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Cited by 561Neurological disorders and treatmentsObsessive-Compulsive Spectrum DisordersAdvanced Neuroimaging Techniques and Applications

Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression

Open access
Johansen-Berg, H., Gutman, D. A., Behrens, T. E. J., Matthews, P. M., Rushworth, M. F. S., Katz, E., Lozano, A. M., Mayberg, H. S.·2008·Cerebral Cortex
DOI 10.1093/cercor/bhm167PMC PMC7610815
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Abstract

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

AI snapshot

Written from the paper’s full text.

TL;DR

Diffusion tractography in healthy controls identified two distinct connectivity-based subregions within the perigenual anterior cingulate: a pregenual region and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. Effective electrode contacts from 9 successfully treated deep brain stimulation patients fell predominantly within the subgenual region, supporting a distributed frontal-limbic-visceromotor network as the likely substrate of treatment efficacy.

Key findings

  • Connectivity-based parcellation defined 2 regions within the perigenual ACC: a pregenual ACC (pACC) strongly connected to medial prefrontal and anterior midcingulate cortex, and a subgenual ACC (sACC) with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex.
  • Of active electrode contact points from 9 patients successfully treated with subgenual cingulate DBS, 6/9 were located within the sACC region thresholded at >50% population probability; the remaining 3/9 were just outside the superior border of that sACC region, and none were within the pACC white matter population map.
  • The sACC was more strongly connected to orbitofrontal cortex, fornix, and medial temporal lobe near amygdala and anterior hippocampus; pACC was more strongly connected to frontal pole and less strongly to medial temporal lobe.
  • The authors conclude that DBS efficacy may be mediated via a distributed network of frontal, limbic, and visceromotor brain regions, and hypothesize that the subgenual region with greatest connectivity across this network may prove most effective.

Methods

  • Diffusion-weighted MRI was acquired in 17 healthy right-handed subjects (11 males, 6 females, aged 20–38 years) on a 1.5-T scanner with 60 diffusion directions at b = 1000 s/mm² and 2 × 2 × 2 mm voxels; T1-weighted anatomical images were also acquired.
  • Probabilistic tractography used a multi-fiber diffusion model with 25,000 streamline samples per seed voxel. Analyses included ROI-based connectivity from perigenual ACC to PET-defined target regions, blind connectivity-based parcellation using cross-correlation and spectral reordering, and projection of electrode contacts from 9 DBS patients onto population parcellations.
  • Population probability maps were thresholded to include voxels present in at least 50% of the population; electrode locations were projected manually onto a standard brain by an experimenter blind to the connectivity-based parcellation.

Limitations

  • The paper states that tractography cannot differentiate anterograde from retrograde or direct from indirect connections, is susceptible to false negatives, and is most sensitive to major fiber bundles; small or tortuous paths are harder to track. It also states that absolute conclusions about absence of a pathway cannot be made.
  • The paper states that connectivity-based parcellation reduces connectivity measures to binary values, and that connection probability estimates can be affected by factors such as path length or geometry.
  • The paper states that patient numbers were small, only patients with good outcome were considered, there was no placebo-controlled design, and electrode contacts were projected onto healthy control DWI data; an explicit analysis relating electrode location, connection patterns, and surgical outcome in depressed patients was not performed. Evident from the text: the connectivity map is derived from healthy controls rather than the depressed patients who received DBS, and the initial ROI-based analysis was limited to regions previously showing PET activation changes after DBS.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/cercor/bhm167

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 72 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Within the perigenual ACC, connections with the anterior midcingulate cortex and frontal pole are more prominent in the pregenual cingulate.

    “Connections with the AMCC and FP are more prominent in the pregenual cingulate (Fig. 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The dominant connection in the most anterior-lateral parts of the perigenual ACC seed ROI was with frontal pole.

    “with FP in the most anterior-lateral parts of the seed ROI”
    Quote in the paperNot a substantial claim
  • Findingown data

    Within the perigenual ACC, connections with the amygdala, hypothalamus, nucleus accumbens, and orbitofrontal cortex are strongest in the more posterior, subgenual part of the ACC.

    “Connections with the amygdala, hypothalamus, NAC, and OFC are strongest in the more posterior, subgenual part of the ACC (Fig. 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Automated, blind connectivity-based parcellation defined two regions with distinct connectivity within the ventral ACC region for each individual.

    “Automated, “blind” connectivity-based parcellation defined 2 regions with distinct connectivity within the ventral ACC region for each individual.”
    Quote in the paperSubstantial claim
  • Findingown data

    The dominant connection from the most dorsal parts of the perigenual ACC seed ROI was with anterior midcingulate cortex.

    “The dominant connections were with AMCC from the most dorsal parts of the perigenual ACC seed ROI”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 20
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim.

    Findingown data

    The two regions were combined in standard brain space to create a probabilistic, population-based parcellation of the perigenual ACC ROI into a pregenual ACC (pACC) and a subgenual ACC (sACC).

    “These were combined in standard brain space to create a probabilistic, population-based parcellation of the perigenual ACC ROI into 2 subregions: a pregenual ACC (pACC, red to yellow, Fig. 3A,B) and an sACC (dark blue to light blue, Fig. 3A,B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Paths from sACC to the medial temporal lobe took two distinct routes: a direct path traveled laterally to the amygdala, and a second route traveled posteriorly along the fornix.

    “Paths to the medial temporal lobe took 2 distinct routes: a direct path traveled laterally to the amygdala, whereas a second route traveled posteriorly along the fornix.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Connections to many of the target ROIs are present throughout the perigenual ACC, but the strength of these connections varies depending on the location within the ACC.

    “Although connections to many of the target ROIs are present throughout the perigenual ACC, the strength of these connections varies depending on the location within the ACC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In human data, connections between pACC and medial OFC on the gyrus rectus are present but weaker than connections between sACC and medial OFC.

    “Connections between pACC and medial OFC on the gyrus rectus were present in our human data albeit, as in the macaque (Carmichael and Price 1996), weaker than connections between sACC and medial OFC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Human pACC has a connection with the fornix, weaker than that from sACC.

    “Human pACC was found to have a connection with the fornix, albeit weaker than that found from sACC.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    The sACC region was more strongly connected with the OFC, fornix, and medial temporal lobe in the vicinity of the amygdala and anterior hippocampus than pACC.

    “For example, the sACC region was more strongly connected with the OFC, fornix, and medial temporal lobe in the vicinity of the amygdala and anterior hippocampus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Electrode sites for patients who responded well to surgery were located within the sACC region, rather than the pACC region in this study, consistent with the intended surgical target.

    “Electrode sites for patients who responded well to surgery were located within the sACC region, rather than the pACC region in this study, consistent with the intended surgical target.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The connections of sACC specifically have not previously been studied in the human brain, and the pathways running through the white matter region underlying sACC and targeted in DBS have not been established.

    “However, the connections of sACC specifically have not previously been studied in the human brain, and the pathways running through the white matter region underlying sACC and targeted in DBS have not been established.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Croxson et al. 2005 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent advances in modeling of local diffusion properties allow estimation of more than one fiber direction at each voxel, enabling tracing of crossing fibers.

    “Recent advances in modeling of local diffusion properties allow estimation of more than 1 fiber direction at each voxel, enabling tracing of crossing fibers (Behrens et al. 2007)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Behrens et al. 2007 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    By modeling local diffusion properties, it is possible to estimate these directions and to follow them using probabilistic tractography.

    “By modeling local diffusion properties, it is possible to estimate these directions and to follow them using probabilistic tractography (Behrens, Johansen-Berg, et al. 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Behrens, Johansen-Berg, et al. 2003

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting of DBS for depression.

    “Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In brain white matter, self-diffusion of water molecules is directionally dependent and the principal diffusion direction corresponds to the predominant direction in oriented fiber bundles.

    “In brain white matter, self-diffusion of water molecules is directionally dependent and the principal diffusion direction corresponds to the predominant direction in oriented fiber bundles (Beaulieu and Allen 1994).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Beaulieu and Allen 1994

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  • Classified as probably not a substantial claim.

    Interpretationcitation

    It is possible that slight variations in electrode placements could have a substantial impact on outcome.

    “it is possible that slight variations in electrode placements could have a substantial impact on outcome.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Carmichael and Price 1994, 1996

      Not checked in the free run.

    • cites Vogt et al. 2005 source

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  • May combine two claims.

    Premisecitation

    Only preliminary data concerning the anatomical connectivity of ACC are available for the human brain, and regional variations in connectivity between subregions of human ACC have not previously been investigated.

    “Only preliminary data concerning the anatomical connectivity of ACC are available for the human brain (Croxson et al. 2005), and regional variations in connectivity between subregions of human ACC have not previously been investigated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Croxson et al. 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pathways traced using this tractography approach are reproducible and generally reproduce those identified using postmortem dissection or tract tracing.

    “Pathways traced in this way are reproducible (Heiervang et al. 2006) and generally reproduce those identified using postmortem dissection or tract tracing (Stieltjes et al. 2001; Croxson et al. 2005).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Heiervang et al. 2006 source

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    • cites Stieltjes et al. 2001 source

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    • cites Croxson et al. 2005 source

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

    Premisecitation

    The volume of sACC is reduced in certain depressed groups.

    “The volume of sACC is reduced in certain depressed groups (Botteron et al. 2002; Coryell et al. 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Botteron et al. 2002 source

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    • cites Coryell et al. 2005 source

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

    Study design and conductnone given

    Representations of the pathways from pACC and sACC, and the differences between them, are dependent on data quality, the performance of the tractography algorithm, and the thresholds used to display the paths.

    “Note also that representations of the pathways from pACC and sACC (Fig. 4), and the differences between them, are dependent on data quality, the performance of the tractography algorithm, and the thresholds used to display the paths.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    We previously found prominent connections between cingulate gyrus and amygdala, cingulum bundle, and NAC in both human and macaque.

    “Consistent with our current findings on the connectivity of sACC specifically, we previously found prominent connections between cingulate gyrus and amygdala, cingulum bundle, and NAC in both human and macaque (Croxson et al. 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Croxson et al. 2005 source

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  • May combine two claims.

    Premisecitation

    sACC is functionally and cytoarchitectonically distinct from the more dorsal part of the anterior cingulate, located anterior to the genu, comprising BA32 and inferior parts of BA24.

    “It is functionally and cytoarchitectonically distinct from the more dorsal part of the anterior cingulate, located anterior to the genu, comprising BA32 and inferior parts of BA24 (Carmichael and Price 1994; Vogt et al. 1995, 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carmichael and Price 1994 source

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    • cites Vogt et al. 1995, 2005

      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).

    Premisecitation

    Previous brain imaging studies have implicated sACC in experience of negative mood states.

    “Previous brain imaging studies have implicated sACC in experience of negative mood states (George et al. 1995; Mayberg et al. 1999).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites George et al. 1995 source

      Not checked in the free run.

    • cites Mayberg et al. 1999 source

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

    Interpretationreasoning

    It is not possible to make absolute conclusions about the absence of a given pathway.

    “It is therefore not possible to make absolute conclusions about the absence of a given pathway.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    This latter route is consistent with previously reported hippocampal inputs to medial prefrontal areas and with reports that the hippocampal projections from adjacent orbitofrontal areas travel via the fornix.

    “This latter route is consistent with previously reported hippocampal inputs to medial prefrontal areas (Carmichael and Price 1995a, 1995b) and with reports that the hippocampal projections from adjacent orbitofrontal areas travel via the fornix (Cavada et al. 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carmichael and Price 1995a, 1995b

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    • cites Cavada et al. 2000 source

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

    Premisecitation

    Over-activation of limbic regions including the hypothalamus and amygdala and underactivation of medial prefrontal cortex have been observed during performance of a sustained attention task in patients with bipolar disorder studied when euthymic.

    “Over-activation of limbic regions including the hypothalamus and amygdala and underactivation of medial prefrontal cortex have been observed during performance of a sustained attention task in patients with bipolar disorder studied when euthymic (Strakowski et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Strakowski et al. 2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    We found evidence for anatomical pathways linking the perigenual ACC with remote areas that had altered functional responses following chronic subgenual DBS, providing a potential anatomical substrate for these altered functional responses.

    “We found evidence for anatomical pathways linking the perigenual ACC with these remote areas, providing a potential anatomical substrate for these altered functional responses.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Locations of electrode contacts used for stimulation were projected manually onto a standard brain based on distances from clearly visible local landmarks by an experimenter blind to the connectivity-based parcellation.

    “Locations of electrode contacts used for stimulation were therefore projected manually onto a standard brain based on distances from clearly visible local landmarks (e.g., edges of ventricles, corpus callosum) by an experimenter blind to the connectivity-based parcellation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The connectivity-based division between pACC and sACC does not require the tractography analysis to accurately identify all the connections of these two regions; it depends only on detection of a change in connectivity between the two regions.

    “Note that the connectivity-based division between pACC and sACC does not require the tractography analysis to accurately identify all the connections of these 2 regions. The connectivity-based division depends only on detection of a change in connectivity between the 2 regions.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Decreases in sACC activity have been reported following successful treatment of depression with a variety of nonsurgical interventions including pharmacological treatments, electroconvulsive therapy, and transcranial magnetic stimulation.

    “Decreases in sACC activity have been reported following successful treatment of depression with a variety of nonsurgical interventions including pharmacological treatments (Mayberg et al. 2000; Drevets et al. 2002), electroconvulsive therapy (Nobler et al. 2001), and transcranial magnetic stimulation (Mottaghy et al. 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Mayberg et al. 2000 source

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    • cites Drevets et al. 2002 source

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    • cites Nobler et al. 2001 source

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  • May combine two claims.

    Premisecitation

    Resting blood flow recordings reveal hypoperfusion across a network of frontoparietal regions and hyperperfusion in subgenual cingulate and anterior insular cortices both in mood disorder and also with induction of transient sadness in healthy subjects.

    “Resting blood flow recordings reveal hypoperfusion across a network of frontoparietal regions and hyperperfusion in subgenual cingulate and anterior insular cortices both in mood disorder and also with induction of transient sadness in healthy subjects (Mayberg et al. 1999; Liotti et al. 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mayberg et al. 1999 source

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    • cites Liotti et al. 2002 source

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

    Interpretationnone given

    The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections.

    “The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Failure to respond to treatment can be predicted by altered functional interactions across a corticolimbic circuit including sACC.

    “Failure to respond to treatment can be predicted by altered functional interactions across a corticolimbic circuit including sACC (Seminowicz et al. 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Seminowicz et al. 2004 source

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

    Premisecitation

    In monkey brain, amygdala projections are stronger from the subgenual than the pregenual cingulate region.

    “The strength of connections from different cingulate subregions is rarely systematically compared in macaque, but it has been claimed that, as we have found for the human brain, amygdala projections are stronger from the subgenual than the pregenual cingulate region in the monkey brain (Chiba et al. 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chiba et al. 2001 source

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

    Premisecitation

    A number of ACC regions are interconnected with the amygdala.

    “A number of ACC regions are known to be interconnected with the amygdala (Van Hoesen et al. 1993; Morecraft et al. 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Van Hoesen et al. 1993

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    • cites Morecraft et al. 2007 source

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

    Premisecitation

    Successful treatment of mood disorder results in a relative normalization of these activity patterns.

    “Successful treatment of mood disorder results in a relative normalization of these activity patterns (Mayberg et al. 1999, 2005; Goldapple et al. 2004; Kennedy et al. 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Mayberg et al. 1999, 2005

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

    • cites Goldapple et al. 2004 source

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    • cites Kennedy et al. 2007 source

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  • May combine two claims.

    Interpretationreasoning

    Human evidence is largely consistent with available data from nonhuman primates and confirms the relevance of work in macaques for understanding the functional anatomy of this region.

    “Our evidence in the human brain is therefore largely consistent with available data from nonhuman primates and so confirms the relevance of work in macaques for understanding the functional anatomy of this region.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In macaque, area 32 is interconnected with the hippocampus.

    “In the macaque, area 32 is interconnected with the hippocampus (Carmichael and Price 1995a, 1995b)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carmichael and Price 1995a

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    • cites Carmichael and Price 1995b

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  • May combine two claims.

    Study design and conductcitation

    Use of a multi-fiber tractography algorithm increased the chances of tracking through regions of fiber complexity or crossing, but the approach is potentially susceptible to false negatives.

    “Although use of a multi-fiber tractography algorithm will have increased our chances of tracking through regions of fiber complexity or crossing (Behrens et al. 2007), the approach is nevertheless potentially susceptible to false negatives.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Behrens et al. 2007 source

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  • May combine two claims.

    Study design and conductreasoning

    The current study considered only patients with good outcome, and an investigation of the relationship between electrode location and surgical outcome would be premature at this stage.

    “The current study considered only patients with good outcome as the number of patients implanted and studied to date is relatively small, and therefore, an investigation of the relationship between electrode location and surgical outcome would be premature at this stage.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Animal studies have revealed differences between sACC and pACC connections to the shell and core of the NAC, respectively.

    “Similarly, although animal studies have revealed differences between sACC and pACC connections to the shell and core of the NAC, respectively (Haber et al. 1995), the current resolution of imaging tractography limits delineations of these distinctions in the human brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Haber et al. 1995 source

      Not checked in the free run.

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

    Premisecitation

    Previous studies using diffusion imaging have demonstrated reduced fractional anisotropy in ACC and prefrontal white matter generally in depressed subjects.

    “Previous studies using diffusion imaging have demonstrated reduced fractional anisotropy in ACC and prefrontal white matter generally in depressed subjects (Taylor et al. 2004; Bae et al. 2006; Nobuhara et al. 2006); future studies using diffusion tractography should test the integrity of the specific tracts identified here in patients with mood disorders.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Taylor et al. 2004 source

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    • cites Bae et al. 2006 source

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    • cites Nobuhara et al. 2006 source

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

    Study design and conductcitation

    Measures of connection probability provided by tractography can be used to make inferences about the relative strength of different fiber populations, but such conclusions must be made with care as other factors, such as the length or geometry of a path, will also affect these measures.

    “However, although the measures of connection probability provided by tractography can be used to make inferences about the relative strength of different fiber populations (as in Fig. 2), such conclusions must be made with care as other factors, such as the length or geometry of a path, will also affect these measures (Johansen-Berg and Behrens 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Johansen-Berg and Behrens 2006

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings provide proof of principle support for the feasibility of characterizing these tracks in depressed patients and potentially for refining DBS electrode targeting using preoperatively acquired DWI data in individual patients.

    “These findings provide proof of principle support for the feasibility of characterizing these tracks in depressed patients and potentially for refining DBS electrode targeting using preoperatively acquired DWI data in individual patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Connectivity patterns in nondepressed healthy subjects are representative of those in depressed patients.
41 of 41

  • The authors state this as an assumption.

    The number of streamline samples passing through a brain voxel is proportional to the probability of connection to the seed voxel.

    “The number of these samples passing through each brain voxel is interpreted as proportional to the probability of connection to the seed voxel.”

  • The paper relies on this without support.

    Anatomical connectivity measured by diffusion tractography in healthy control subjects is representative of the connectivity in patients with treatment-resistant depression who received DBS.

    “We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects.”

  • The paper relies on this without support.

    Manual projection of electrode contact locations onto a standard brain based on local landmarks accurately reflects the true anatomical positions of the electrodes.

    “Locations of electrode contacts used for stimulation were therefore projected manually onto a standard brain based on distances from clearly visible local landmarks (e.g., edges of ventricles, corpus callosum) by an experimenter blind to the connectivity-based parcellation.”

  • The paper relies on this without support.

    The active electrode contacts used for stimulation are the effective contacts responsible for clinical response.

    “Each of the 4 electrode contacts was tested for adverse effects and clinical benefits.”

  • The paper relies on this without support.

    Tractography cannot differentiate between anterograde and retrograde or direct and indirect connections.

    “Tractography cannot differentiate between anterograde and reterograde or direct and indirect connections.”

  • The paper relies on this without support.

    Tractography is most sensitive to major fiber bundles, and small or tortuous paths are more challenging to track.

    “Tractography is most sensitive to major fiber bundles, and small or tortuous paths are more challenging to track.”

  • The paper relies on this without support.

    Connectivity patterns in nondepressed healthy subjects are representative of those in depressed patients.

    “It is difficult to determine a general relationship between response to surgery and connectivity with small patient numbers and when projecting electrode contacts onto healthy control DWI data.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Anterior cingulate and neighbouring medial frontal regions and linked basal ganglia have been linked with mood regulation, including depression and anxiety.

    “In addition, this structure and neighbouring medial frontal regions and linked basal ganglia have been also been strikingly linked with mood regulation, including depression and anxiety (Drevets et al., 2008; Gutman et al., 2009; Johansen-Berg et al., 2008; Mayberg et al., 2005).”

    From The human parental brain: In vivo neuroimaging (2011) · cites this paper as Johansen-Berg et al., 2008

  • Electrical stimulation of the subcallosal region, which includes parts of the ventromedial prefrontal cortex, that may relieve depression, may do so at least in part by activating connections involving the OFC, other parts of the anterior cingulate cortex, and the striatum.

    “Furthermore, the possibility is considered that electrical stimulation of the subcallosal region, which includes parts of the ventromedial prefrontal cortex (Laxton et al., 2013), that may relieve depression, may do so at least in part by activating connections involving the OFC, other parts of the anterior cingulate cortex, and the striatum (Johansen-Berg et al., 2008; Hamani et al., 2009; Lujan”

    From The orbitofrontal cortex: reward, emotion and depression (2020) · cites this paper as Johansen-Berg et al., 2008

  • Subcallosal cingulate stimulation affects pathways that connect with the orbitofrontal cortex.

    “it is possible that the subcallosal cingulate stimulation affects pathways that connect with the OFC (Johansen-Berg et al., 2008; Lujan et al., 2013; Dunlop et al., 2017; Riva-Posse et al., 2018).”

    From The orbitofrontal cortex: reward, emotion and depression (2020) · cites this paper as Johansen-Berg et al., 2008

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. 2003, PROC IEEE NUCL SCI SYMP MED IMAG CONF, 95, 1813
  2. Ong  r, 1998, The Journal of comparative neurology, 401, 480, 10.1002/(SICI)1096-9861(19981130)401:4<480::AID-CNE4>3.0.CO;2-F · DOI · Paper page
  3. 2005, Cerebral Cortex, 16, 811

Cited by

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Authors
Johansen-Berg, H., Gutman, D. A., Behrens, T. E. J., Matthews, P. M., Rushworth, M. F. S., Katz, E., Lozano, A. M., & Mayberg, H. S.
Affiliations
  • Emory University (US)
  • University of Oxford (GB)
  • GlaxoSmithKline (United Kingdom) (GB)
  • Toronto Western Hospital (CA)
ORCID
Venue
Cerebral Cortex
Publisher
Oxford University Press (OUP)
Published
2007-10-10
Volume
18
Issue
6
Pages
1374-1383
ISSN
  • 1047-3211 (ISSN-L)
  • 1460-2199
DOI
10.1093/cercor/bhm167
PMC
PMC7610815
OpenAlex
W2099527308
Cited by
561
References
77
Citations by year
2026: 11 · 2025: 8 · 2024: 10 · 2023: 21 · 2022: 22 · 2021: 27 · 2020: 26 · 2019: 28 · 2018: 35 · 2017: 27 · 2016: 38 · 2015: 42 · 2014: 50 · 2013: 34 · 2012: 36
FWCI
24.08
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Cerebral Cortex (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc)
Funders
Wellcome Trust (078204)
Topics
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
  • Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
Keywords
deep brain stimulation, treatment-resistant depression, subgenual anterior cingulate cortex, anterior cingulate cortex, structural connectivity, diffusion tractography, white matter, nucleus accumbens, amygdala, hypothalamus, orbitofrontal cortex, medial prefrontal cortex, anterior midcingulate cortex, limbic network
MeSH terms
Adult, Depressive Disorder, Female, Gyrus Cinguli, Humans, Male, Deep Brain Stimulation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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