All vPFC axons enter the UF immediately adjacent to their cortical region. Within the UF, fiber bundles from each injection site split into three groups, a medial, dorsal, and lateral group. Each of these groups of fibers contains subsets of axons that travel in different WM tracts, the specifics of which depend on the location of the injection site (, , ). Axons from all vPFC areas travel in the UF, corpus callosum, cingulum bundle, superior longitudinal fasciculus, IC, EC, and EmC. In addition, fibers from specific vPFC regions also travel in the middle longitudinal fasciculus, ventral amygdalofugal pathway, stria terminalis, and the medial forebrain bundle. Most subcortical fibers pass through the EC initially before breaking into separate bundles, including those that travel to the striatum, or enter the internal capsule.
Figure 2 Photomicrographs and schematics of vmPFC and mOFC pathways. a, vmPFC axons leave the injection site traveling dorsally and divide into the dorsal and lateral bundles. Some dorsal fibers enter the emerging corpus callosum. The medial bundle remains ventral (more ...)
Figure 3 Photomicrographs of cOFC and lOFC pathways. a, lOFC fibers dividing into medial (UF), dorsal, and lateral bundles. Fibers in the dorsal bundle pass directly through the frontal white matter to reach the corpus callosum and superior longitudinal fasciculus (more ...)
vmPFC and mOFC
Axons in the medial bundle from both the vmPFC and mOFC travel through the UF to terminate in multiple vmPFC areas. Other axons from vmPFC and mOFC leave the UF to join the medial forebrain bundle (). The medial forebrain bundle splits into fibers that terminate in the preoptic region and hypothalamus, enter the fornix, or sweep ventral and lateral into the amygdalofugal pathway to terminate in the amygdala (). The dorsal bundle travels through the UF, with some fibers terminating in the dorsal vmPFC. Other axons continue dorsally in the UF to merge with fibers of the corpus callosum, cingulum bundle, and superior longitudinal fasciculus. Axons from anterior, medial regions travel posteriorly through the UF to reach the corpus callosum and cross to the contralateral hemisphere. The lateral bundle splits almost immediately into dorsal and lateral groups (). Axons in the dorsal group travel through the EC to terminate in the striatum, enter the IC, or continue in the EC to the claustrum. The lateral group follows the UF before splitting into UF fibers traveling to the lateral OFC and temporal cortex and fibers that enter the EmC that terminate in the insula.
Axons from both the vmPFC and mOFC enter the IC ventrally. As they travel posteriorly, fibers move dorsally within small fascicles that are embedded within the VS and anterior commissure (). Within the IC, a dorsal group of vmPFC fibers crosses through the AC, sweeping through the inferior thalamic peduncle to the midline and the medial dorsal thalamic nuclei. Those en route to the brainstem (periaqueductal gray, midbrain, and dorsal pons), however, travel in the fascicles ventral to the AC. At the level of the AC, a small group of ventral vmPFC fibers leaves the IC and enters the stria terminalis, providing an additional pathway to the amygdala. mOFC fibers en route to the thalamus travel dorsal to the vmPFC thalamic fibers, passing through or just dorsal to the AC. Axons traveling to the brainstem pass through or ventral to the AC. In addition, some fibers from the mOFC also descend into the pontine nucleus, whereas axons from vmPFC do not. Those fibers are located between mOFC thalamic and brainstem axons in the IC.
In summary, projections from vmPFC and mOFC follow similar routes with three notable exceptions: (1) vmPFC fibers within the IC and corpus callosum travel ventrally to those from mOFC within the same structure; (2) mOFC sends fibers into the pontine nucleus, but the vmPFC does not; and (3) some vmPFC fibers traveling to the amygdala enter the stria terminalis, but the mOFC fibers do not.
cOFC and lOFC
Like those from vmPFC and mOFC, cOFC and lOFC fibers also use the medial bundle through the UF to innervate other vPFC regions () and the dorsal bundle to reach the corpus callosum, cingulum bundle, and the superior longitudinal fasciculus. However, the dorsal bundle that carries fibers from these cortical areas does not travel within the UF to reach these WM tracts. Rather, it cuts directly through the UF and travels in the overlying frontal WM before turning medially to the corpus callosum, cingulum bundle, or the superior longitudinal fasciculus (, ). An important exception is axons from the posterior cOFC. These fibers must travel either medially or laterally within the UF to circumvent the lateral ventral ventricle and striatum. Thus, fibers from the medial posterior cOFC travel medially within the UF to follow the trajectory of mOFC fibers to the cingulum bundle and corpus callosum. In contrast, axons from lateral posterior cOFC regions travel in the opposite direction to arch laterally around the striatum.
cOFC and lOFC fibers travel through the EC and enter the IC laterally (). Within the IC, axons to the thalamus are dorsal to those terminating in the brainstem. cOFC fibers are located ventral and somewhat medial to lOFC axons (, ). As fibers travel posteriorly, axons from both regions move ventrally such that, at the level of the AC, cOFC thalamic fibers are just dorsal to the AC, with its brainstem axons positioned ventrally, some of which are embedded within the AC (, ). In contrast, both thalamic and brainstem lOFC fibers travel dorsal to the AC (, ).
Unlike axons from the vmPFC and mOFC, cOFC and lOFC fibers travel in the EC for some distance posteriorly before forming small fascicles. These fascicles travel medially through the putamen and globus pallidus to take a position ventral and lateral to those already within the IC (). Fibers from these fascicules continue to the subthalamic nucleus, midbrain, and dorsal pons. In some cases, a few fibers reach dorsal brainstem regions by a small bundle of fibers traveling through the thalamus. In addition, some small bundles enter the ventral amygdalofugal pathway or terminate in the hypothalamus. Finally, a group of axons continues in the EC to the claustrum. Axons in the lateral bundle from both the cOFC and lOFC include the UF fibers traveling to the temporal cortex and those that enter the EmC to terminate in the insula ().
Rules of organization
The uncinate fasciculus
Although the UF is known for its frontotemporal lobe connection (Schmahmann and Pandya, 2006
; Petrides and Pandya, 2007
), these frontotemporal axons do not form a distinct bundle within the ventral plate of the vPFC. Rather, fibers that pass through here also connect distal regions of the vPFC. Thus, fibers from each cortical region travel anteroposteriorly and mediolaterally through this WM tract, terminating throughout the vPFC. In addition, vPFC axons use this bundle as a conduit for channeling fibers to other WM tracts. For example, vmPFC and mOFC fibers travel for some distance through the UF to reach the corpus callosum, cingulum bundle, and superior longitudinal fasciculus (, ). Thus, the UF contains three components: connections between the vPFC and temporal lobe, between distal parts of vPFC regions, and between the vPFC and other WM bundles. Although these three components are intertwined at the base of the vPFC, the projection to the temporal cortex is most isolated laterally as the fiber bundle turns into the temporal lobe.
Figure 4 Schematic and photomicrographs illustrating the complexity of the uncinate fasciculus. a, Schematic illustrating vPFC axons crossing through the UF to reach other fiber tracts. Note that the medial and central parts of the UF have more crossing fibers (more ...) Internal capsule
Axons from the vPFC occupy the most ventral part of the rostral anterior limb of the IC. Importantly, this includes the small fascicules embedded within the VS itself and fibers running ventral to and through the anterior commissure perpendicularly (, ). Fibers within the IC are organized according to destination. Overall, thalamic IC fibers from each cortical region travel dorsal to their brainstem axons (). Moreover, corticopontine fibers are dorsal to those terminating in the subthalamic nucleus, midbrain, and medulla fibers, but they are ventral to corticothalamic axons. Thus, there is a dorsoventral IC organization from each vPFC area: the dorsal fibers en route to the thalamus, followed by pontine fibers, with the most ventral group traveling to the other brainstem regions. The latter form small bundles, some of which initially course through the VS and globus pallidus before joining the IC ().
Figure 5 Coronal sections illustrating the different positions of thalamic versus brainstem mOFC fibers (yellow–tan) and lOFC (dark blue–light blue) entering and traveling through the IC. Brainstem fibers (tan and light blue) travel ventral to (more ...) vPFC position
The medial/lateral position within the vPFC dictates both the route that fibers take to enter major WM tracts as well as the position they take within some of those tracts. Both vmPFC and mOFC fibers travel in the medial bundle to the amygdalofugal pathway via the medial forebrain bundle. In contrast, the more lateral OFC regions first use the dorsal bundle to enter the EC and then form fascicules that are embedded within the basal forebrain, some of which enter the amygdalofugal pathway. Only axons from the vmPFC use the stria terminalis as an additional pathway to the amygdala and the bed nucleus stria terminalis.
Fibers from the vmPFC and mOFC travel for some distance through the UF to reach the corpus callosum and cingulum bundle. In contrast, the more lateral regions cut directly across the UF to travel in the frontal WM to reach these bundles (, , ). vPFC axons also enter the IC with a medial to lateral topography. The vmPFC and mOFC fibers enter the IC (and striatum) ventrally, directly through the subcaudate WM, whereas the cOFC and lOFC pass through the EC and enter the IC from a more lateral and dorsal position. The vmPFC and mOFC fibers move dorsal through the IC as they travel posteriorly. In contrast, fibers from the more lateral cortical regions move ventrally (, ).
Within specific WM pathways, the medial/lateral cortical position also dictates the position within the tract. Fibers from all vPFC areas enter the internal capsule anteriorly and follow a medial/lateral, ventral/dorsal topography. Thus, fibers from medial areas travel ventral to axons from lateral vPFC regions (). Axons from vmPFC regions remain within small fascicules embedded within ventral striatum or AC. In contrast, axons from the cOFC and lOFC are located dorsally in the IC. Thus, fibers are stacked in the internal capsule with the vmPFC axons ventral or embedded within the AC and the lateral OFC regions positioned dorsal to the AC. This topography is maintained (albeit with a great deal of compression) as they enter the inferior thalamic peduncle.
Figure 6 vPFC fibers through internal capsule. a, Overview of the internal capsule in the parasagittal plane. b, Enlargement of the anterior internal capsule showing the dorsal/ventral topography rostral to the AC. Note the medial/lateral topography, with medial (more ...)
Axons traveling in the corpus callosum are organized similarly. Axons from more medial vPFC areas travel ventral to those fibers originating in lateral regions. Thus, vmPFC and mOFC fibers are ventral to cOFC, etc. (). However, in most association WM tracts, such as the cingulum bundle or the UF, it was difficult to discern a topographic arrangement. Thus, axons from different vPFC regions appeared to overlap extensively as they travel to their destinations.
Figure 7 Organization of vPFC pathways in the corpus callosum. a, Sagittal view of 3D model of vPFC pathways in corpus callosum. Fibers originating from more lateral vPFC regions (blue) cross dorsally to fibers from more medial vPFC areas (red). b, Micrograph (more ...)
In summary, important characteristics and rules that govern vPFC fiber trajectories are as follows: (1) vPFC fibers travel primarily in the amygdalofugal pathway to reach the amygdala. (2) vPFC efferent fibers to subcortical thalamic and brainstem targets pass through small fascicles embedded in the VS and anterior commissure, suggesting that these bundles are part of the IC. Moreover, within the IC, there is a topographic organization of thalamic and brainstem fibers from each vPFC region, such that each set of descending fibers occupies a specific position within the IC. (3) Importantly, it is not possible to separate a specific frontal-temporal set of fibers from the axons connecting the vPFC or those that join other WM bundles with the exception of the most lateral part. Thus, the vPFC uses the UF to connect not only the vPFC–temporal cortices, but also vPFC–vPFC areas and as a conduit to reach other WM tracts. (4) Finally, the medial/lateral position of the vPFC fiber origin affects the route those efferents take to their terminals, allowing predictions about where fibers from each area likely travel.
Deep brain stimulation sites
The most effective SCGwm contacts (1 and 2) are at the border between the SCG and the inferior rostral gyrus (Hamani et al., 2009
). Contact 1 is within the inferior rostral gyrus, contact 2 is within the SCG, and contracts 0 and 3 are ventral and dorsal, respectively. Placing the electrode representation in the same position in the 3D monkey model shows that contacts 0–2 involve (1) all connections from vmPFC areas adjacent to the electrode contacts (both cortical and subcortical projections) (), (2) UF fibers from non-adjacent vmPFC and mOFC as they travel medially to other vPFC areas and/or enter the medial forebrain bundle (), (3) a subset of cOFC fibers traveling medially to innervate medial PFC areas (), (4) axons traveling from the contralateral vmPFC and mOFC (not illustrated), and (5) a subset of anterior vmPFC and mOFC en route to the corpus callosum through the UF. Contact 3 involves primarily fibers in the corpus callosum. In addition, this site captures a subset of fibers traveling from the mOFC and posterior cOFC to the cingulum bundle and superior longitudinal fasciculus.
Figure 8 Modeled DBS electrodes at the SCGwm and VC/VS targets. a, The SCGwm target involves all fibers from cortical areas adjacent to the electrode, including descending projections. b, SCGwm target also involves other vPFC fibers that pass through the site, (more ...)
The VC/VS electrode is implanted at an angle, positioning contact 0 most posteriorly. Each contact activates a different subset of corticothalamic and brainstem fibers (). Axons from the vmPFC and mOFC pass through contact 0, most traveling to the brainstem, with few to the thalamus (). In contrast, contact 1 captures fibers from the vmPFC traveling to the thalamus, but not those to the brainstem. Contact 1 involves some cOFC brainstem axons, but few thalamic cOFC fibers (). Contact 2 captures more mOFC thalamic fibers, but none traveling to the brainstem. cOFC brainstem fibers also pass through this site (). Contact 3 captures both brainstem and thalamic cOFC fibers and brainstem fibers from lOFC, but few, if any, of the vmPFC, mOFC, or lOFC thalamic fibers ().
DBS field modeling reveals additional important detail about pathways likely to be captured by DBS. Stimulation parameters scaled to 40% of those in humans give an effective stimulation diameter of 3.10 mm (). Contact 0 captures fibers traveling to the thalamus from both the vmPFC and mOFC (). Contact 1 includes some cOFC thalamic fibers and a few lOFC brainstem fibers (). At contact 2, some fibers from the vmPFC and more of those from the mOFC and cOFC traveling to the thalamus will be included along with fibers from the brainstem component from the mOFC and the lOFC (). Finally, contact 3 captures most cOFC thalamic fibers and some brainstem axons (). In addition, some mOFC thalamic fibers are captured and both thalamic and brainstem lOFC axons.
Finally, contact 0 at the nucleus accumbens site is placed in the shell of the VS and contact 1 in the core. In contrast to the SCG and VC/VS, stimulation of the ventral 2 contacts is located primarily in gray matter, but within corticostriatal fibers. Contacts 2 and 3 are within the VC and likely involve similar cortical connections as those described above for the VC/VS target.