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Original research study

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Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

F : Mavridis IN, Anagnostopoulou S. Cortical connections of the human nucleus accumbens: meas-urements and correlations. OA Anatomy 2013 Feb 25;1(1):7.

Cortical connections of the human nucleus accumbens: measurements and correlations

IN Mavridis*, S Anagnostopoulou

AbstractIntroductionThe main purpose of our study was to measure the cortical thickness of the cortical connections of the human nucleus accumbens in order to explore potential morphometric correlations. Furthermore, we tested the hypothesis of a morphometric correlation between the nucleus accumbens and the cingulate gyrus.Materials and methodsThe material consisted of 41 cerebral hemispheres (25 left and 16 right) from 25 normal human brains. They were obtained from 22 males who were 50–90 years old, and from three females who were 67–94 years old. We measured the thickness of four cortical areas connected to the nucleus accumbens: the cingulate, entorhinal, orbitofrontal and piri-form cortices, as well as the height of the subgenual part of the cingulate gyrus.ResultsWe found a very statistically signifi-cant correlation between the orbit-ofrontal and entorhinal cortices, significant correlation between the cingulate and orbitofrontal cortices, significant correlation between the piriform and orbitofrontal cortices and significant correlation between the piriform and entorhinal cortices.ConclusionOur study indicated that the cingu-late cortex is probably the thickest cortical area connected to the nucleus accumbens. It also suggested

a potentially more significant rela-tion between the orbitofrontal cortex and the limbic system than what is currently believed. Furthermore, we provided evidence that the size of the nucleus accumbens is neither corre-lated with the thickness of its cortical connections nor with the size of the cingulate gyrus.

IntroductionThe human nucleus accumbens (NA), which belongs to the basal ganglia of the brain, is the main part of the ventral striatum1. It is a round-shaped, dorsally flattened structure, symmetrically placed anterior to the anterior commissure (AC) and

lies parallel to the midline2. It covers a large area of the basal forebrain (Figure 1) and is the region of conti-nuity between the putamen and the head of the caudate nucleus1-5. The NA is generally accepted to be located underneath the anterior limb of the internal capsule, laterally to the vertical part of the Broca’s diagonal band and medially to the claustrum and piriform cortex. It extends dorso-laterally into the putamen and dorso-medially into the caudate nucleus (Figure 2) without a sharp demarca-tion2. The NA is chemically divided into two parts: a shell, laterally and a core, medially6. The first is more related to the limbic system and the second to the extrapyramidal motor system2. The ΝΑ, having dopamine

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* Corresponding authorEmail: [email protected]

Department of Anatomy, University of Athens School of Medicine, Athens, Greece

Figure 1: Formalin-fixated human brain from a middle-aged male, left hemisphere, sagittal section, 7 mm lateral to the midline (coronal sec-tion 2 mm anterior to the AC) reveal-ing the NA location. 1: NA, 2: internal capsule (anterior limb), 3: caudate nucleus (head), 4: lateral ventricle (frontal horn), 5: fibres of the corpus callosum (genu).

Figure 2: Formalin-fixated human brain from a middle-aged male, right hemisphere, transverse section at the AC-PC plane (coronal section 2 mm anterior to the AC) revealing the NA location. 1: NA, 2: diagonal band of Broca, 3: caudate nucleus (head), 4: internal capsule (anterior limb), 5: putamen, 6: external capsule.


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as a major transmitter5, is a crucial centre for the experience of reward and pleasure7 and is also considered to be a psychosurgery target2,7. It is also a part of the forebrain circuitry involved in the regulation of behav-ioural activation and effort-related decision-making8.

Connections of the NAAfferent connectionsThe ventromedial striatum (con-taining the ventromedial caudate nucleus, NA core and NA shell) receives inputs through the ante-rior internal capsule (Figure 3) from the medial orbitofrontal cortex and the anterior and subgenual cingu-late cortex (Brodmann areas lateral 10, 11, 12, 13, 24, 25 and 32)9. The NA receives mainly glutamatergic projections from the anterior cingulate cortex8, frontal cortex8, prefrontal cortex8,10, amygdala2,8,10 (central and medial amygdaloid nuclei)2, hippocampus8,10 and thal-

amus10, and a strong dopaminergic projection from the mesencephalon, i.e. ventral tegmental area (VTA)2,8,10 and substantia nigra (SN)10.

The NA shell receives inputs from the prefrontal cortex (infral-imbic, ventral agranular insular and ventral prelimbic cortices)10,11, dorsal peduncular cortex, piriform cortex, medial and lateral entorhinal cortex, orbital cortex11, amygdala (caudal basolateral amygdaloid and rostral basal amygdaloid complexes), hippocampus (ventral subiculum/cornu Ammonis field 1), thalamus (anterior and posterior paraven-tricular nucleus) and mesencephalon (medial VTA, lateral VTA/SN compact part/retrorubral nucleus)10.

The NA core receives inputs from the prefrontal cortex (dorsal agranular insular and dorsal prelimbic cortices)10,11, perirhinal cortex, anterior cingulate cortex, premotor and supplemental motor cortices11, amygdala (basal amygda-loid complex), thalamus (interme-diodorsal nucleus/central medial nucleus) and mesencephalon (medial SN compact part)10.

Efferent connectionsThe main efferents of the NA inner-vate the pallidum, striatum, medi-odorsal thalamus, prefrontal and cingulate cortices and mesolimbic dopaminergic areas2. The major efferent projection from the NA terminates in the ventral pallidum and is principally gamma-amin-obutyric acid-ergic8,10. The ventral pallidum, in turn, projects strongly to the SN compact part (mediolateral part), as well as to the limbic part of the subthalamic nucleus (STN), and to the latter’s extensions into the local hypothalamus10. It also projects to mediodorsal thalamus and various brainstem motor areas8. It has been hypothesised that the ventral pallidum acts as a relay station and as an integrator of information related to diverse limbic and striatal inputs8. In addition, the NA provides a recur-rent projection to the VTA and SN10.

The NA shell projects to the lateral hypothalamus, extended amygdala, ventrolateral and ventro-medial (subcommissural) ventral pallidum9-11 and dorsal SN reticular part/VTA9. The NA core projects to the dorsolateral ventral pallidum10,11 (internal part of the ventromedial globus pallidus)9, STN11 and dorsal SN reticular part/VTA9. Both path-ways terminate in the thalamus, which receives and sends fibres to the medial orbitofrontal cortex/ante-rior and subgenual cingulate cortex9. An important difference between the NA core and the NA shell is the efferent projection from the NA shell to the lateral hypothalamus and the extended amygdala, which does not exist in the NA core10.

Th e limbic cortico-striato-pallido-thalamo-cortical loopThe concept of the ventral striato-pallidal system provided the first indication for the existence of parallel cortico-striato-pallido-thalamo-cortical circuits, which in turn led to the theory of segregated cortical-subcortical re-entrant circuits as a conceptual framework for the study of psychiatric disorders. The NA, an integral and important part of the limbic and prefrontal cortico-striato-pallido-thalamic circuits, seems to function as a limbic-motor interface and is involved in several cognitive, emotional and psychomotor func-tions, which have been found to be altered in some psychopathological conditions2.

The existence of a robust and direct striato-pallido-thalamo-cortico-striatal pathway from the shell to the core, suggests that significant co-ordination of the levels of activity in the two sub-territories should exist. Furthermore, the intimate connectional relations of the shell and core with the dorsal pre-limbic and dorsal agranular insular cortices are consistent with the role of the NA in the regulation of cognitive aspects of adaptive responding, possibly involving the gating of response initi-ation11.

Figure 3: Formalin-fixated human brain from a middle-aged male, left hemisphere, coronal section 2 mm anterior to the AC. 1: NA, 2: pinhead representing an electrode’s target point for NA deep brain stimulation, 3: caudate nucleus (head), 4: puta-men, 5: internal capsule (anterior limb), 6: external capsule, 7: claus-trum, 8: extreme capsule, 9: AC–PC plane, 10: corpus callosum, 11: sep-tum pellucidum, 12: lateral ventricle (frontal horn).


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Purpose of the studyThe main purpose of our study was to measure the cortical thickness of the NA cortical connections in order to explore potential morphometric correlations between the NA and each of the studied cortical areas, as well as among the individual cortical areas. Furthermore, we tested the hypothesis of a morphometric corre-lation between the NA and cingulate gyrus (CG) (subgenual part). The importance of the cingulate cortex as a NA connection is described in the discussion section of this article.

Materials and methodsThis work conforms to the values laid down in the Declaration of Helsinki (1964). The protocol of this study has been approved by the relevant ethical committee related to our insti-tution in which it was performed.

The material consisted of 41 cere-bral hemispheres (25 left and 16 right) from 25 normal human brains that we had in our department. They were obtained from 22 males, 50–90 years old and 3 females, 67–94 years old, who were cadaver donors for students’ education. These brains had been fixated in formalin solution.

We measured the thickness of four cortical areas connected to

the NA: the cingulate, entorhinal, orbitofrontal and piriform cortices. Specifically, we chose the thickness of the cingulate cortex anterior to the genu of the corpus callosum (C), the orbitofrontal cortex thickness at the intercommissural (anterior commis-sure– posterior commissure, AC–PC) plane, 10 mm laterally off the midline (O), the piriform cortex thickness posterior to the olfactory tract (P) and the entorhinal cortex thickness at the midpoint of the hippocampal uncus (E). Methodologically, we used a transparent plastic tube of about 25 mm length and 2 mm diam-eter, inserted perpendicularly to the cerebral surface, to remove a cylin-drical piece of brain tissue from each selected area. The transparency of the tube allowed us to identify the cortex-white matter limit and hence allowed us to measure the cortical thickness (Figure 4). A scalpel was occasionally used to help the removal of the brain tissue piece (Figure 4).

We also measured the height of the subgenual part of the CG (CGH), 12 mm rostral to the anterior border of the AC, in order to test the hypothesis of an existing morphometric correla-tion between the NA and the CGH. We also tested the hypothesis of such a correlation between the NA and the C, O, P and E. As an index of the NA size, we used its maximum coronal dimension (diameter), 2 mm anterior to the AC (Dmax). Our methodology to measure Dmax has been previ-ously published12.

ResultsTable 1 presents our measurements. The C varied from 0.8 mm to 5 mm and its mean value (MV) ± standard deviation (SD) was C = 2.41 ± 1.07 mm (n = 26). For right hemispheres, we found C = 2.53 ± 1.61 mm (n = 9) and for left, C = 2.35 ± 1.29 mm(n = 17). The O varied from 1.1 mm to 5.0 mm and its MV ± SD was O = 2.16 ± 0.8 mm (n = 36). For right hemi-spheres, we found O = 2.27 ± 1.23 mm (n = 14) and for left, O = 2.09 ± 1.01 mm (n = 22). The P varied from

1.0 mm to 4.0 mm and its MV ± SD was P = 2.19 ± 0.74 mm (n = 31). For right hemispheres, we found P = 2.06 ± 1.25 mm (n = 12) and for left, P = 2.27 ± 1.24 mm (n = 19). The E varied from 1.0 mm to 5.0 mm and its MV ± SD was E = 2.11 ± 0.87 mm (n = 37). For right hemispheres, we found E = 2.13 ± 1.33 mm (n = 14) and for left, E = 2.10 ± 1.19 mm (n = 23). We found no statistically significant difference in the MVs of the C, O, P and E between the right and left hemispheres.

The CGH varied from 5 mm to 10 mm and its MV ± SD was CGH = 7.21 ± 1.26 (n = 29). For right hemispheres, we found CG = 7.00 ± 1.33 (n = 10) and for left, CGH = 7.32 ± 1.25 (n = 19). We found no significant differ-ences in the CGH between the right and left hemispheres.

The statistical analysis of our measurements revealed the following correlations (beginning from the most powerful):• Statistically very significant corre-

lation between the O and E (r =0.609, df = 32, p<0.001).

• Statistically significant correlationbetween the C and O (r = 0.540, df= 24, p<0.01).

• Statistically significant correlationbetween the P and O (r = 0.489, df= 29, p<0.01).

• Statistically significant correlationbetween the P and E (r = 0.425, df= 27, p<0.05).

We also found no statistical corre-lation between: Dmax and CGH (r = 0.277, df = 26, p > 0.1), Dmax and C (r = 0.084, df = 22, p > 0.1), Dmax and O (r = 0.240, df = 25, p > 0.1), Dmax and P (r = 0.007, df = 20, p > 0.1), and Dmax and E (r = 0.106, df = 25, p > 0.1).

DiscussionTo the best of our knowledge, our anatomical method for the meas-urement of cortical thickness has not been previously described. Our choice of these specific cortical points (C, O, P and E) was based on easy-to-locate areas of the specific

Figure 4: Instruments used for tak-ing a cortical sample from brain re-gions. 1: tube, 2: cerebral cortex, 3: subcortical white matter, 4: scalpel, 5: scalpel blade.


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brain surface areas studied, hence being easily reproducible. Except for the cingulate cortical thickness C, we also used the CGH as an index of the CG size. The cingulate cortex is a quite important connection of the NA because it is one of the very few brain areas connected to this nucleus with both afferent and efferent fibres2,8. We chose this particular part (CGH) of the CG because of its clearer limits, which provided easier and more reli-able measurements, and because the CGH is the nearest to the NA part of this gyrus.

Considering the C, O, P, E and CGH, we would like to emphasise the absence of a significant morpho-metric correlation with the NA and also the absence of a significant inter-hemispheric difference. Regarding the mean thickness results, we observed that C>P>O>E (Table 1). Consequently, the cingulate cortex is probably the thickest cortical area connected to the NA (at least of those studied). The very signifi-cant correlation between the orbito-frontal and entorhinal cortices is quite an interesting finding, difficult to be explained. Together with the significant correlation between the cingulate and orbitofrontal cortices, it might suggest a more significant relation of the orbitofrontal cortex to the limbic lobe (where cingu-late and entorhinal cortices belong) than what is currently believed. The significant correlation between the piriform and orbitofrontal cortices is an interesting finding too, although not so surprising. Finally, the signifi-cant correlation between the piri-form and entorhinal cortices could be explained considering that they are both central olfactory connections1.

Cortical thickness studies are not common in the literature. Feczko et al.13 described a novel protocol for measuring the thickness, surface area and volume of three medial temporal lobe sub-regions. Participants included younger (ages 18–30) and older (ages 66–90) normal subjects, as well as patients (ages 56–90)

Table 1. Measurements of the cingulate gyrus height and thickness of the cingulate, orbitofrontal, piriform and entorhinal cor ces.

Hemisphere CGH (mm) C (mm) O (mm) P (mm) E (mm)1 R1 5 2.5 2.0 3.0 1.52 R2 8 1.9 3.0 3.0 2.73 R3 6 3.0 3.0 2.0 3.04 R4 9 1.5 1.6 - 1.55 R5 9 2.9 2.5 3.0 1.56 R6 6 1.8 1.8 1.8 1.97 R7 6 5.0 5.0 - 5.08 R8 7 2.0 2.0 2.2 1.09 R9 7 - 2.1 2.4 2.910 R10 7 - - - 1.411 R11 - - - - -12 R12 - - 1.8 2.0 -13 R13 - - 1.9 1.2 1.614 R14 - - 1.5 1.1 1.315 R15 - - 1.9 1.0 1.216 R16 - 2.2 1.7 2.0 2.817 L1 7 1.5 2.5 4.0 3.018 L2 8 2.7 3.9 1.9 2.119 L3 10 4.0 2.9 2.5 3.020 L4 7 3.0 2.6 3.0 4.021 L5 6 2.8 1.8 - 1.622 L6 5 1.3 1.5 2.0 2.523 L7 6 1.2 1.1 1.4 2.024 L8 6 2.0 2.0 - 2.025 L9 8 5.0 2.5 2.6 1.226 L10 7 0.8 2.0 2.5 1.027 L11 8 2.0 3.0 - 2.028 L12 9 - 3.0 4.0 2.929 L13 7 1.9 1.6 1.9 1.530 L14 7 3.8 1.4 2.0 1.431 L15 8 1.8 1.4 1.4 2.932 L16 8 2.3 3.0 2.4 3.033 L17 7 - - - 2.234 L18 9 1.5 2.0 1.7 2.035 L19 6 - 1.6 2.5 -36 L20 - - - - -37 L21 - - 1.6 1.3 2.038 L22 - - 1.3 2.0 1.439 L23 - - 1.9 1.6 1.040 L24 - 2.3 1.4 2.4 2.041 L25 - - - - 1.6MV 7.21 2.41 2.16 2.19 2.11SD 1.26 1.07 0.8 0.74 0.87n 29 26 36 31 37

C, cingulate cortex thickness anterior to the genu of the corpus callosum; CGH, cingulate gyrus height 12 mm rostral to the anterior commissure; E, entorhinal cortex thickness at the midpoint of the hippocampal uncus; L, left; MV, mean value; n, sample number; O, orbitofrontal cortex thickness at the AC–PC plane, 10 mm laterally off the midline; P, piriform cortex thickness posterior to the olfactory tract; R, right; SD, standard deviation.


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with mild Alzheimer’s disease (AD). Cortical surface models were recon-structed from the grey/white and grey/cerebrospinal fluid boundaries, and a hybrid visualisation approach was implemented to trace the entorhinal cortex, perirhinal cortex and parahippocampal cortex, using both orthogonal magnetic resonance imaging (MRI)—slice- and cortical surface-based visualisation of land-marks. They found that the entorhinal cortex thickness in younger normal individuals was 2.65–2.94 mm (n = 58), in older normal individuals was 2.54–2.76 mm (n = 94) and in AD patients was 2.03–2.28 mm (n = 58)13. The MV ± SD of our study’s E was 2.11 ± 0.87 mm (n = 37). Given the similarity of age between older normal individuals of their study and our specimens, the compara-tively thinner entorhinal cortex of our specimens could be either due to the restricted point of the entorhinal cortex we chose or due to the formalin-effect to the specimen.

It is controversial whether entorhinal cortex atrophy is present in normal aging. It is possible that such effects observed in clinically normal older groups result from the presence of subclinical AD pathology. With the use of MRI data at the current resolution, it can be diffi-cult for computational algorithms to exclude the dural layer that typically overlies the crown of the parahip-pocampal gyrus, potentially arti-ficially thickening the estimate of entorhinal cortex thickness13. This could be another explanation for the comparatively thinner entorhinal cortex of our specimens, and in our opinion, the most probable. We consider our anatomical method for the measurement of cortical thick-ness as being precise and reliable (we were able to see and touch the cortical layer).

The NA is involved in the patho-physiology of depression and is moreover a deep brain stimulation target for selected patients suffering from treatment-resistant depres-

sion7. According to the findings of van Tol et al.14, reduced volume of the rostral-dorsal, anterior CG is a generic effect in depression and anxiety disorders, independent of illness severity, medication use and sex. This generic effect supports the notion of a shared aetiology and may reflect a common symptom dimen-sion related to altered emotion processing. Early onset of depres-sion is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder14.

ConclusionOur study indicates that the cingu-late cortex is probably the thickest cortical area connected to the NA and suggests a potentially more significant relation between the orbitofrontal cortex and the limbic lobe, than what is currently believed. Furthermore, we provided evidence that the NA size is corre-lated neither with the thickness of its cortical connections nor with the size of the CG. We have also provided a reliable anatomical method for cortical thickness meas-uring. Further research is needed to explain the correlations we found, setting them in a wider frame of the understanding of brain mecha-nisms. Functional brain techniques seem, in our opinion, more appro-priate for this purpose.

Abbreviations listAC, anterior commissure; AD, Alzhei-mer’s disease; CG, cingulate gyrus; CGH, cingulate gyrus height 12 mm rostral to the anterior commissure; MRI, magnetic resonance imaging; MV, mean value; NA, nucleus accum-bens; PC, posterior commissure; SD, standard deviation; SN, substantia nigra; STN, subthalamic nucleus; VTA, ventral tegmental area.

AcknowledgementsThis study was carried out in the context of the first author’s doctoral research entitled: ‘Stereotactic

neurosurgical anatomy of the nucleus accumbens’ which took place at the Department of Anatomy, University of Athens School of Medicine, Athens, Greece.

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