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This paper reviews architectonic subdivisions and connections of the orbital and medial prefrontal cortex (OMPFC) in rats, monkeys and humans. Cortico-cortical connections provide the basis for recognition of 'medial' and 'orbital' networks within the OMPFC. These networks also have distinct connections with structures in other parts of the brain. The orbital network receives sensory inputs from several modalities, including olfaction, taste, visceral afferents, somatic sensation and vision, which appear to be especially related to food or eating. In contrast, the medial network provides the major cortical output to visceromotor structures in the hypothalamus and brainstem. The two networks have distinct connections with areas of the striatum and mediodorsal thalamus. In particular, projections to the nucleus accumbens and the adjacent ventromedial caudate and putamen arise predominantly from the medial network. Both networks also have extensive connections with limbic structures. Based on these and other observations, the OMPFC appears to function as a sensory-visceromotor link, especially for eating. This linkage appears to be critical for the guidance of reward-related behavior and for setting of mood. Imaging and histological observations on human brains indicate that clinical depressive disorders are associated with specific functional and cellular changes in the OMPFC, including activity and volume changes, and specific changes in the number of glial cells.

Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann's area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions.

The structure of the human orbital and medial prefrontal cortex (OMPFC) was investigated using five histological and immunohistochemical stains and was correlated with a previous analysis in macaque monkeys [Carmichael and Price (1994) J. Comp. Neurol. 346:366-402]. A cortical area was recognized if it was distinct with at least two stains and was found in similar locations in different brains. All of the areas recognized in the macaque OMPFC have counterparts in humans. Areas 11, 13, and 14 were subdivided into areas 11m, 11l, 13a, 13b, 13m, 13l, 14r, and 14c. Within area 10, the region corresponding to area 10m in monkeys was divided into 10m and 10r, and area 10o (orbital) was renamed area 10p (polar). Areas 47/12r, 47/12m, 47/12l, and 47/12s occupy the lateral orbital cortex, corresponding to monkey areas 12r, 12m, 12l, and 12o. The agranular insula (areas Iam, Iapm, Iai, and Ial) extends onto the caudal orbital surface and into the horizontal ramus of the lateral sulcus. The growth of the frontal pole in humans has pushed area 25 and area 32pl, which corresponds to the prelimbic area 32 in Brodmann's monkey brain map, caudal and ventral to the genu of the corpus callosum. Anterior cingulate areas 24a and 24b also extend ventral to the genu of the corpus callosum. Area 32ac, corresponding to the dorsal anterior cingulate area 32 in Brodmann's human brain map, is anterior and dorsal to the genu. The parallel organization of the OMPFC in monkeys and humans allows experimental data from monkeys to be applied to studies of the human cortex.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.