,
respectively.
It is likely that both DA and norepinephrine
actions contribute to the therapeutic efects of stim-
ulants in patients with ADHD. Electrophysiologic
studies in animals suggest that DA decreases “noise”
through modest levels of stimulation of D1 receptors,
abundantly present in prefrontal cortex, while nore-
pinephrine enhances “signals” through post-synaptic
alpha2A-adrenoceptors in prefrontal cortex [70, 171].
Alpha2-receptor stimulation increases delay-related
neuronal iring [172], the cellular measure of working
memory and behavioral inhibition.
Depression
Both structural and functional brain-imaging stud-
ies have supported an association between lesions
disrupting frontostriatal or paralimbic pathways
and depressed mood. OF-inferior prefrontal cortex
metabolism is lower in depressed when compared
with non-depressed HD patients [173], and PD
patients with depression show signiicantly lower
metabolic activity both in the orbital-inferior frontal
cortex and head of the caudate nucleus compared
with those without depression [174]. his is consistent
with pathological evidence in depressed, cognitively
impaired parkinsonian patients of disproportionate
degeneration of DA neurons in the VTA, a system that
is linked to motivation and reward (see below) [152]
and which projects to OF and prefrontal cortex.

Frontolimbic DA deiciency may underlie clinical
similarities between the anhedonia and “psychomo-
tor retardation” (PsR) of major depression and the
lethargy of thought, afect, and movement that consti-
tutes “bradyphrenia” in PD [175]. Anhedonia has been
linked with novelty reward, mediated by dopaminergic
projections to the ventral striatum, and reward scores
in response to a dopaminergic challenge correlate with
activity changes in ventrolateral prefrontal cortex and
caudate/putamen on fMRI in major depression [176].
Depressed patients with PsR show decreased presy-
naptic DA function in the let caudate [177] and ele-
vated putaminal D2 receptor binding [178]. he DA
metabolite homovanillic acid (HVA) is diminished
in depressed patients with PsR [179] and levodopa
improves the PsR of major depression [180]. Further-
more, clinical improvement in depressed patients with
PsR parallels the dopamimetic speciicity of the antide-
pressants administered [181]. However, DA agonists
alone have limited efect on depressive symptoms in
PD [182] and cerebrospinal luid (CSF) HVA levels do
not correlate with mood in PD [183].
Based on convergent indings from patients with
primary and secondary depression, a model of depres-
sion has been proposed which implicates failure of the
coordinated interactions of a distributed network of
cortical-limbic pathways [184]. In this model, a dorsal
(“attention-cognition”) compartment which includes
both neocortical (DLPF) and superior limbic (AC) ele-
ments is postulated to regulate attentional and cogni-
tive aspects of depression, such as apathy, psychomo-
tor slowing, and impaired attention and EF. A ventral
(“vegetative-circadian”) compartment, which is com-
posed of limbic, paralimbic, and subcortical regions
(anterior insula, hippocampus, subgenual cingulate,
and hypothalamus) is recognized as mediating circa-
dian and vegetative aspects of the illness, including
sleep, appetite, libidinal, and endocrine disturbances.
Both PET and fMRI studies have revealed decreased
function of dorsal regions, such as the ventral AC cor-
tex, and increased limbic metabolism and activation
in depression [185], while fMRI has shown reciprocal
efects of antidepressant treatment on activity and con-
nectivity in these regions [186]. he rostral anterior
(pregenual) cingulate is isolated from both the ventral
and dorsal compartments based on its cytoarchitec-
tural characteristics and its reciprocal connections to
both compartments and may serve an important reg-
ulatory role in mediating interactions between them
[187].
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Chapter 5: Frontal-subcortical circuits
An important role for the subgenual cingulate (BA
25) in depression was irst provided by the observa-
tion of metabolic change (overactivity) in this region
in treatment-resistant depression, which uniquely pre-
dicted antidepressant response [184, 185]. Deep brain
stimulation (DBS) of white matter tracts adjacent to
the subgenual cingulate was subsequently shown to
efectively reverse symptoms in otherwise treatment-
resistant depression [188, 189] (see below). Distur-
bances in the subgenual cingulate circuit have been
linked also with the rapid mood shits in bipolar dis-
order, and may have a role in the pathophysiology of
OCD [190, 191].
Mania and the lateralization
of emotional behavior
Afective response to brain injury may relect the
hemisphere involved. hus, crying is more common
in patients with let hemispheric lesions, while laugh-
ter occurs with right-sided lesions [192]. Let frontal
and let basal ganglia infarctions are most likely to
be associated with depression [103, 193] and in PD
depression is more common with right hemiparkin-
sonism (let striato-frontal dysfunction) [194]. Con-
versely, mania frequently results from right-sided tha-
lamic or right medial diencephalic lesions that may
disrupt hypothalamic circuits or disturb modulating
transmitters traversing the medial forebrain bundle
[106, 107]. Mania has also been observed in patients
with MOF cortex lesions and caudate dysfunction in
basal ganglia disorders such as HD [193, 195]. he
increase in appetite drives that oten accompanies
mania has suggested underlying hyperfunctioning of
the paleocortical paralimbic belt [51].
Whereas depressed patients show bilateral tem-
poral hypometabolism on FDG-PET scans, patients
with mania exhibit unilateral, right-sided tempo-
ral hypometabolism [194]. A diferential biochemi-
cal response to injury in the two hemispheres may
contribute to the polarity of the expressed mood
disorder. hus, right but not let frontolateral cor-
tical lesions in rat models produce hyperactivity,
widespread depletion of brain norepinephrine, and an
increased turnover of DA in the NAc. Correspond-
ingly, right but not let hemispheric stroke in humans
leads to an increase in 5-HT-2 serotonin receptor bind-
ing in both temporal and parietal cortex [194].
71
 Section I: Structural and Functional Neuroanatomy
Bipolar disorder
Vulnerability to bipolar disorder (BD) is linked with
the gene coding for diacylglycerol (DAG) kinase
eta, an enzyme that metabolizes DAG, inhibiting
phosphatidylinositol-protein kinase C intracellular
signaling [196–198]. he phospho-inositol second
messenger system is concentrated in striosomes in
limbic brain regions. his chemoarchitectural disor-
ganization in BD is consistent with a disease model
that involves dysfunction within both striato-thalamo-
prefrontal networks and limbic modulating regions
[199–202]. Support for this model includes MRI
abnormalities in prefrontal cortical areas, striatum and
amygdala, and activation diferences in anterior limbic
regions shown by functional imaging studies. Specif-
ically, reduced ventral and orbital prefrontal activ-
ity and increased amygdala activity has been noted,
both during episodes and in remission. his suggests
that dysregulation of mood in BD may result from
diminished prefrontal modulation of subcortical lim-
bic structures [199, 203].
Schizophrenia
Failures of stimulus iltering and gating in
schizophrenic patients have been linked with
abnormalities of cortico-striato-pallido-thalamic
circuitry [204–206]. Evidence implicating the DLPF
circuit in schizophrenia includes the similarity of
observed neuropsychological deicits to symptoms
associated with DLPF lesions, decreased regional
metabolism and blood low activation, disruption of
cortical subplate activity (required for connectivity
of thalamocortical neurons), and decreases in major
components of the GABA cortical inhibitory system
[207–209].
he DLPF cortex is part of a task-related fronto-
parietal neuronal network, the activity of which
is anticorrelated with a “default” network that is
normally active at rest. he latter network, which
includes medial prefrontal and posterior cortices,
has been linked with internally generated “stimulus-
independent” thought as well as self-monitoring and
salience monitoring [210]. Using a brain-imaging
technique based on low-frequency luctuations of
the blood oxygen level-dependent (BOLD) signal,
schizophrenic patients exhibited striking deicits in
regions associated with the default network, including
the posterior cingulate and medial prefrontal regions
[211]. his supports earlier data showing deicits in
72
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small interneurons in cingulate and prefrontal cor-
tices in schizophrenic patients [212]. It has been sug-
gested that if the default network in schizophrenia
is associated with decreased communication between
the medial prefrontal and posterior cingulate regions,
self-monitoring systems may become split, leading to
the perception that auditory thoughts are externally
produced [213].
Substance abuse disorders and impulse
control disorders
he principal components of the drug reward circuit
are the A10 dopaminergic cell group of the VTA, lim-
bic structures of the basal forebrain (OF cortex, AC
cortex and ventral striatum, particularly NAc) and
the dopaminergic connection between the VTA and
basal forebrain limbic system (mesocorticolimbic DA
system). his network links substance addiction to
brain motivational and reward systems. Linked brain
regions include the amygdala, which provides afective
salience, and the hippocampus, relaying contextual
memories. While early phases of drug-seeking behav-
ior and addiction are probably characterized by inter-
actions between these systems, the dorsal striatum
appears to become involved in later phases when drug-
taking has become a habit [214–218]. Other compo-
nents of the drug reward circuit are the opioid peptide,
GABA, glutamate, and serotonin systems, and other
neural inputs that interact with the VTA and basal
forebrain [219–221].
Impulse control disorders (ICDs), including patho-
logical gambling, compulsive sexual behavior, and
compulsive buying, are characterized by a failure to
resist an impulse, drive, or temptation to perform a
typically pleasurable activity. A range of ICDs occur at
a greater frequency in PD than in the general popula-
tion and are linked particularly with the use of direct
DA agonist drugs [222]. Compared with levodopa,
DA agonists have signiicantly greater occupation of
D3 DA receptors which are concentrated in limbic
brain regions, including ventral striatum, with high-
est concentrations in the shell of the NAc [223]. Even
within the dorsal striatum, the D3 receptor is primar-
ily localized to the patch/striosome compartment that
is anatomically connected to limbic structures [224,
225]. his and other evidence suggests that patholog-
ical gambling and other ICDs in PD may result from
dopaminergic overstimulation of a relatively preserved

mesocorticolimbic DA pathway in predisposed indi-
viduals [226].
Although considered by some as OCD-spectrum
disorders, there is broader support for categorizing
ICDs as behavioral addictions [227–230]. Supporting
such a model, a single photon emission computed
tomography (SPECT) study of PD patients with patho-
logical gambling showed resting state overactivity in a
right hemisphere network that included the OF cortex,
hippocampus, amygdala, insula, and ventral pallidum
[226]. he ventral pallidum is part of the limbic cir-
cuitry (see above) and is implicated in the modulation
of hedonic responses to natural and drug rewards,
and subsequent reward seeking-motivated drive
[231].
Therapeutic interventions for
frontal-subcortical circuit disorders
Pharmacologic interventions
The dorsolateral prefrontal syndrome:
executive dysfunction
In PD, speciic executive functions, including working
memory, cognitive sequencing, and attention shiting,
may respond at least partially to dopaminergic thera-
pies [232, 233]. his relects the combined impact in
PD of caudate nuclear DA deiciency, which creates a
partial “disconnection syndrome” of subcortical origin
[234] and a lesser reduction of DA in the DLPF cor-
tex [235]. However, incomplete reversal of cognitive
deicits with DA agonists is typically noted in PD [233,
236], relecting the importance of non-dopaminergic
neuronal dysfunction, especially cholinergic dysfunc-
tion, in PD dementia.
Executive dysfunction in PD may also be ame-
liorated by the selective norepinephrine reuptake
inhibitor atomoxetine [237]. his is consistent with
psychopharmacologic and anatomical studies, which
implicate the noradrenergic as well as the dopamin-
ergic system as an important modulator of frontal
lobe function [172, 238, 239]. Noradrenergic agents
may also ameliorate executive dysfunction in a vari-
ety of other clinical states. he alpha-2 adrenergic ago-
nists clonidine and guanfacine both enhance working
memory performance in aged monkeys [240, 241] and
cognitive tasks mediated by prefrontal cortex, such as
Trails B, Word Fluency and Stroop tasks, are improved
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Chapter 5: Frontal-subcortical circuits
by clonidine in patients with schizophrenia and Kor-
sakof ’s syndrome [242–244]. In patients with demen-
tia of the frontal lobe type, EF may be selectively
enhanced by the alpha-2 adrenergic antagonist ida-
zoxan [245].
In ADHD and TS, a variety of agents having impor-
tant efects on the noradrenergic system, dopaminer-
gic system, or both, may ameliorate features of both
DLPF (attentional/executive) and OF (inhibitory) dys-
function (see below). Such drugs include selegiline,
stimulant medications, low-dose tricyclic antidepres-
sants, clonidine, and guanfacine [246–251].
The anterior cingulate syndrome: akinetic
mutism and apathy
In animals, a syndrome similar to akinetic mutism
(AM) was irst demonstrated by bilateral or unilateral
injection of 6-hydroxydopamine into the SN, VTA, or
nigrostriatal tract within the medial forebrain bundles
of the lateral hypothalamus [252–254]. hese behav-
ioral deicits could be reversed by the direct DA agonist
apomorphine [255, 256], and blocked by pretreatment
with the DA receptor antagonist spiroperidol [257].
Similarly, in an early clinical report, AM follow-
ing surgical removal of a tumor from the anterior
hypothalamus responded to the DA receptor agonists
lergotrile and bromocriptine but not to the pre-
synaptic dopaminomimetics carbidopa/levodopa or
methylphenidate [258]. his suggested that akinesia
in this setting resulted from loss of dopaminergic
input to AC or other corticolimbic structures rather
than to the striatum. Clinico-pathologic correlations
have subsequently suggested that isolated damage
to any of the projections of brainstem dopaminergic
nuclear groups may result in AM [259]. Chronic AM
secondary to mesencephalic infarction, destroying
ventral tegmental DA neurons at their site of origin,
may also be reversed with DA agonists [260]. Where
DA receptors have been lost, however, as in patients
with lesions involving the AC gyri, response to direct
DA agonists is typically poor.
While requiring conirmation, a recent report sug-
gests that AM may respond successfully to intramus-
cular olanzapine [261], a drug which may also ame-
liorate negative symptoms in schizophrenia. In addi-
tion to blockade of DA D2-receptors in the mesolimbic
pathway, olanzapine blocks serotonin 5HT2A recep-
tors, leading to disinhibition of D2 receptors and
enhanced DA release in the mesocortical pathway.
73
 Section I: Structural and Functional Neuroanatomy
A preponderance of the latter action might explain
observed increases in levels of DA in the medial pre-
frontal cortex in response to olanzapine administra-
tion [261].
Dopaminergic agents may also aford a clinically
signiicant and sustained improvement in apathetic
states encountered in a variety of neuropsychiatric
disorders including Wilson’s disease, PD and human
immunodeiciency virus (HIV)-associated dementia,
subcortical strokes and anterior communicating artery
aneurysm [209, 262–266]. Efective agents in such con-
ditions may include direct DA agonists, particularly
pramipexole and ropinirole, which have some selec-
tivity for D3 receptors, amantadine, selegiline, bupro-
pion, amphetamine, and methylphenidate.
Apathy is the most commonly observed behav-
ioral disturbance in Alzheimer’s disease (AD) and is
associated with AC hypoperfusion [267]. he doc-
umented improvement in AD-related apathy with
cholinesterase inhibitor therapy [268] may relect par-
tial correction of cholinergic disconnection of AC
structures. he latter include the basal nucleus of
the amygdala [51], innervated by cholinergic projec-
tions from basal forebrain structures, and the mid-
line thalamic nuclei which receive input both from the
basal forebrain and from cholinergic pedunculopon-
tine projections that form part of the ascending retic-
ular activating system. Cholinesterase inhibitors may
also ameliorate apathy in traumatic brain injury [269,
270].
The orbitofrontal syndrome: personality change
A variety of pharmacologic agents may ameliorate, at
least partially, the disinhibited behavior of the patient
with OF circuit dysfunction [271]. Such drugs include
the major and minor tranquilizers, propranolol, bus-
pirone, carbamazepine, sodium valproate, lithium,
clonidine, and selective serotonin reuptake inhibitors
(SSRIs).
Robust data, including studies using 5HT1B
receptor gene knockout mice [272], link behavioral
disinhibition with central serotonergic deiciency
[273–276]. he eicacy of serotonergic agonists,
including luoxetine and clomipramine, for impulsive,
aggressive, or sexually disinhibited behaviors [275,
277, 278] may relate to the density of serotonin
receptors in the ventral striatum and other limbic
brain regions. Certain 5-HT1A agonists (“serenics”)
exert a dose-dependent decrease in aggression with
a concomitant increase in social interest in animal
74
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paradigms [279]. In man, both propranolol and pin-
dolol have agonist efects at limbic somato-dendritic
5-HT1A receptors at dosages used in the treatment of
aggressive behavior [280–282] and the partial 5-HT1A
agonist buspirone may also be efective in the treat-
ment of aggression in a variety of neuropsychiatric
conditions. In addition to their dopaminergic activity,
neuroleptics may have a serotonergic mode of action
in the treatment of impulsive aggression by binding
to and down-regulating the 5-HT2 receptor [274],
which is represented in intermediate levels in the NAc
and striatum. Lithium’s mood-stabilizing action may
be mediated by efects both on the serotonin system
and on phosphoinositide [283, 284], which is selec-
tively concentrated in striosomes of the medial and
ventral striatum [64], regions which receive dense OF
input.
Clonidine is an alpha-2 noradrenergic agonist,
which reduces central noradrenergic transmission by
stimulating presynaptic autoreceptors [285, 286]. Its
eicacy for OF syndrome is exempliied by the report
of a patient with OF dysfunction including mania sec-
ondary to bilateral OF contusions [105]. he rapid
response to clonidine in this case was attributed to
reduction of noradrenergic overactivity induced by
lesions of prefrontal areas projecting to noradrenergic
systems [287] which, in turn, innervate and modulate
prefrontal cortex [238, 239, 288]. Clonidine may also
successfully ameliorate symptoms characteristic of OF
circuit dysfunction, including distractibility, impulsiv-
ity and emotional lability, in children with ADHD and
TS [246, 248, 289].
Several classes of drugs thus have the potential to
favorably inluence symptoms of OF circuit dysfunc-
tion, relecting serotonergic, dopaminergic, and nora-
drenergic modulation of functions of the OF cortex
and connected brain regions.
Obsessive-compulsive disorder
Serotonin is robustly implicated in the pathophysiol-
ogy of OCD and SSRIs are efective treatments for
this condition [290, 291]. he serotonergic innerva-
tion of the striatum is dense and is localized to those
basal ganglia regions which receive input from the
OF and AC cortices, via the ventromedial caudate
nucleus head and ventral striatum, respectively [62].
Glucose metabolic rates in the head of the caudate
nucleus diminish when OCD is treated successfully
with SSRIs, a result that may be attributable to the
action of serotonin aferents from the dorsal raphe on

caudate interneurons [130, 292]. he thalamofrontal
pathways, lesioned at diferent sites in anterior capsu-
lotomy and subcaudate tractotomy (see below), con-
tain both serotonergic and dopaminergic tracts [293].
he improvement in OCD that may be observed with
adjunctive DA receptor blockers, particularly in TS
[294], relects the functionally coupled interactions
between brain 5-HT and DA systems [295].
Neurosurgical interventions
Obsessive-compulsive disorder and Tourette syndrome
Anterior cingulotomy or limbic leucotomy have been
used successfully in the past to treat disabling ritualis-
tic behaviors in selected patients with OCD [296] and
TS [297–299]. he rationale for lesioning the anterior
cingulate in these disorders derives from its role as the
conduit for frontal cortex input to the Papez circuit and
limbic system [300, 301], while limbic leucotomy selec-
tively targets both anterior cingulate cortex and fron-
tothalamic projections. he beneicial efect of anterior
capsulotomy in OCD [302] would also be predicted by
the proposed models, as this procedure severs a path-
way for reciprocal tracts interconnecting the OF cor-
tex with the dorsomedial and related thalamic nuclei
[143, 303]. More recently this has been replaced efec-
tively by DBS of the ventral anterior internal capsule
[304], a procedure which has been shown to modu-
late activity in the dorsal and ventral striatum, subgen-
ual cingulate cortex, MOF cortex, and thalamus [191,
305, 306]. his demonstrates how the stimulation of a
single region can generate complex changes through-
out the interconnected network [303]. Electrode place-
ments in ventral caudate, STN, zona incerta (near the
STN), and ventral striatum have also been efective for
refractory OCD [98].
Deep brain stimulation of several targets has
been used efectively to treat severe pharmacologi-
cally refractory TS. hese include the nucleus ven-
tralis oralis, the motor and limbic portions of GPi
[307–311], NAc/anterior limb of the internal capsule
[312], and the centromedian parafascicular complex
of the median and intralaminar thalamic nuclei [311,
313–317], a unit which has signiicant projections into
motor striatum as well as limbic and associative areas
of the subthalamic nucleus [318]. Targeting of these
sites oten results in at least 70% long-term reductions
in vocal or motor tics, with accompanying disappear-
ance of the preceding sensory urge.
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Chapter 5: Frontal-subcortical circuits
Depression
Five potential targets have been identiied in the litera-
ture as potential surgical targets for DBS in treatment-
resistant depression: (1) ventral striatum/NAc; (2) sub-
genual cingulate cortex (area 25); (3) inferior thalamic
peduncle; (4) rostral cingulate cortex (area 24a); and
(5) lateral habenula [319]. Although it has been sug-
gested that the subgenual cingulate region may prove
to be most efective, based on its anatomic connectiv-
ity [189], further studies are required in larger patient
groups to assess both the safety and eicacy of these
targets.
Addiction
In the past, procedures such as cingulotomy, hypotha-
lamotomy, and resection of the substantia innominata
and NAc have been recommended as treatments for
severe addictive disorders. With expansion of knowl-
edge concerning its neurobiology, refractory addictive
states might also prove amenable to DBS of relevant
brain targets [320].
Conclusion
Frontal-subcortical circuits (FSCs) are efector mech-
anisms that allow the organism to act on the envi-
ronment. he DLPF circuit allows the organization
of information to facilitate a response; AC circuitry
is required for motivated behavior; the LOF cir-
cuit allows the integration of limbic and emotional
information into contextually appropriate behavioral
responses; and mood regulation and integration of
information pertaining to emotions are functions,
respectively, of the subgenual cingulate and MOF cir-
cuits. Correspondingly, impaired EFs, apathy, impul-
sivity, and depression are hallmarks of FSC dysfunc-
tion. Movement disorders typically involve not only
the motor circuit but also other FSCs as they project
through the basal ganglia. A variety of other neuropsy-
chiatric disorders may result from disturbances that
impact directly or indirectly on the integrity or func-
tioning of these circuits. Examples of such conditions
include OCD and TS, ADHD, substance abuse and
impulse control disorders, BD and schizophrenia. he
circuits involve a number of transmitters, receptor sub-
types, and second messengers that can be manipu-
lated pharmacologically. In addition, for an increas-
ing number of conditions, such as disabling OCD, TS
and depression, discrete neurosurgical approaches to
75
 Section I: Structural and Functional Neuroanatomy

speciic FSC dysfunctions are being explored more
actively, with advances in DBS showing particular
promise.
Acknowledgments
Special thanks are ofered to John Nyquist for prepara-
tion of the igures.
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