If you ever said to yourself, “I wonder whether the human mid- and posterior ventrolateral prefrontal cortex has a homologue in the monkey, and what features of its cytoarchitecture or subcortical connectivity may differentiate it from other regions of PFC” then this post is for you.
Otherwise, move along.
The mid/posterior ventrolateral prefrontal cortex (pars opercularis and pars triangularis, or Brodmann’s Areas 44 and 45) is very clearly different, both anatomically and functionally, from its anterior sector (which involves the pars orbitalis, or Brodmann’s Area 47). It is also probably (though not yet certainly) true that these sections of posterior ventrolateral prefrontal cortex are functionally distinct from the inferior frontal junction area (i.e., at the junction of the inferior frontal sulcus with the precentral sulcus, and therefore dorsal to the pVLPFC areas I will be focusing on; it is probably most similar to “Walker’s Area 45” or the “frontal eye field area 45” in the monkey, which has more dorsal sources of parietal input than the more ventral pVLPFC area of interest here).
This area is also differentiable from more anterior (BA 47/12) and more dorsal (46v) areas by virtue of its connectivity with the superior temporal sulcus. Classically the pVLPFC is sometimes referred to as “Broca’s Area”, and although it turns out that’s somewhat of a misnomer, it is a (largely) fortunate one for our purposes: there’s lots of detailed neuroanatomical research done on this area, both in the human and the primate.
In this light, our first problem may seem surprising: does this area exist in the monkey?
Yes is the short answer, although about 10 years of debate surround that simple answer (as stated by Gerbelli et al., “[this sector] occupies a cortical sector of a highly controversial architectonic attribution, assigned to areas 46 and 12 by Walker (1940), to areas 8 ventral and 46 by Barbas and Pandya (1989) and mostly to area 12 by Preuss and Goldman-Rakic (1991) and Romanski (2004, 2007)”).
The long answer is most easily grasped visually (image from Leh, Petrides & Strafella):
As reviewed by Petrides, Cadoret & Mackey, it has been argued that human BA44 has no homologue in the monkey. Others have argued that it does, such that human BA 44 corresponds to monkey area F5, sometimes termed PMv (ventral premotor cortex – behind the arcuate sulcus), with the monkey homologue of human BA 45 lying just anterior to the arcuate. But on the basis of their own careful analysis, Petrides et al suggest that BA 44 actually lies within the arcuate sulcus in the monkey, with ventral BA6 lying behind it; BA 45 is anterior to 44. We will assume Petrides et al’s view to be the correct one for the remainder of this post.
Now that we have identified where in the monkey these areas exist, it is worth covering the noteworthy differences between 44 and 45. And there is one – although perhaps only one: in terms of the presence of layer IV neurons, which are only “incipient” in 44, but well developed in area 45. Otherwise, these two areas share many features, including large pyramidal cells in deep layers III & V, the lack of a clear border between layers II vs. III, and a low cell density in layer VI. Gerbella et al., on the basis of cyto-, myelo-, and chemo-architectural studies, suggest that the relevant region (45B, although they did not report data from deep within the arcuate) can be defined solely on the basis of its extremely large outstanding layer III pyramidal cells, which are comparaitvely greater and more dense than those in layer V.
The functional significance of these laminar features may be better understood with respect to general principles of cortico-basal ganglia and cortico-thalamic projections (as described by McFarland & Haber, 2002). Layer V is reciprocally/bidirectionally connected with thalamus and represents a kind of positive feedback loop for corticothalamic processing. (A subset of these layer V neurons with bidirectional thalamic connectivity also have axon collaterals that project to the striatum). Layer I tends to be a recipient of more diverse corticothalamic projections, and thus represents a kind of “open loop” in the thalamocortical architecture. Finally, Layer III neurons tend to project preferentially to the striatum in prefrontal cortex (whereas in posterior cortex it represents a source of more local, cortico-cortical loops). MD subregions in particular may receive nonreciprocal projections from ACC and pre-SMA.
These claims, however, are not very specific to our particular region of interest. So what about the connectivity of this pVLPFC region in particular?
Human BA 44/45, aka pars opercularis and triangularis, of the human VLPFC, and its cortical/thalamic/striatal interconnectivity.
Striato-thalamic input to pVLPFC has been investigated by Tanibuchi, Kitano & Jinnai 2009 who studied precisely the area Petrides et al consider to be the monkey homologue of the human pVLPFC (check out recording site PSvc). Yet the connectivity here is somewhat surprising: this area is innervated by thalamic area MDmf/pc, which is itself innervated by the caudal area of the substantia nigra pars reitculata, as opposed to the pallidostriatal pathway that is commonly thought the dominant striatal pathway for innervating the thalamic areas that project to more dorsal regions of premotor and prefrontal cortex. This is in turn reflected in the cortical input to these pathways; as noted by Kitano, Tanibuchi & Jinnai 1998, SNr neurons with multisynaptic inhibitory input from dorsal prefrontal cortex are three times fewer than those with multisynaptic inhibitory input from ventral prefrontal cortex; conversely, dorsal prefrontal input to striatum is conveyed mainly by through GPi. Similar results were observed by Middleton & Strick 2002, and Middleton & Strick 2001, who said “Labeled neurons were found mainly in GPi after virus injections into area 46d [dorsal PFC], whereas labeled neurons were found mainly in SNpr after virus injections into area 46v [ventral PFC].”
Tanibuchi et al argued that “signals emanating from the PSv [primarily PSvc, or our pVLPFC region – CHCH], via inhibitory caudatonigral and nigrothalamic pathways, have a disinhibitory effect on thalamic neurons in the rostrolateral MD, wherefrom they may eventually return to the same cortical area as positive feedback signals.” These authors further argued that this PMv/SNr circuit is “concerned with recognition of the relationship between the visual stimulus and the behavior.”
But aren’t GPi and SNr just interchangeable (except that maybe SNr is more involved in “oculomotor behavior” and GPi in “skeletomotor behavior”)? If that were true, the observation that pVLPFC may interact rather preferentially with SNr has little functional punch. Moreover, everyone seems to write about GPi and SNr as though they’re interchangeable – separated by the internal capsule by some evolutionary mishap, and the SNr simply more involved in oculomotor behavior. With respect to that latter point, I’ll quote from Shin &
“When we began our study, the direct pathway through GPi and the indirect pathways through GPe had not been ruled out as oculomotor circuits; to our knowledge they simply had not been studied (with one exception: Kato and Hikosaka 1995).”
In fact, SNr and GPi can be differentiated in a number of ways. As extensively described by Romanelli, Esposito, Schaal and Heit, 2005, the SNr does not receive the same highly topographic input as GPi does, and as such represents a major departure from the highly topographic organization of the rest of the basal ganglia. Indeed, the SNr has been argued to be far more integrative or associative. Here I might as well just quote from Kaneda, Nambu, Tokuno & Takada 2001:
It has long been believed that the GPi and SNr belong to a single entity that is split rostrocaudally by the internal capsule (Parent 1986). In this view, the two structures are likely to play exactly the same role in the processing of information along the cortico-basal ganglia loop. However, in terms of the parallel versus convergent rules of information processing, the present work provides anatomical evidence that the mode of dealing with corticostriatal motor information from the MI and SMA through the striatopallidal and striatonigral projections is target-dependent, such that the parallel rule governs striatopallidal input distribution, whereas the convergent rule determines striatonigral input distribution. This strongly implies that the arrangement of the striatopallidal system closely reflects the organization of the corticostriatal system, while that of the striatonigral system does not. It has also been reported that the firing pattern of SNr neurons is less affected in parkinsonian monkeys than that of GPi neurons, suggesting their functional differences in motor behavior (Wichmann et al. 1999).
In other words, we can’t just conflate GPi and SNr, with the exception of domain (skeletomotor vs. oculomotor). Moreover, the intrinsic organization of these structures is quite different: GPi maintains segregation [i.e., follows the “parallel” rule of Kaneda et al] whereas SNr is more convergent) AND the inputs to these regions are quite different (with GPi afferents originating from motor and dorsal prefrontal cortex, and SNr afferents originating from orbital and lateral prefrontal cortex, and perhaps pVLPFC predominantly).
As mentioned in the above Kaneda et al quote, GPi is more strongly implicated in Parkinson’s and movement disorders. In contrast, the role of the SNr is widely considered to be more attentional, associative or sensory in nature. For example, it is more often implicated in so-called “sensory gating” than “motor gating” of the kind commonly thought to characterize dorsal prefrontal cortex. For example, as compared to GPi, SNr has an abundance of visual (but not merely oculomotor) responses and a relative paucity of reward-related responses.
Perhaps the most compelling demonstration of this difference in function is Wichman et al 1999, who showed that administration of the toxin MPTP (which kills dopaminergic cells in the substantia nigra, which are concentrated in the pars compacta segment) had actually less of an effect on substantia nigra pars reticulata firing than on GPi firing! This is surprising given that SNr neurons are thought to be modulated directly by the SNc neurons, and yet the effects are far more pronounced in the structure on the other side of the internal capsule, the GPi.
Summary: Cytoarchitectural and Connectivity of pVLPFC
pVLPFC is preferentially interconnected with the MDmf nucleus of the thalamus and contains large layer V neurons, which seem in large part to support direct corticothalamocortical “positive feedback” loops in prefrontal cortex. pVLPFC also contains large layer III pyramidal cells which project, via caudo-nigro-thalamic projections, back to the MDmf, through the substantia nigra pars reticulata. This connectivity pattern is distinct from other areas of PFC, notably from the more dorsal sector with which pVLPFC is sometimes lumped, insofar as those more dorsal prefrontal regions may more strongly interact with the other major output nucleus of the basal ganglia – the internal segment of the globus pallidus. The functional significance of this distinction is not yet perfectly clear, but does not solely reflect specializations for oculomotor vs. skeletomotor behavior in the SNr and GPi respectively. Instead, it appears that the nature of information processing in the SNr is substantially more associative or convergent than the more segregated somato/corticotopic that occurs in the GPi; it may also be more sensory (or, at least visual) in nature than motoric. This claim is paralleled by a reduced involvement of the SNr in Parkinsonian phenomena relative to the GPi, and the SNr’s comparatively greater involvement in phenomena like sensory gating and visual processing.