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Schizophrenia Bulletin Advance Access published online on April 23, 2008
Schizophrenia Bulletin, doi:10.1093/schbul/sbn025
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© The Author 2008. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Anatomical Abnormalities of the Anterior Cingulate Cortex in Schizophrenia: Bridging the Gap Between Neuroimaging and Neuropathology

Alex Fornito1,2, Murat Yücel2,3, Brian Dean4,6, Stephen J. Wood2 and Christos Pantelis2,7
2 Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Victoria, Australia
3 ORYGEN Research Centre, Department of Psychiatry, The University of Melbourne, Victoria, Australia
4 The Rebecca L Cooper Research Laboratories, The Mental Health Research Institute, Parkville, Victoria, Australia
5 Departments of Pathology and Psychiatry, The University of Melbourne, Victoria, Australia
6 Department of Psychological Medicine, Monash University, Victoria, Australia
7 Howard Florey Institute, The University of Melbourne, Victoria, Australia


   Abstract
Top
 Abstract
Structure and function of...
 Structural magnetic resonance...
 Neuropathology of the ACC...
 Are the changes secondary...
 Bridging the gap: implications...
 Conclusions
 References
 
The anterior cingulate cortex (ACC) is a functionally heterogeneous region involved in diverse cognitive and emotional processes that support goal-directed behaviour. Structural magnetic resonance imaging (MRI) and neuropathological findings over the past two decades have converged to suggest abnormalities in the region may represent a neurobiological basis for many of the clinical manifestations of schizophrenia. However, while each approach offers complimentary information that can provide clues regarding underlying patholophysiological processes, the findings from these 2 fields are seldom integrated. In this article, we review structural neuroimaging and neuropathological studies of the ACC, focusing on the unique information they provide. The available imaging data suggest grey matter reductions in the ACC precede psychosis onset in some categories of high-risk individuals, show sub-regional specificity, and may progress with illness duration. The available post-mortem findings indicate these imaging-related changes are accompanied by reductions in neuronal, synaptic, and dendritic density, as well as increased afferent input, suggesting the grey matter differences observed with MRI arise from alterations in both neuronal and non-neuronal tissue compartments. We discuss the potential mechanisms that might facilitate integration of these findings and consider strategies for future research.

Keywords: psychosis / neuron / VBM / glia / limbic / prefrontal

Neurobiological research has been critical in identifying the brain regions involved in the pathogenesis of schizophrenia, implicating several structures extending across limbic, frontal, temporal, and subcortical areas.1–5 One brain region commonly reported to show abnormal structure and function in patients with the disorder is the anterior cingulate cortex (ACC), an area crucial for integrating cognitive and emotional processes in support of goal-directed behaviour.6–10 The functional diversity of the ACC, which encompasses executive, social cognitive, affective, and skeleto- and visceromotor functions,6,11–17 suggests that abnormalities in the region may partly explain the difficulties in cognitive and emotional integration that characterize the clinical manifestations of schizophrenia.15,18

Both neuropathological and neuroimaging findings support a role for ACC dysfunction in schizophrenia. Neuropathological research has revealed alterations in the cellular and synaptic architecture of the region,19,20 while imaging work has identified ACC abnormalities that correlate with the disorder's characteristic symptoms and cognitive deficits,21,22 and which ameliorate with treatment response.23,24 However, the precise ACC subregion affected, and the nature of the underlying changes, has varied across these reports, making it difficult to discern their pathophysiological significance. Moreover, while both neuroimaging and neuropathological approaches offer complimentary information, their findings are seldom integrated systematically, making it unclear how changes in cell density or synaptic morphology relate to volumetric differences identified with imaging.

In this article, we review magnetic resonance imaging (MRI) and neuropathological studies of the ACC in schizophrenia in an attempt to understand the pathological processes underlying the changes observed with in vivo imaging. Our discussion is organized around key questions that speak to the particular strengths of the 2 approaches. For neuroimaging research, we ask whether there is evidence of (1) regionally specific abnormalities, (2) abnormalities predating illness onset, and (3) variation in the abnormalities across different illness stages. For neuropathological work, we ask whether the evidence (1) supports the existence of volumetric changes in the ACC, (2) supports the occurrence of cell loss in the ACC of schizophrenia patients, and (3) identifies changes in the intercellular neuropil. We then discuss the influence of psychotropic treatment on the findings, before providing a synthesis and consideration of their implications for uncovering underlying pathophysiological mechanisms. We primarily discuss structural MRI research and neuropathological studies of cell counts and cortical, axonal, dendritic, and cellular morphology, as these data are the most comparable, although we draw on other relevant literature where necessary. Rather than propose a definitive unitary pathophysiological process, we use the available data to stimulate discussion regarding which mechanisms might be most useful in integrating findings from these diverse fields. We begin with a brief overview of ACC anatomy and function.


   Structure and function of the anterior cingulate cortex
Top
 Abstract
 Structure and function of...
Structural magnetic resonance...
 Neuropathology of the ACC...
 Are the changes secondary...
 Bridging the gap: implications...
 Conclusions
 References
 
Located bilaterally in the medial frontal lobes, the ACC comprises the cytoarchitectonic areas 24/24’ and 32/32’, with area 25, commonly called the subgenual cingulate,25 located posterior to the subcallosal extension of area 24, ventral to the genu. Areas 24’/32’ are located dorsal to the corpus callosum, while areas 24/32 occupy a pregenual position.26 Areas 32 and 32’ have been termed transition cortex because they possess cytoarchitectonic features common to areas 24/24’ and adjacent frontal regions.26 Other authors have labeled areas 32/32’ as paralimbic, or paracingulate, cortex and areas 24/24’ as limbic ACC due to the latter's denser connections with emotional centres.6 The relative location and size of these regions change in accordance with variability in sulcal and gyral anatomy. In particular, the paracingulate sulcus (PCS), which is present in 30%–60% of cases and runs dorsal and parallel to the cingulate sulcus (CS),27,28 is associated with a relative expansion of area 32, such that it extends from the depths of the CS across the crown of the paracingulate gyrus that forms between the CS and PCS, contrasting its location on the dorsal bank of the CS when a PCS is absent.26 This variability has functional consequences29–34 and is an important consideration when interpreting morphometric studies of the region, as discussed below. Figure 1 presents a simplified illustration of how the major cytoarchitectonic fields vary as a function of PCS variability.


Figure 1
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  		Fig. 1. Simplified Illustration of How Anterior Cingulate Cortex (ACC) Cytoarchitecture is Altered by Variations in Morphology of the Paracingulate Sulcus (PCS). Top row presents a sagittal slice through the left (right column) and right (left column) hemisphere of the N27 template,179 which provides a good example of a "present" and "absent" PCS. Middle row illustrates the locations of the PCS and cingulate sulcus (CS) on cortical surface reconstructions generated from the N27 template using freely available software (http://brainmap.wustl.edu/caret). The surfaces run midway through the thickness of the cortical ribbon, facilitating visualization inside the sulcal walls. Bottom row illustrates how major cytoarchitectonic fields in the area are altered by PCS variability. The posterior vertical black line approximates the caudal border of what is termed the dorsal division of the ACC, and the anterior vertical black line approximates the border between areas 24/32 and 24’/32’. Note how areas 32/32’ extend across the crown of the paracingulate gyrus when a PCS is present, in contrast to being buried in the depths of the CS when the PCS is absent. The purple area corresponds to what is termed the limbic ACC, the pink area to the paralimbic ACC. The borders are only intended as a rough approximation of their actual location.

 
Several meta-analyses of functional MRI (fMRI) and positron emission tomography (PET) studies have demonstrated that cognitive paradigms tend to elicit activation in dorsal areas 24’/32’, whereas affective tasks produce increased activation in rostral areas 24/32, a distinction that parallels the greater connectivity between these rostral areas and limbic structures.12,14,17,35 Within the rostral ACC, activation during negative emotional conditions tends localize within the subcallosal extension of area 24 and the adjacent area 25, while positive emotions elicit activations in the pregenual portion of area 24, supporting a further functional distinction.17 Evidence of functional dissociations between areas 24 and 32, and 24’ and 32’, are also being uncovered,7,36 consistent with differences in their functional connectivity with other brain regions.37,38 Some evidence suggests certain paralimbic areas mediate self-reflective and social cognitive processes,14,39,40 although the precise nature of functional specialization in this region remains unclear. Broadly however, such findings suggest the ACC may be grossly partitioned into limbic (ACCL) and paralimbic (ACCP) regions, each containing dorsal, rostral, and subcallosal divisions (see figure 1). There is also evidence for a caudal division involved in motor control,16 but it will not be considered further in this discussion. (For further details regarding ACC functional specialization, see 6–9,11,12,14,17,41,42.)


   Structural magnetic resonance imaging research
Top
 Abstract
 Structure and function of...
 Structural magnetic resonance...
Neuropathology of the ACC...
 Are the changes secondary...
 Bridging the gap: implications...
 Conclusions
 References
 
Are changes in the ACC regionally specific?
Structural MRI studies have used 2 approaches to investigating neuroanatomical changes in patients with schizophrenia. One, the region-of-interest (ROI) method, involves manual delineation of the ACC on each scan, with morphometric parameters such as gray matter volume calculated secondarily. The second, commonly termed voxel-based morphometry (VBM), is an automated technique that involves spatial normalization of each participant's scan to a common stereotactic space, followed by voxelwise statistical comparison of group differences in gray matter measures. This has provided an attractive alternative to the ROI methodology because it affords a relatively unbiased assessment of gray matter changes across the entire brain, although errors in spatial normalization, particularly in morphologically variable regions such as the ACC, can complicate interpretation of findings.43–45 We collectively refer to reports using one of the several variants of this technique46–50 as whole-brain mapping (WBM) studies from hereon.

The findings of cross-sectional WBM studies investigating anatomical changes in the ACC of patients with schizophrenia are summarized in table 1, and stereotactic foci representing regions of maximal gray matter change reported in these studies are plotted in figure 2. The results suggest ACC gray matter reductions in schizophrenia are dispersed across dorsal and rostral divisions of the limbic and paralimbic regions, with few differences being noted in the subcallosal area. One-third (13/39) of WBM studies failed to identify any significant differences in ACC grey matter.


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  		Table 1. Details of Voxel-Based, Whole-Brain Mapping Studies in Schizophrenia

 

Figure 2
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  		Fig. 2. Stereotactic Foci (Bottom Row) Representing Regions of Maximal Anterior Cingulate Cortex (ACC) Gray Matter Reductions Reported in Whole-Brain Mapping Studies of Schizophrenia. Blue foci correspond to differences between first-episode patients and controls, and red foci correspond to differences between patients with established schizophrenia and controls. Top row presents the same surfaces illustrating the approximate locations of the dorsal (d-ACC), rostral (r-ACC) and subcallosal (s-ACC) divisions of the anterior cingulate cortex. Limbic ACC is shown in purple and paralimbic ACC is in pink. Left hemisphere is presented on the right side.

 
Results obtained using the ROI approach are summarized in table 2. Studies examining the entire anterior cingulate gyrus (ie, the ACCL) have been variable, reporting right-sided,51,52 bilateral,53–59 or no group differences.21,60–62 Similarly, those focusing on the dorsal ACCL have found either left-sided63 or right-sided64,65 reductions or no group differences.66–68 Studies of the rostral ACC have been more consistent, with most finding no gray matter differences,63,65,67–69 although one found a left lateralized thickness increase that was positively correlated with years of antipsychotic treatment.70 Relatively few (4/28) ROI studies have examined the subcallosal ACC, with no significant differences reported.52,68,71,72


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  		Table 2. Details of Region-of-Interest Magnetic Resonance Imaging Studies Examining the Anterior Cingulate Cortex in Schizophrenia

 
Only 3 ROI studies have separately parcellated the ACCP. The first53 found bilateral volumetric reductions in the region to be among the largest seen across 48 ROIs in patients with established schizophrenia. The second73 found a right-sided reduction in a first-episode (FE) sample but not patients with established schizophrenia. In the third, we found a bilateral reduction in thickness, but not volume or surface area, of the ACCP extending across dorsal, rostral, and subcallosal subregions in FE patients,68 with no differences being identified in limbic subregions.

In summary, most MRI studies suggest schizophrenia patients show reduced ACC gray matter, although the location of these changes has been variable. Generally, the reductions seem to extend across the dorsal and rostral ACCL and ACCP, with limited subcallosal involvement. Methodological differences, such as variations in ROI parcellation schemes or image pre-processing steps implemented in WBM research, likely contribute to these inconsistencies, as do variations in sample characteristics. An additional, major and often-neglected influence on the findings is variability in the incidence and extent of the PCS. As previously mentioned, PCS variability can alter the location and extent of paralimbic ACC,26 with MRI studies suggesting its appearance can produce up to an 88% increase in ACCP volume and 39% decrease in ACCL volume.28,45 People with schizophrenia are less likely to show a PCS in the left hemisphere,56,74,75 suggesting that the results of ROI or WBM studies will be biased unless the comparison groups are well matched for sulcal morphology. Our recent study of FE patients68 attempted to control for this variability by matching patients and controls for PCS morphology.34,45 While our finding of reduced bilateral ACCP thickness suggests that gray matter reductions in schizophrenia are not entirely attributable to group differences in sulcal and gyral anatomy, it needs to be replicated in independent samples.

Do anatomical changes in the ACC predate illness onset?
The question of whether neuroanatomical changes precede illness onset has typically been examined by studying individuals at elevated risk for schizophrenia to determine whether they show changes similar to those observed in affected probands. Cross-sectional studies of unaffected relatives of patients have yielded conflicting findings. Goghari et al,76 using an ROI approach, found a bilateral reduction in ACC thickness in patients’ relatives, in addition to a right-sided decrease in volume and surface area extending across the entire cingulate gyrus, although 2 earlier WBM studies failed to find any association between changes in ACC gray matter and genetic risk for schizophrenia.77–79 This discrepancy may partly reflect differences in the sensitivity of ROI and WBM methods for assessing ACC changes, as a WBM study by Job et al80 found reduced ACC gray matter in a sample of individuals at genetic risk for schizophrenia after restricting their analysis to this region (the differences did not emerge in a whole brain analysis). However, the unknown rate of illness transition in these samples makes it difficult to determine whether the findings reflect changes associated with imminent illness onset or a generalized at-risk status.

Studies incorporating a longitudinal component to ascertain the diagnostic outcome of their high-risk samples have yielded more consistent findings. The first such study applied WBM techniques to scans acquired in a group of individuals deemed to be at ultra-high risk (UHR) for psychosis onset81 based on a combination of state and trait criteria associated with a 30%–40% rate of transition to frank psychosis within 1 year.82 Comparing UHR individuals who did develop psychosis (UHR-P) with those who did not (UHR-NP) revealed reduced ACC gray matter in UHR-P individuals prior to psychosis onset, as well as longitudinal reductions in this region during the transition to psychosis that were not apparent in the UHR-NP group. Independently, Borgwardt et al83 found reduced ACC gray matter in their UHR-P group (defined using similar criteria) when using uncorrected thresholds to account for their limited sample size. However, in a longitudinal study of individuals at genetic high risk, Job et al84 found no differences in ACC gray matter between those who did and those who did not subsequently become psychotic, despite there being ACC gray matter reductions in the high-risk sample as a whole at baseline.80 Job et al84 also found no ACC differences in a small subgroup (n = 8) who eventually developed schizophrenia. The discrepancy in these findings suggests that prepsychotic ACC abnormalities may vary depending on whether individuals are at elevated risk for genetic or nongenetic reasons because a positive family history was not necessary for inclusion in the UHR samples.

We have recently examined ACC morphometry in the largest cohort of high-risk people making the transition to psychosis to date (Fornito, Yung, Wood, Phillips, Nelson, Cotton, Velakoulis, McGorry, Pantelis & Yücel, in revision), using the same approach implemented in our previous work68,85 to account for the confounding effects of PCS variability. Relative to healthy controls, UHR-P (n = 35) individuals displayed bilateral thinning of the rostral ACCP, whereas UHR-NP (n = 35) individuals showed increased thickness bilaterally in the dorsal ACCL. Subdiagnostic analyses suggested that these pre-onset changes were specific to UHR-P individuals that went on to develop a schizophrenia-spectrum psychosis, with none being noted in those who developed affective or other psychoses.

Together, these findings suggest that ACC gray matter reductions precede psychosis onset and that these pre-onset changes may be specific to schizophrenia-spectrum disorders. However, they may be more prevalent in individuals at clinical, rather than genetic, high risk. Studies of people with schizotypal personality disorder have generally failed to find any ACC differences,63,86–88 further underscoring the need to examine how different risk factors relate to pre-onset neuroanatomical changes in schizophrenia.

Do the changes vary across illness stages?
The most straightforward method for examining whether ACC changes vary across illness stages is to compare results identified in FE and established patient samples. In this context, the most notable finding in ROI work is that none of the FE studies published to data have found significant group differences in ACCL gray matter.21,67,68,73 In contrast, both of the studies that parcellated the ACCP separately reported gray matter reductions in their FE samples,68,73 suggesting that the earliest changes in schizophrenia occur in paralimbic regions. Consistent with this view, a recent longitudinal study of childhood-onset schizophrenia found the earliest gray matter reductions extended across the dorsal and rostral ACCP and spread to encompass the ACCL over a 5-year period. Such findings are also consistent with evidence of gray matter reductions in the rostral ACCP prior to schizophrenia onset81 longitudinal changes in the rostral and dorsal ACCP during the transition to psychosis,81 and more diffuse reductions extending across the rostral, dorsal, and subcallosal ACCP in FE patients,68,73 with further reductions possibly occurring after the first episode.89

However, not all imaging findings support a paralimbic to limbic progression of abnormalities in schizophrenia. As indicated in figure 2, comparing the peaks of gray matter differences identified in WBM studies of FE and chronic patients does not reveal clear, regionally specific changes associated with illness stage. Furthermore, not all longitudinal studies have reported evidence for a progression of ACC abnormalities. Job et al84 failed to find any evidence of longitudinal changes in ACC gray matter in genetic high-risk individuals who either developed schizophrenia or subthreshold psychotic symptoms, although power may have been limited due to restricted sample sizes. In a larger sample, Whitford et al90 found no evidence of excess ACC gray matter reduction in the first 2–3 years following schizophrenia onset, nor were excess reductions found in a separate 5-year follow-up study of patients with established schizophrenia.91

In summary, while there is some cross-sectional and longitudinal evidence to suggest that the earliest ACC changes in schizophrenia appear in the rostral ACCP prior to psychosis onset, extend across the ACCP during the transition to a FE psychosis, and spread to engulf limbic areas with continued illness, not all data support this view. Medication is likely to complicate interpretation of these findings, following evidence that exposure to atypical antipsychotics is associated with increased ACC gray matter over time whereas treatment with typical agents is associated with decreased ACC gray matter.92 Further longitudinal work that accounts for these medication effects will therefore be necessary to better characterize the trajectory of ACC changes across the course of schizophrenia.


   Neuropathology of the ACC in schizophrenia and bipolar disorder
Top
 Abstract
 Structure and function of...
 Structural magnetic resonance...
 Neuropathology of the ACC...
Are the changes secondary...
 Bridging the gap: implications...
 Conclusions
 References
 
Are volume changes apparent in postmortem samples?
The preceding discussion indicates that most imaging studies in schizophrenia have found evidence for reduced ACC gray matter. However, anatomical changes detected using MRI may result from a variety of nonpathological physiological and developmental processes,93–95 highlighting the need to validate such findings with postmortem techniques. This task is complicated by the relative paucity of postmortem work published in this area and the considerable variability in the ACC subregions sampled (see table 3).


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  		Table 3. Details of Studies Examining Anterior Cingulate Volume and/or Cortical Thickness in Schizophrenia

 
Two postmortem studies, both examining the volume of the entire anterior cingulate gyrus, found no significant volumetric differences,96,97 while one focusing on dorsal area 24’ reported reduced volume in both the left and right hemispheres of schizophrenia patients.98 In a separate report, no group differences were found in the subcallosal portion of area 24,99 consistent with the aforementioned MRI findings suggesting few changes in this region. However, some of these studies collapsed data from samples taken from both hemispheres,96,99 adding noise to the group comparisons. Moreover, only one study attempted to control for differences in overall brain size.97 The sole postmortem investigation of paralimbic ACC found no significant differences.96

Three studies have investigated ACC laminar thickness in patients with schizophrenia. Two studies examining dorsal area 24’ both found reductions in total cortical thickness (collapsed across all layers), with one reporting a bilateral reduction98 and the other examining left hemisphere samples only.100 Bouras et al100 also reported reduced thickness in specific layers of subcallosal area 24, while the only study of rostral area 24 found no significant differences in laminar thickness.101 Together, these findings suggest that schizophrenia is associated with volumetric and thickness reductions, at least in the dorsal and subcallosal ACC. These results are broadly consistent with the gray matter reductions reported in imaging research, although more postmortem studies are required before firm conclusions can be drawn.

Is there evidence of cell loss?
Cortical gray matter reductions are often interpreted as reflecting neuronal loss, although providing unambiguous evidence for neuronal loss is a nontrivial task as a definitive answer requires precise counting of each neuron within a defined region, a goal that poses several technical challenges (see 102,103 for detailed discussion). Only 2 studies have estimated absolute cell counts in the ACC of schizophrenia patients (see table 4). The first, by Ongur et al,99 found no differences in overall neuronal number in subcallosal area 24, consistent with their finding of no changes in the gray matter volume of this region. The second, by Stark et al,96 examined multiple sections through the limbic (24/24’) and paralimbic (32/32’) ACC and also found no differences.


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  		Table 4. Details of cell-counting and synaptic morphology studies of the anterior cingulate cortex in schizophrenia.

 
Most cell-counting studies have examined cell density rather than absolute cell number. Cell density is a more practical measure because it can be obtained from a restricted tissue sample rather than the entire extent of a region. It therefore estimates the relative cellular abundance per unit volume, rather than providing an absolute cell count. The reported findings have been somewhat contradictory, with decreases,101,104,105 increases,106 and no changes99,100,107,108 being found in patients relative to controls (see table 4). Part of this inconsistency is likely related to differences in the precise ACC subregion sampled. For example, most studies of dorsal area 24’ have reported no changes in neuronal density,99,100,107 with one reporting increased density in patients.106 Only 2 studies have examined the subcallosal ACC region separately,99,100 with neither reporting group differences in overall neuron density. However, they did find a decrease in the density of large-diameter neurons and an increase in small-diameter neurons in both subcallosal and dorsal regions, suggesting a selective shrinkage of large (presumably pyramidal) neurons. (Reports by others of changes in neuron size have been variable; see table 4.) Findings in the rostral ACC have been more consistent, although all the work in this area has been conducted by one group (table 4). A recent meta-analysis of their findings19 suggests that, while the density of both pyramidal and nonpyramidal neurons is reduced in schizophrenia patients, the reduction is greater for pyramidal neurons. In contrast, patients with bipolar disorder showed larger reductions in nonpyramidal neuron density. Independent replication of these results will be critical in establishing their generalizability.

In summary, the only 2 studies reporting absolute cell counts do not support neuronal loss in the ACC of schizophrenia patients, while the much larger literature examining cell density suggests that there are indeed reductions in the number of neurons per unit volume in some subregions. However, for a reduction in neuronal density to reflect neuronal loss, the degree of neuronal loss would either have to be accompanied by no change in cortical volume, or the reduction in neuron number would need to exceed the magnitude of any volumetric reduction since findings of reduced neuron density may also arise if neuron number remains unchanged but volume is increased (see 109 for similar arguments). Given the aforementioned MRI and neuropathological evidence for gray matter reductions in some ACC subregions, any reductions in neuron density would need to exceed the magnitude of the volumetric decrement to be interpreted as neuronal loss. Differences in cell-counting methodologies and subregions sampled across studies make it difficult to obtain a robust estimate of the magnitude of the density or volumetric reductions observed, and the 4 studies that have measured neuron density and gray matter thickness or volume concurrently have yielded inconsistent results: Benes et al101 found that minimal change in rostral ACC thickness was accompanied by a 40% reduction in pyramidal and 16% reduction in nonpyramidal neurons; Bouras et al100 reported larger reductions in thickness than neuron density in dorsal and subcallosal subregions; Ongur et al99 reported comparable reductions in density and volume in the subcallosal ACC; and Stark et al96 found no differences in either neuron density or volume in areas 24 and 32. Such results suggest that neuronal loss may be more pronounced in the rostral ACC, consistent with other reports of quite large (~50%) reductions in some neuronal subtypes in this area.110 However, differences in cell-counting techniques might contribute to inconsistencies across studies, given the ongoing debate regarding the accuracy and validity of 2- vs 3-dimensional methods (see 103 and related commentaries). In this context, it is noteworthy that studies employing 3-dimensional methods have been less likely to find significant differences in cell density (see table 4). The lack of studies examining the same subregion using these different approaches complicates comparison of findings reported by different research groups. However, one early report by Benes and Bird111 suggested that interneuronal distance is increased in the ACC of schizophrenia patients, supporting the notion that any reductions in cortical volume are not accompanied by an increase in packing density, which would be expected if cell number were unchanged. Findings of either no change 106,107,101,104 99 or a reduction in ACC glial density 96 in schizophrenia patients suggest that, if neuronal loss does occur in this disorder, it is not accompanied by the gliotic reactions associated with traditional neurodegenerative processes.1,112

Is there evidence of changes in the inter-cellular neuropil?
Accumulating evidence implicates synaptic pathology in schizophrenia 113,114. The first study of ACC synaptic morphology in the disorder was conducted by Aganova and colleagues 115, who found decreased density of axospinous and axodendritic synapses in a small (n = 5) sample. A later study investigating a larger sample (n = 11) found reduced dendritic density in layers III and V of rostral area 32 20 consistent with reports of decreased expression of synaptic proteins in the ACC of schizophrenia patients 108,116–118.

In rostral area 24, Benes et al. 119 reported an increase in the number of vertical afferents entering layers II and III in schizophrenia patients. These afferents were later confirmed to be glutamatergic in nature 120. In separate work, they found reduced density of fibers immunoreactive for tyrosine hydroxylase in the inter-neuronal neuropil, combined with a relative increase in the density of such fibers in apposition with small compared to large neurons 121. Collectively, these findings suggest that the ACC of schizophrenia patients possesses excess glutamatergic input, aberrant wiring of glutamatergic and dopaminergic circuits, and reduced synaptic and dendritic density.


   Are the changes secondary to antipsychotic treatment?
Top
 Abstract
 Structure and function of...
 Structural magnetic resonance...
 Neuropathology of the ACC...
 Are the changes secondary...
Bridging the gap: implications...
 Conclusions
 References
 
As previously mentioned, some MRI studies have found that medication can affect ACC gray matter measures, although the precise nature of such influences remains contentious. Only 2 studies of ACC gray matter in antipsychotic-naive patients have been conducted: an ROI study that found no differences between patients and controls67 and a WBM report finding that, relative to drug-free patients with psychosis (both schizophreniform and affective patients), those treated with typicals showed reduced ACC gray matter while those treated with atypicals showed no differences.122 We have found no differences in ACC gray matter between FE schizophrenia patients taking typical or atypical antipsychotics, after accounting for the confounding influence of PCS variability.68 While our study did not include unmedicated patients, findings of pre-onset changes in UHR individuals suggest that medication effects are insufficient to account for all the ACC gray matter reductions associated with schizophrenia.80,81 The duration of antipsychotic treatment may still play an important role however, given the aforementioned evidence suggesting that cumulative exposure to typical and atypical agents may have a differential effect on ACC gray matter over time,70,92 although several authors have failed to find any correlations between ACC gray matter measures and antipsychotic exposure.52,53,88

In postmortem work, restrictions on tissue availability make it difficult to comprehensively rule out treatment influences on the findings. Some authors have tested for medication effects by dividing their sample into patients taking or not taking medications prior to death,101 or examining statistical associations between indices of antipsychotic exposure and the measures of interest104,107(the latter is also commonly used to rule out an influence of other confounds associated with tissue handling and processing or demographic characteristics). However, given that the initial sample is often small, the power of such secondary analyses is limited. Most of the patients studied by Bouras et al100 lived prior to the introduction of neuroleptics, suggesting that not all neuropathological changes are attributable to medication effects, although these authors only found differences in ACC laminar thickness and neuron size, not density. Research in nonhuman primates suggests that, in some brain regions, antipsychotic exposure produces increased cortical volume and glial density with no change in neuronal number, findings that contrast with human data.123 Further characterization of the cellular changes induced by psychotropic medications will be necessary to facilitate interpretation of neuropathological research.


   Bridging the gap: implications for pathophysiology
Top
 Abstract
 Structure and function of...
 Structural magnetic resonance...
 Neuropathology of the ACC...
 Are the changes secondary...
 Bridging the gap: implications...
Conclusions
 References
 
To summarize, the available MRI data suggest that gray matter reductions in some ACC subregions, particularly dorsal and rostral areas, are a robust finding and are present prior to psychosis onset in some categories of high-risk individuals. There is some evidence to suggest that the earliest changes appear in the rostral ACCP, extend across the entire paralimbic region during the transition to psychosis, and spread to engulf limbic regions with ongoing illness, but more longitudinal data are required to confirm this. The postmortem findings indicate that these changes are accompanied by a reduction in neuronal, synaptic, and dendritic density, as well as increased afferentation, in some subregions. Given these data, how might the neuropathological and neuroimaging findings be integrated in a manner that provides clues regarding underlying pathophysiological mechanisms?

One important question is whether these changes are specific to the ACC. Volumetric reductions are commonly found in MRI studies of different brain regions in schizophrenia, although their neuropathological concomitants are not always the same. For example, reductions in dendritic density have been observed in both cingulate and prefrontal cortices,20,124 but the repeated reports of reduced cell density in some ACC subregions contrast with findings in the prefrontal cortex, where either no differences125–127 or density increases128,129 are more commonly found. Similarly, the increased density of ACC glutamatergic afferents identified by Benes et al119 was not observed in prefrontal area 10, although a similar increase is apparent in the entorhinal cortex of schizophrenia patients,130 implying similar pathologies may characterize functionally related networks.131 Such findings indicate that attributing differences in MRI measures of gray matter to a unitary process may be inaccurate and that a greater appreciation of the regional specificity of pathological processes in schizophrenia is required.132 Indeed, the findings reviewed in this article indicate that there is considerable heterogeneity even across ACC subregions.

When considering the histopathological correlates of gray matter reductions observed with MRI, an often overlooked fact that some authors95,133,134 have drawn attention to is that the cortical neuropil, as represented in T1-weighted imaging (the most commonly used protocol in volumetric studies), reflects the contribution of signals emanating from various neuronal and nonneuronal tissue compartments, including glial cell bodies, dendrites and spines, blood vessels, intracortical fibers, and extracellular components. Consequently, differences in cortical gray matter may result from variations in nonneuronal tissue. Indeed, the fraction of cortical volume occupied by axons has been estimated at approximately 29%,135 suggesting that up to one-third of the signal in T1-imaged cortex originates from white matter.134 Based on these findings, Paus134 and Sowell et al133 have argued that reports of longitudinal reductions in cortical gray matter during the course of normal adolescent development 94,136–138 may actually reflect ongoing myelination of axonal fibers penetrating the cortical mantle, rather than (or in addition to) the synaptic pruning that is thought to occur throughout adolescence in some brain regions.139,140 In this context, findings that schizophrenia patients show increased ACC afferentation119,120 suggest that myelination of these excess connections throughout adolescence and early adulthood may contribute to the grey matter reductions observed on MRI. This may also be related to findings of progressive gray matter reductions during transition to psychosis81 and in the first few years following illness onset89,141 because cingulate fibers continue to myelinate well into adulthood.142,143 However, an excess of afferent input has not yet been demonstrated in all ACC subregions, so it is unclear whether this process can explain all the gray matter reductions observed in the area.

An additional limitation associated with positing myelination of excess afferents as the sole cause of the gray matter reductions observed in the ACC is that it cannot account for reports of reduced synaptic and cell density in the region. Excessive synaptic pruning during adolescence is commonly proposed as a key pathophysiological mechanism in schizophrenia,144 and might partially account for the observed pre-onset grey matter reductions in the ACC and possible progression of these changes with continued illness, but it cannot explain the reductions in cell density. As previously discussed, the most straightforward interpretation of such findings is that they reflect cell loss. To some extent, the magnitude of cell density relative to volume reductions indirectly supports this conclusion, raising questions regarding the underlying mechanisms involved. Apoptosis is commonly invoked as a candidate mechanism because it is associated with cell death in the absence of gliosis, although arguments supporting its role have been based largely on speculative grounds. Indeed, the available postmortem data suggest that there is a downregulation, rather than increase, of apoptotic activity in schizophrenia. Benes et al145 have found decreased DNA fragmentation, a marker of oxidative stress, in rostral ACC neurons, while studies of hippocampal slices by this group revealed a downregulation of several proapoptotic genes, which contrasted with the general increases seen in patients with bipolar disorder.146 In temporal cortex, Jarskog et al147 found no evidence for elevations in the proapoptotic protein caspase 3. They also found reduced expression of the antiapoptotic protein Bcl-2 and an increase in the Bax/Bcl-2 ratio, which they interpreted as reflecting a vulnerability to apoptosis.147,148 Jarskog and coworkers114,149,150 have argued that these findings may reflect a compensatory downregulation following increased apoptotic activity occurring around the time of the illness. However, experimental data are lacking, and evidence supporting the occurrence of apoptotic cell death, as defined by ultrastructural criteria, throughout the mature brain appears limited.151,152 It is also possible that alterations in the expression of apoptotic proteins arise through their involvement in other functions.153

An alternative mechanism that can cause cell death in the mature brain without lasting gliosis arises from hypofunction of the N-methyl-D-aspartate receptor (NMDAR), a pathology receiving increasing support as a basis for schizophrenia.154–156 According to one theory, impaired excitation of NMDARs on GABAergic interneurons results in a net reduction of inhibitory tone and consequent increase in glutamatergic and cholinergic transmission at non-NMDA glutamate and muscarinic receptor sites.157 Evidence for its role in schizophrenia pathophysiology is based on findings that NMDAR antagonism with agents such as phencyclidine and ketamine produces psychotic symptoms and schizophrenia-like cognitive deficits in healthy individuals158–161 and exacerbates psychotic symptomatology in schizophrenia patients.156,162,163 In rodents, NMDAR antagonism can cause marked neuronal injury and/or death with only transient gliosis,164,165 and the peak period of neuronal sensitivity to such toxic effects occurs between puberty and adulthood166—the period of highest risk for schizophrenia onset.167 This apparent delay in vulnerability parallels human clinical data indicating that children are relatively immune to the psychotogenic effects of phencyclidine.168,169

While much of the rodent work indicates retrosplenial areas are the most sensitive to the toxic effects of NMDAR hypofunction,165 neuroimaging studies suggest that the ACC may be particularly vulnerable in humans. PET work has shown that ketamine administration causes marked blood flow and metabolism increases in the ACC that correlate with measures of psychotic symptoms in both healthy controls and schizophrenia patients.170–173 One recent study found that while both patients and controls showed increased ACC blood flow following ketamine infusion, the magnitude of the increase was much larger in the patient group,172 suggesting the ACC shows heightened sensitivity to the effects of NMDAR hypofunction in people with schizophrenia. That these blood flow increases are related to excess glutamatergic transmission is suggested by in vivo spectroscopy studies demonstrating elevated levels of glutamine, a metabolic precursor to glutamate, in the ACC of medication-naïve FE schizophrenia patients174,175, and in healthy volunteers following ketamine administration176. Post-mortem data showing large (>50%) decreases in the density of ACC GABAergic neurons bearing NMDAR subunits are also consistent with deficient stimulation of this receptor on GABAergic cells in the region110. Such abnormalities are likely to be potentiated in adolescence and early adulthood by the ongoing myelination of excess glutamatergic afferents to the region142,143. NMDAR hypofunction can also contribute to grey matter volume reductions by affecting synaptic density177, although apoptotic processes may also play a role114. Indeed, it is likely that expression of apoptotic proteins is altered in response to toxic events associated with NMDAR hypofunction 178, so an important avenue of future research will be to better understand interactions between these processes. It must be remembered however, that the evidence for neuronal loss in the ACC remains indirect, based primarily on studies of cell density rather than absolute number. The fact that only two studies, both in relatively small samples, have reported absolute cell counts concurrently with cortical volume means that further work is required to unambiguously interpret reports of reduced neuron density as evidence of cell loss.


   Conclusions
Top
 Abstract
 Structure and function of...
 Structural magnetic resonance...
 Neuropathology of the ACC...
 Are the changes secondary...
 Bridging the gap: implications...
 Conclusions
References
 
The considerable methodological variability across studies makes it difficult to draw firm conclusions regarding the precise nature of ACC pathology in schizophrenia. In this regard, the gap between neuroimaging and neuropathology still needs to bridged. Nonetheless, the evidence reviewed in this article suggests abnormalities in the region are a common finding and suggests strategies for future research that will facilitate more accurate characterization of relevant pathophysiological mechanisms. For neuroimaging researchers, these involve more longitudinal work tracking neuroanatomical changes from the high-risk to chronic illness stages that considers the influence anatomical variability has on the resulting measures. For neuropathologists, comparison of absolute cell counts in cytoarchitectonically defined regions with concurrent measures of cortical volume and thickness will be necessary to characterize the cellular basis of MRI-based morphometric changes. Continued integration of findings from these 2 fields will help identify neurobiological endophenotypes that can guide molecular work aimed at treatment development.


  Footnotes
 
1 To whom correspondence should be addressed; Melbourne Neuropsychiatry Centre, Levels 2 and 3, National Neuroscience Facility, 161 Barry St, Carlton South, Vic 3053, Australia; tel: + 61-3-8344-1861, fax: + 61-3-9348-0469, email: fornitoa{at}unimelb.edu.au.


   Acknowledgments
 
This research was supported by the Melbourne Neuropsychiatry Centre (Sunshine Hospital), Department of Psychiatry, the University of Melbourne, the National Health and Medical Research Council (ID 236175; 350241), and the Ian Potter Foundation. SJW was supported by a NHMRC Clinical Career Development Award and a NARSAD Young Investigator Award. AF was supported by a JN Peters Fellowship and NHMRC CJ Martin Fellowship (ID: 454797). MY was supported by a NHMRC Clinical Career Development Award (ID: 509345).


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