Widespread reductions in gray matter volume in depression

May combine two claims.

The maximal ACC volume differences were symmetric and corresponded to approximately CVNA: 26 years.

“The maximal ACC volume differences were symmetric and corresponded to approximately CVNA: 26 years.”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The gray matter difference at the maxima in BA 46 corresponded to a 24% volume difference on the left (CVNA: 32 years) and a 27% volume difference on the right (CVNA: 31 years).

“The GM difference centered at the maxima in BA 46 corresponded to a 24% volume difference on the left (CVNA: 32 years) and a 27% volume difference on the right (CVNA: 31 years).”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The anterior cingulate cortex component of cluster 2 was maximal in the caudal ACC (11%) but involved the whole ACC quite homogenously (global ACC ranged from 8 to 11%).

“The anterior cingulate cortex (ACC) component of cluster 2 was maximal in the caudal ACC (11%) but involved the whole of the ACC quite homogenously (global ACC ranged from 8 to 11%).”

May combine two claims.

Volumetric gray matter differences between MDD and controls were greatest in the frontal and temporal lobes (5.4% and 4.8%, respectively), with significant differences also present in the parietal and occipital lobes.

“These volumetric differences were greatest in the frontal and temporal lobes (5.4% and 4.8%, respectively), with significant differences also present in the parietal and occipital lobes.”

May combine two claims.

MDD participants had additional cortical gray matter reductions in posterior temporal and parieto-occipital cortices and subcortical reductions in basal ganglia and cerebellum.

“Additional reductions were observed cortically in the posterior temporal and parieto-occipital cortices and, subcortically in the basal ganglia and cerebellum.”

May combine two claims.

The VBM analysis showed large areas of decreased gray matter volume in MDD distributed across the brain, with no regions of increased gray matter volume.

“The VBM analysis showed large areas of decreased GM volume in MDD distributed across the brain, with no regions of increased GM volume.”

May combine two claims.

The gray matter volume decrease involved the entire mid- and posterior cingulate cortices, with volume differences ranging from 8 to 11% (CVNA: 32-42 years) and anatomically symmetric.

“The GM volume decrease involved the entire mid- and posterior cingulate cortices. The volume differences were quite homogenous and similar in magnitude to that seen in the ACC, ranging from 8 to 11% (CVNA: 32–42 years). The changes were anatomically symmetric.”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

MDD participants had reduced gray matter volume in the anterior cingulate cortex, regions of the prefrontal circuits including dorsolateral and dorsomedial prefrontal cortices, and lateral and medial orbitofrontal cortices, but not in limbic regions.

“MDD participants had reduced gray matter volume in the anterior cingulate cortex, regions of the prefrontal circuits, including dorsolateral and dorsomedial prefrontal cortices, and lateral and medial orbitofrontal cortices, but not in limbic regions.”

May combine two claims.

The lobar gray matter volume differences equated to CVNA values of 12 years (frontal), 10 years (parietal), 15 years (temporal), and 14 years (occipital).

“The lobar GM volume differences equated to CVNA values of 12 years (frontal), 10 years (parietal), 15 years (temporal) and 14 years (occipital).”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The decreased gray matter volume in the medial OFC cluster corresponded to a difference of approximately 8-10% (CVNA: 23-25 years), and the changes were anatomically symmetric.

“The decreased GM volume in this cluster corresponded to a difference of approximately 8–10% (CVNA: 23–25 years). The changes were anatomically symmetric.”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The gyrus rectus gray matter differences were 26% but restricted to the posterior portion (CVNA: > 50 years).

“The gyrus rectus GM differences (26%) were profound but restricted to the posterior portion (CVNA: > 50 years).”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The quote only partly states this claim.

The VBM analysis found a dominant bilateral posterior temporal lobe cluster spanning the inferior/middle/superior temporal gyri.

“a broad region in the posterior temporal lobe spanning the inferior/middle/superior temporal gyri”

May combine two claims.

For the lateral OFC, the peak cluster was located in the middle frontal gyrus with a gray matter difference of 19% (CVNA: 24 years).

“For the lateral OFC, the peak cluster was located in the middle frontal gyrus (GM difference of 19%, CVNA: 24 years).”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The cortical thickness data confirmed the GM changes present in the medial OFC, but did not detect cortical thinning elsewhere.

“Our cortical thickness data confirmed the GM changes present in the medial OFC, but did not detect cortical thinning elsewhere.”

May combine two claims.

Scattered gray matter volume differences were present in the cerebellum; the largest were located bilaterally in the posterior crus I region (23%; CVNA: > 50 years).

“Scattered GM volume differences were present in the cerebellum; the largest of these were located bilaterally in the posterior crus I region (23%; CVNA: > 50 years).”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

The authors identified a generalized midline GM volume loss that correlates anatomically with the midline resting state default mode network regions, as well as strong GM loss in the medial temporal lobe, cerebellum and pre/post central gyrus.

“In addition to these “usual suspects”, we identified a generalized midline GM volume loss that correlates anatomically with the midline resting state default mode network regions which have been implicated in depression, as well as strong GM loss in the medial temporal lobe, cerebellum and pre/post central gyrus.”

May combine two claims.

Additional regions of the brain were found to have significant GM loss with MDD, including the medial temporal lobe (13%), the gyrus rectus (26%) and the occipital lobe (8-14%).

“Additional regions of the brain were also found to have significant GM loss with MDD, including the medial temporal lobe (13%), the gyrus rectus (26%) and the occipital lobe (8–14%).”

May combine two claims.

No significant hippocampal or amygdala GM volume loss was present with MDD.

“One of the most striking findings in our study was that no significant hippocampal or amygdala GM volume loss was present with MDD.”

May combine two claims.

Regional GM differences were present in the DLPFC (27%), ACC (11%) and the medial orbital frontal cortex (10%).

“Regional GM differences were present in the DLPFC (27%), ACC (11%) and the medial orbital frontal cortex (10%), all regions that have an established role in the pathophysiology of MDD.”

May combine two claims.

When the contrast MDD > controls was tested, MDD participants had a focal region of left lateral OFC with increased cortical thickness compared to controls; the cluster size was very small at 8 vertices (16% increase; FDR-corrected p-value < 0.001).

“Interestingly, when the contrast MDD > controls was tested, MDD participants were found to have a focal region of left lateral OFC with increased cortical thickness compared to controls; however, the cluster size for this finding was very small at 8 vertices (16% increase; FDR-corrected p-value < 0.001).”

• Also stated in: § Discussion · hedged

  “In contrast to the GM findings, we found a very focal region of increased thickness in the left lateral OFC; however the significance of this finding is unclear.”

May combine two claims.

Strong abnormal fMRI measures affecting the amygdala were observed in the current cohort, but the associated GM volume changes in the amygdala were weak and may not be as robust to observe for assessments made at the whole brain level.

“Although, we observe strong abnormal fMRI measures affecting the amygdala in the current cohort, the associated GM volume changes in the amygdala were weak (Grieve et al., 2013) and may not be as robust to observe for assessments made at the whole brain level.”

• cites Grieve et al., 2013 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Focal regions of gray matter volume difference were present in the left anterior thalamus, left putamen, and left caudate, with gray matter volume decreases of 9%, 7%, and 8%, respectively (CVNA 13-15 years).

“Focal regions of GM volume difference were also present in the left anterior thalamus, left putamen and left caudate (GM volume decrease: 9%, 7% and 8%, respectively; CVNA 13–15 years).”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Prevailing theories of MDD mechanisms highlight an imbalance between an overactive salience network (putamen, amygdala, anterior cingulate) and decreased responsiveness in contextual processing regions (dorsal striatum and DLPFC).

“These data have informed prevailing theories of the mechanisms of MDD, which highlight an imbalance between an overactive salience network (involving in the putamen, amygdala, and anterior cingulate) and decreased responsiveness in regions involved in contextual processing (dorsal striatum and dorsolateral prefrontal cortex — DLPFC) (Hamilton et al., 2012).”

• cites Hamilton et al., 2012 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Heterogeneity of the condition itself likely contributes to variability in the structural literature relating to MDD.

“A further factor that likely contributes to the variability in the nature of the structural literature relating to MDD is the heterogeneity of the condition itself.”

May combine two claims.

The data supporting gray matter changes in MDD is limited due to small participant numbers in most studies, large variation in identified regions, and enormous variation in methodology.

“Considered overall, the data that supports these changes is limited due to the small number of participants in most studies, the large amount of variation in the regions identified and the enormous variation in methodology.”

May combine two claims.

Two recent meta-analyses show convergent findings for cingulate and orbitofrontal cortex regions but differ in findings relating to striatal and limbic structures.

“The heterogeneity between studies is echoed in two recent meta-analyses which show convergent findings for cingulate and OFC regions but differ in their findings relating to striatal and limbic structures (Egger et al., 2008; Tang et al., 2007).”

• cites Egger et al., 2008 sourceNot checked yet

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• cites Tang et al., 2007Not checked yet

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May combine two claims.

Volumetric gray matter regional loss occurs in MDD, but the precise pattern of this loss has not been clearly defined.

“While it is clear that volumetric GM regional loss occurs in MDD, the precise pattern of this loss has not been clearly defined.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The DLPFC has been consistently identified in functional imaging studies of MDD.

“Another region which has been consistently identified in functional imaging studies of MDD is the DLPFC”

Probably not a substantial claim: may not pass S3 (load-bearing).

A recent analysis of gray matter structural networks highlighted global organizational abnormalities associated with a diagnosis of depression.

“A recent analysis of gray matter structural networks highlighted the presence of global organizational abnormalities that are associated with a diagnosis of depression (Singh et al., in press).”

• cites Singh et al., in pressNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

A substantial body of imaging data demonstrates spatially distributed functional abnormalities occurring throughout the brain in MDD.

“A substantial body of imaging data demonstrates spatially distributed functional abnormalities occurring throughout the brain in MDD (Drevets et al., 2008).”

• cites Drevets et al., 2008 sourceNot checked yet

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Classified as probably not a substantial claim.

Previous data from this study support the concept that functional and white matter DTI structural deficits underlie the fronto-limbic dysfunction observed in MDD.

“We have recently presented data from this study supporting the concept that functional and white matter Diffusion Tensor Imaging (DTI) structural deficits underlie the fronto-limbic dysfunction observed in MDD (Grieve et al., 2013; Korgaonkar et al., 2011, 2012).”

• cites Grieve et al., 2013 sourceNot checked yet

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• cites Korgaonkar et al., 2011, 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim. May combine two claims.

Global patterns of abnormalities identified using DTI and functional MRI suggest that associated gray matter changes may also be present and might reflect these abnormal networks.

“The global patterns of the abnormalities that are being identified using DTI and functional MRI suggest that associated GM changes may also be present which might reflect these abnormal networks.”

May combine two claims.

Existing studies in MDD have shown loss of gray matter volume across cortical regions including medial prefrontal anterior cingulate and orbitofrontal cortex, lateral prefrontal cortex, temporal cortex, and pre- and post-central gyri.

“Existing studies in patients with MDD have shown loss of GM volume across a range of cortical brain regions, including the medial prefrontal regions of the anterior cingulate cortex and orbitofrontal cortex (OFC), the lateral prefrontal cortex, the temporal cortex (Ballmaier et al., 2004), and the pre- and post-central gyri (Taki et al., 2005).”

• cites Ballmaier et al., 2004 sourceNot checked yet

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• cites Taki et al., 2005Not checked yet

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Classified as probably not a substantial claim.

Because the cohort was age and gender matched, the analyses did not co-vary for age and gender.

“Since our cohort was age and gender matched we did not co-vary for these parameters.”

• AssumptionRests on an assumption: Age and gender matching is sufficient to remove confounding by age and gender.

May combine two claims.

The relatively young age of the cohort is important because the DLPFC undergoes accelerated GM loss during normal aging, so in a geriatric MDD cohort these changes may be attenuated relative to the normal population due to age-related changes common to both groups.

“The relatively young age of our cohort is also important since the DLPFC undergoes accelerated GM loss during “normal” aging (Grieve et al., 2005), so in a geriatric MDD cohort these changes may be attenuated relative to the normal population due to age-related changes common to both groups.”

• cites Grieve et al., 2005 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

This study is the largest to specifically examine GM volumetric changes in MDD and provides a very robust level of evidence documenting the structural pattern of GM loss.

“Ours is the largest study to specifically examine GM volumetric changes in MDD and it provides a very robust level of evidence documenting the structural pattern of GM loss.”

May combine two claims.

The medial orbital prefrontal cortex/gyrus rectus is badly affected by magnetic susceptibility artifact in fMRI studies, and to a lesser extent in DTI studies, due to the sensitivity of the echo planar imaging sequence to magnetic field gradients that occur adjacent to the paranasal sinuses.

“Importantly, the medial orbital prefrontal cortex/gyrus rectus is badly affected by magnetic susceptibility artifact in fMRI studies, and to a lesser extent in DTI studies, due to the sensitivity of the echo planar imaging sequence to magnetic field gradients that occur adjacent to the paranasal sinuses.”

• cites Cusack et al., 2005 sourceNot checked yet

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• cites Grieve, 2000 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A VBM analysis is an unbiased method to tackle these issues, but the necessity for a severe correction for type 1 error at the whole brain level may limit statistical power especially with smaller cohorts.

“While a VBM analysis is an unbiased method to tackle these issues, the necessity for a severe correction for type 1 error at the whole brain level may limit statistical power especially with smaller cohorts.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Cortical segmentation and labels were manually inspected for accuracy.

“Cortical segmentation and labels were manually inspected for accuracy.”

Classified as probably not a substantial claim.

A statistical threshold of p < 0.05 (false discovery rate corrected for multiple comparisons) was used.

“A statistical threshold of p < 0.05 (false discovery rate [FDR] corrected for multiple comparisons) was used.”

Classified as probably not a substantial claim.

Cross-sectional data is unable to clarify whether these volume changes precede the development of depression or whether they occur secondary to the depressive state.

“Cross-sectional data is unable to clarify whether these volume changes precede the development of depression or whether they occur secondary to the depressive state.”

Classified as probably not a substantial claim. May combine two claims.

These gradients reduce the contrast-to-noise of the Blood Oxygenation Level-Dependent response and also cause geometric distortion.

“These gradients reduce the contrast-to-noise of the Blood Oxygenation Level-Dependent response and also cause geometric distortion (Cusack et al., 2005; Grieve, 2000).”

• cites Cusack et al., 2005 sourceNot checked yet

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• cites Grieve, 2000 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The focal region of increased thickness in the left lateral OFC may be secondary to the loss in sensitivity implicit in a whole-brain analysis, or may be a reflection that the GM volume changes are not adequately captured by cortical thickness measures.

“This finding may be secondary to the loss in sensitivity implicit in a whole-brain analysis, or may be a reflection that the GM volume changes are not adequately captured by cortical thickness measures.”

May combine two claims.

The key methodological factors contributing to heterogeneity in DLPFC findings are the variability in delineating this region across previous studies employing a region of interest approach and the large inter-individual variability for this region.

“The key methodological factors contributing to this are the variability in delineating this region across previous studies employing a region of interest approach and the large inter-individual variability for this region (Sanches et al., 2009).”

• cites Sanches et al., 2009 sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

The study presents a highly powered, highly standardized cross-sectional analysis of a well-described cohort with depression.

“Our study presents a highly powered, highly standardized cross-sectional analysis of a well-described cohort with depression, providing valuable and novel insights into the GM volume changes that characterize depression.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The study was conducted according to the principles of the Declaration of Helsinki 2008.

“This study was conducted according to the principles of the Declaration of Helsinki 2008.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The cohort is well characterized and non-geriatric, with an average age of 34 years (standard deviation: 13 years).

“Our cohort is well characterized and non-geriatric, with an average age of 34 years (standard deviation: 13 years).”

Classified as probably not a substantial claim.

The CVNA comparisons are based on previously presented data on normal aging in 476 individuals without a psychiatric or other medical diagnosis.

“These comparisons are based on our previously presented data on normal aging in 476 individuals without a psychiatric or other medical diagnosis (Grieve et al., 2005, 2011).”

• cites Grieve et al., 2005, 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The whole-brain analysis approach used in the study means that no a priori regional bias was added to the findings.

“The whole-brain analysis approach used in the study also means that no a priori regional bias was added to our findings.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The OFC has extensive connections with the limbic system, including from the cingulate cortex.

“The OFC has extensive connections with the limbic system, including from the cingulate cortex (Ongür and Price, 2000).”

• cites Ongür and Price, 2000Not checked yet

  Not checked in the free run.

May combine two claims.

The cohort is a relatively young population and has an average duration of depression of 11 years.

“Our cohort is a relatively young population and has an average duration of depression of 11 years.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Volumetric changes of the hippocampus that occur with age, with various neuropsychiatric disorders, and also in response to stress are quite heterogeneous.

“While some of the reasons for this may be methodological such as MR image acquisition parameters, post acquisition processing and the method used for volumetric assessment (Geuze et al., 2005; Morey et al., 2009), it is clear that volumetric changes of the hippocampus that occur with age, with various neuropsychiatric disorders, and also in response to stress are quite heterogeneous.”

• cites Geuze et al., 2005 sourceNot checked yet

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• cites Morey et al., 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Previous studies with different MDD cohorts that looked at both GM volume and cortical thickness measures have shown mixed data, with some having shown no cortical thickness changes while others have shown changes.

“Previous studies (with different MDD cohorts) that looked at both of these measures have shown mixed data, with some having shown no cortical thickness changes while others have shown changes.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The lack of correlation in this study replicates previous studies that found the same, but a significant association between GM volume and depression severity has also been previously reported.

“While the lack of correlation in our study replicates previous studies that found the same (McKinnon et al., 2009; Zou et al., 2010), a significant association between GM volume and depression severity has also been previously reported (Chen et al., 2007; Cheng et al., 2010).”

• cites McKinnon et al., 2009 sourceNot checked yet

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• cites Zou et al., 2010 sourceNot checked yet

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• cites Chen et al., 2007 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Hippocampal volume loss has been identified as a significant feature of MDD in one recent meta-analysis of structural brain changes in depression, but not in a second meta-analysis.

“Hippocampal volume loss has been identified as a significant feature of MDD in one recent meta-analysis of structural brain changes in depression, but not in a second meta-analysis.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Previous work using DTI data showed that connectivity in the cingulate portion of the cingulate bundle has structural changes with MDD at baseline and also has an impact on remission.

“Our previous work using DTI data showed that connectivity in the cingulate portion of the cingulate bundle has structural changes with MDD at baseline and also has an impact on remission (Korgaonkar et al., under review).”

• cites Korgaonkar et al., under reviewNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The functional role of the cingulate cortex-and specifically the ACC-in depression is well described.

“The functional role of the cingulate cortex—and specifically the ACC—in depression is well described (Drevets et al., 2008).”

• cites Drevets et al., 2008 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Abnormal resting state functional connectivity of these same regions has been described in MDD.

“Abnormal resting state functional connectivity of these same regions has been described in MDD (Greicius et al., 2007).”

• cites Greicius et al., 2007 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Heritability analyses using twins data have demonstrated that there are different genetic drivers for GM volume and cortical thickness measures.

“Heritability analyses using twins data have demonstrated that there are different genetic drivers for GM volume and cortical thickness measures (Winkler et al., 2010).”

• cites Winkler et al., 2010 sourceNot checked yet

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