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Cited by 156Hallucinations in medical conditionsSchizophrenia research and treatmentFunctional Brain Connectivity Studies

Elevated functional connectivity along a corticostriatal loop and the mechanism of auditory/verbal hallucinations in patients with schizophrenia

Open access
Hoffman, Ralph E., Fernandez, Thomas, Pittman, Brian, Hampson, Michelle·2011·Biological Psychiatry
DOI 10.1016/j.biopsych.2010.09.050PMC PMC3039042
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Abstract

Background Higher levels of inter-region functional coordination can facilitate emergence of neural activity as conscious percepts. We consequently tested the hypothesis that auditory/verbal hallucinations (AVHs) arise from elevated functional coordination within a speech processing network.Methods Functional coordination was indexed with functional connectivity (FC) computed from functional magnetic resonance imaging data. Thirty-two patients with schizophrenia reporting AVHs, 24 similarly diagnosed patients without hallucinations, and 23 healthy control subjects were studied. FC was seeded from a bilateral Wernicke's region delineated according to activation detected during AVHs in a prior study.Results Wernicke's-seeded FC with Brodmann area 45/46 of the left inferior frontal gyrus (IFG) was significantly greater for hallucinating patients compared with nonhallucinating patients but not compared with healthy control subjects. In contrast, Wernicke's-seeded FC with a large subcortical region that included the thalamus, midbrain, and putamen was significantly greater for the combined patient group compared with healthy control subjects after false discovery rate correction, but not when comparing the two patient groups. Within that subcortical domain, the putamen demonstrated significantly greater FC relative to a secondary left IFG seed region when hallucinators were compared with nonhallucinating patients. A follow-up analysis found that FC summed along a loop linking the Wernicke's and IFG seed regions and the putamen was robustly greater for hallucinating patients compared with nonhallucinating patients and healthy control subjects.Conclusions These findings suggest that higher levels of functional coordination intrinsic to a corticostriatal loop comprise a causal factor leading to AVHs in schizophrenia.

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Written from the paper’s full text.

TL;DR

In patients with schizophrenia, auditory/verbal hallucinations were associated with elevated functional connectivity along a corticostriatal loop linking Wernicke’s area, left inferior frontal gyrus, and putamen. The authors propose this hyperconnectivity as a causal factor for AVHs, though they note alternative explanations.

Key findings

  • In 32 hallucinating patients, 24 nonhallucinating patients, and 23 healthy controls, Wernicke’s-seeded functional connectivity (FC) with left BA45/BA46 was greater in hallucinators than nonhallucinating patients, but hallucinators did not differ significantly from healthy controls.
  • A voxel-based analysis found greater Wernicke’s-seeded FC in a large bilateral subcortical cluster including thalamus, midbrain, and putamen for the combined patient group versus healthy controls after false discovery rate correction; no hallucinator-versus-nonhallucinator differences survived FDR correction.
  • Within that subcortical domain, the putamen showed greater FC relative to a left IFG seed in hallucinators versus nonhallucinating patients (t(52) = 2.7, p = .009 × 3 = .027 after Bonferroni correction).
  • FC summed along a loop linking Wernicke’s, left IFG, and putamen was greater for hallucinators than nonhallucinating patients and healthy controls (F(2,76) = 9.84, p = 0.0002); at a cut-off score of 0.5, sensitivity was 0.78 and specificity was 0.67 versus nonhallucinating patients and 0.65 versus healthy controls.

Methods

  • Functional connectivity was computed from fMRI BOLD data in 32 patients with schizophrenia reporting AVHs, 24 similarly diagnosed patients without hallucinations, and 23 healthy controls; the bilateral Wernicke’s seed was defined from activation during AVHs in a prior study.
  • Left IFG ROIs (BA44, BA45, BA46, BA47) were analyzed with a linear mixed model; exploratory voxel-based FC used FDR correction; subcortical ROIs included putamen, thalamus, and midbrain.
  • A follow-up composite FC measure summed connectivity along the Wernicke’s–IFG–putamen loop; group effects were tested with univariate linear models and ANCOVAs controlling for button-pressing and negative symptoms.

Limitations

  • Stated: the authors cannot rule out that elevated corticostriatal FC is secondary to repeated AVH experience rather than causal; the FC method does not distinguish absent positive BOLD correlation from greater anti-correlation; partial overlap between groups suggests other unidentified factors; the Wernicke’s seed may be suboptimal on a subject-by-subject basis; and conclusions based on equivalence of FC in button-pressing versus non-button-pressing hallucinators must remain tentative.
  • Stated: a positive but nonsignificant correlation was found between hallucination frequency and corticostriatal FC among the 11 patients who signaled events during scanning, and this could reflect either vulnerability or coactivation from hallucination events themselves.
  • Evident from the text: the design is cross-sectional, almost all patients were receiving antipsychotic drugs (all but 3), and the sample size is modest, so causal direction and generalizability are not established.

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Registry

Crossref · 10.1016/j.biopsych.2010.09.050

Cites

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Statistics

Claims the paper makes

0 of 64 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A large bilateral subcortical cluster exhibited greater Wernicke's-seeded FC in the combined patient group compared with healthy controls after FDR correction.

    “A large, bilateral subcortical cluster was detected in the combined patient group relative to healthy controls after FDR correction (Figure 2, and Table S1 in the Supplement).”
    • Also stated in: § Follow-up analysis of a corticostriatal loop · plain
      “a voxel-based analysis revealed a large cluster of subcortical voxels exhibiting excessive FC relative to the Wernicke’s seed region when comparing the combined patient group to healthy controls following FDR correction.”
    Quote in the paperSubstantial claim
  • Findingown data

    After FDR correction at p=0.05, no region expressed FC differences when comparing hallucinators and nonhallucinating patients.

    “After false discovery rate (FDR) correction (55) with cut-off set at p=0.05, no region expressed FC differences when comparing hallucinators and nonhallucinating patients.”
    • Also stated in: § Follow-up analysis of a corticostriatal loop · plain
      “An exploratory, voxel-based analysis did not reveal any differences in Wernicke’s-seeded FC comparing hallucinating and nonhallucinating patients after FDR correction.”
    Quote in the paperSubstantial claim
  • Findingown data

    A left IFG cluster showed greater FC relative to the Wernicke's seed region in hallucinators compared with nonhallucinating patients at an uncorrected cut-off of p=0.005.

    “a second seed region was defined as the left IFG cluster showing greater FC relative to the Wernicke’s seed region comparing hallucinators with non-hallucinating patients at an uncorrected cut-off level of p=0.005 (Figure 1B).”
    Quote in the paperSubstantial claim
  • Findingown data

    After eliminating hallucinators who signaled AVHs during scanning and including negative symptoms as a covariate, remaining hallucinators showed significantly greater Wernicke's-seeded FC with left BA45 and BA46 compared to nonhallucinating patients.

    “Significantly greater Wernicke’s-seeded FC for remaining hallucinators compared to nonhallucinating patients was confirmed (for FC with left BA45, F(2,53)=4.4, p=.018; for FC with left BA46, F(2,53)=7.6, p=.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    An ANCOVA comparing hallucinators and healthy controls controlling for button-press frequency and duration revealed a parallel group difference (F(1,51)=12.9, p=0.001).

    “An ANCOVA comparing hallucinators and healthy controls controlling for button-press frequency and duration revealed a parallel group difference (F(1,51)=12.9, p=0.001).”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    There was no main effect of button-pressing on corticostriatal FC (F(1,73)=2.61, p=0.11), but trend-level evidence of a group × button-pressing interaction (F(2,73)=2.55, p=0.085).

    “There was no main effect of button-pressing (F(1,73)=2.61, p=0.11), but trend-level evidence of a group × button-pressing interaction (F(2,73)=2.55, p=0.085).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After adding button-pressing during fMRI as a second categorical fixed effect, a similar group effect remained (F(2,73)=9.9, p=0.0002), with hallucinating patients significantly greater than nonhallucinating patients and healthy controls.

    “A similar group effect remained (F(2,73) = 9.9, p = 0.0002, with hallucinating patients significantly greater than nonhallucinating patients and healthy controls (pairwise Duncan post hoc tests with α=0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After eliminating hallucinators who signaled hallucinations during scanning, a significant group effect on corticostriatal loop FC was again detected (F(2,65)=7.54, p=0.001), with remaining hallucinating patients demonstrating greater corticostriatal FC compared to both nonhallucinating patients and healthy controls, who were not significantly different.

    “A significant group effect was again detected (F(2,65) = 7.54, p = 0.001), with remaining hallucinating patients demonstrating statistically greater corticostriatal FC compared to both nonhallucinating patients and healthy controls, who were not significantly different from each other (pairwise Duncan post hoc tests with α=0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Healthy controls demonstrated greater Wernicke's FC with left BA47 compared to both patient groups, who were not different from each other.

    “Healthy controls demonstrated greater Wernicke’s FC with left BA47 compared to both patient groups, who were not different from each other for this measure (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both hallucinators and healthy controls demonstrated greater Wernicke's-seeded FC with left BA45 and BA46 compared to nonhallucinating patients, but were not significantly different from each other.

    “Both hallucinators and healthy controls demonstrated greater Wernicke’s-seeded FC with left BA45 and BA46 compared to nonhallucinating patients, but were not significantly different from each other (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The composite corticostriatal loop FC measure demonstrated a significant group effect (F(2,76)=9.84, p=0.0002), with hallucinators greater than nonhallucinating patients and healthy controls, who did not differ from each other.

    “This composite FC measure demonstrated a significant group effect (F(2,76)=9.84, p= 0.0002), with hallucinators greater than nonhallucinating patients and healthy controls, who were not different from each (Duncan pairwise comparisons with α=0.05; Figure 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wernicke's-seeded FC with left IFG ROIs showed a main effect of group (F(2,76)=5.04, p=.009), a main effect of subregion (F(3,76)=15.08, p<.0001), and a group × subregion interaction (F(6,76)=2.87, p=.014).

    “These data yielded a main effect for group (F(2,76) = 5.04, p = .009) and subregion (F(3,76)=15.08, p <.0001) with a significant group x subregion interaction (F(6,76)=2.87, p =.014).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using a corticostriatal FC cut-off score of 0.5, sensitivity in classifying patients correctly as hallucinators was 0.78, specificity was 0.67 relative to nonhallucinating patients and 0.65 relative to healthy controls.

    “Using a corticostriatal FC cut-off score of 0.5, sensitivity in classifying patients correctly as hallucinators was 0.78, while specificity was 0.67 relative to nonhallucinating patients and 0.65 relative to healthy controls.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The correlation between corticostriatal FC and frequency of hallucination events among patients who signaled these events during scanning was positive but not significant (N=11, Spearman rho=0.50, p=0.11).

    “The correlation between corticostriatal FC and frequency of hallucination events among patients who signaled these events during scanning was found to be positive although not significant due to small sample size (N=11, Spearman rho=0.50, p=0.11).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cross-hemisphere functional connectivity linking left and right components of the more posterior Wernicke's seed region was significantly greater for healthy controls compared to nonhallucinating patients, with hallucinators intermediate and not significantly different than either group.

    “Cross-hemisphere FC linking these two locations was significantly greater for healthy controls compared to nonhallucinating patients, with hallucinators intermediate and not significantly different than either group.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Network coordination involving inferior frontal and temporal regions during speech perception has been detected as elevated functional connectivity computed from interregional correlations of fMRI activity.

    “Network coordination involving inferior frontal and temporal regions during speech perception has been detected as elevated functional connectivity (FC) computed from interregional correlations of functional magnetic resonance imaging (fMRI) activity (17–20).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Obleser, 2007, Functional integration across brain regions improves speech perception under adverse listening conditions, J Neurosci source

      Not checked in the free run.

    • cites [18] Tyler, 2008, Fronto-temporal brain systems supporting spoken language comprehension, Philos Trans R Soc Lond B Biol Sci source

      Not checked in the free run.

    • cites [19] Peelle, 2010, Neural processing during older adults' comprehension of spoken sentences: Age differences in resource allocation and connectivity, Cereb Cortex source

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    • cites [20] Londei, 2010, Sensory-motor brain network connectivity for speech comprehension, Hum Brain Mapp source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Functional pathways critical to vision, motor function, audition, language, reading, and attention are detectable as enhanced FC computed from at rest inter-region oscillatory synchronization determined via fMRI.

    “Functional pathways critical to vision, motor function, audition, language, reading, and attention are detectable as enhanced FC computed from at rest inter-region oscillatory synchronization determined via functional magnetic resonance imaging (34–42).”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [34] Biswal, 1995, Functional connectivity in the motor cortex of resting human brain using echo-planar MRI, Magn Reson Med source

      Not checked in the free run.

    • cites [35] Lowe, 1998, Functional connectivity in single and multislice echoplanar imaging using resting-state fluctuations, Neuroimage source

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    • cites [36] Xiong, 1999, Interregional functional connectivity to primary motor cortex revealed using MIR resting state images, Hum Brain Mapp source

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    • cites [37] Cordes, 2000, Mapping functionally related regions of brain with functional connectivity MR imaging, AJNR Am J Neuroradiol

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    • cites [38] Hampson, 2002, Detection of functional connectivity using temporal correlations in MR images, Hum Brain Mapp source

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    • cites [39] Fox, 2006, Spontaneous neuronal activity distinguishes human dorsal and ventral attention systems, Proc Natl Acad Sci U S A source

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    • cites [40] Hampson, 2006, Connectivity-behavior analysis reveals that functional connectivity between left BA39 and Broca's area varies with reading ability, Neuroimage source

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    • cites [41] Seeley, 2007, Dissociable intrinsic connectivity networks for salience processing and executive control, J Neurosci source

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    • cites [42] Shmuel, 2008, Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: implications for functional connectivity at rest, Hum Brain Mapp source

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  • May combine two claims.

    Premisecitation

    AVHs are generally cast in distinct, nonself speaking voices, whereas inner speech is typically cast in the first-person voice.

    “For instance, AVHs generally are cast in distinct, nonself speaking voices, whereas inner speech is typically cast in the first-person voice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Hoffman, 2008, Experiential features used by patients with schizophrenia to differentiate voices from ordinary verbal thought, Psychol Med source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The left IFG is critically involved in self-generated auditory imagery of spoken speech.

    “Wernicke’s-seeded FC was computed for subregions of the left IFG based on studies highlighting the critical involvement of the latter during self-generated auditory imagery of spoken speech (22,23), perception of external speech (24,25), and AVHs themselves (26,27).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] McGuire, 1996, Functional anatomy of inner speech and auditory verbal imagery, Psychol Med source

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    • cites [23] Shergill, 2001, A functional study of auditory verbal imagery, Psychol Med source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The left IFG is critically involved in AVHs.

    “Wernicke’s-seeded FC was computed for subregions of the left IFG based on studies highlighting the critical involvement of the latter during self-generated auditory imagery of spoken speech (22,23), perception of external speech (24,25), and AVHs themselves (26,27).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Shergill, 2000, Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging, Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [27] Hoffman RE, Pittman B, Constable RT, Bhagwagar Z, Hampson M (in press): Time-course of regional hemodynamic activation accompanying auditory/verbal hallucinations in patients with schizophrenia-spectrum disorders. Br J Psychiatry.

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    Premisecitation

    The left IFG is critically involved in perception of external speech.

    “Wernicke’s-seeded FC was computed for subregions of the left IFG based on studies highlighting the critical involvement of the latter during self-generated auditory imagery of spoken speech (22,23), perception of external speech (24,25), and AVHs themselves (26,27).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Friederici, 2002, Toward a neural basis of auditory sentence processing, Tr Cognit Sci source

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    • cites [25] Peelle, 2004, Dissociable patterns of brain activity during comprehension of rapid and syntactically complex speech: Evidence from fMRI, Brain Lang source

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    Premisecitation

    Patients with AVHs show non-suppression of the N100 event-related potential and impaired pre-speech inter-trial EEG coherence.

    “This hypothesis is supported by studies showing non-suppression of the N100 event-related potential and impaired pre-speech inter-trial electroencephalographic (EEG) coherence in patients with AVHs (6,7).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Heinks-Maldonado, 2007, Relationship of imprecise corollary discharge in schizophrenia to auditory hallucinations, Arch Gen Psychiatry source

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    • cites [7] Ford, 2007, Synch before you speak: Auditory hallucinations in schizophrenia, Am J Psychiatry source

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    Premisecitation

    Network coordination facilitating perceptual processing, including speech comprehension, has been detected as elevated FC.

    “Network coordination facilitating perceptual processing, including speech comprehension, has been detected as elevated FC (17,20,43–47).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [17] Obleser, 2007, Functional integration across brain regions improves speech perception under adverse listening conditions, J Neurosci source

      Not checked in the free run.

    • cites [20] Londei, 2010, Sensory-motor brain network connectivity for speech comprehension, Hum Brain Mapp source

      Not checked in the free run.

    • cites [43] Sergent, 2004, Neural processes underlying conscious perception: Experimental findings and a global neuronal workspace framework, J Physiol Paris source

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    • cites [44] von Kriegstein, 2006, Implicit multisensory associations influence voice recognition, PLoS Biol source

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    • cites [45] McNamara, 2008, Neural dynamics of learning sound-action associations, PLoS ONE source

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    • cites [46] Arnal, 2009, Dual neural routing of visual facilitation in speech processing, J Neurosci source

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    • cites [47] van de Ven, 2009, Neural network of speech monitoring overlaps with overt speech production and comprehension networks: A sequential spatial and temporal ICA study, Neuroimage source

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    Premisecitation

    Inter-region BOLD signal oscillatory synchronization is expressed almost entirely below 0.1 Hz.

    “for functional pathways; inter-region BOLD signal oscillatory synchronization is expressed almost entirely below this frequency cut-off (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Cordes, 2001, Frequencies contributing to functional connectivity in the cerebral cortex in “‘resting-state'” data, AJNR Am J Neuroradiol

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    Study design and conductown data

    Hallucinators and nonhallucinating patients had near identical levels of delusions, disorganization, and composite positive symptoms, and differed at a trend level (p=0.09) for composite negative symptoms.

    “Hallucinators and nonhallucinating patients had near identical levels of delusions, disorganization, and composite positive symptoms, while differing at a trend level (p =0.09) for composite negative symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The ventral aspect of BA46 lies in IFG, participates in language processes, and has been implicated in the genesis of AVHs.

    “Although BA46 is typically viewed as a middle frontal region, its ventral aspect lies in IFG and participates in language processes (51–53) and has been implicated in the genesis of AVHs (26,54).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [51] Muller, 1997, Receptive and expressive language activations for sentences: A PET study, Neuroreport source

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    • cites [52] Klein, 1995, The neural substrates underlying word generation: A bilingual functional-imaging study, Proc Natl Acad Sci U S A source

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    • cites [53] Dronkers, 2004, Lesion analysis of the brain areas involved in language comprehension, Cognition source

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    • cites [26] Shergill, 2000, Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging, Arch Gen Psychiatry source

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    • cites [54] Lennox, 2000, The functional anatomy of auditory hallucinations in schizophrenia, Psychiatry Res source

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    Premisecitation

    In a prior fMRI study, sites in left posterior BA22 and right BA21/22 activated concurrent with AVH events in a non-overlapping patient group.

    “A bilateral Wernicke’s seed region comprised of sites in left posterior BA22 and a right homologous site in BA21/22 (Figure 1A) was delineated based on an earlier fMRI study showing activation in these sites concurrent with AVH events in a non-overlapping patient group (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Hoffman, 2008, The time course of regional brain activation associated with onset of auditory/verbal hallucinations, Br J Psychiatry source

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    Premisecitation

    The midbrain region incorporated monoamine neuronal centers implicated in the pathophysiology of schizophrenia.

    “The third region was in the midbrain, and incorporated monoamine neuronal centers implicated in the pathophysiology of schizophrenia (60,61).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Harrison, 1999, The neuropathology of schizophrenia, Brain source

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    • cites [61] Kapur, 2003, Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia, Am J Psychiatry source

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    Premisecitation

    Vercammen et al. patients demonstrated subnormal temporoparietal functional connectivity linking to the right inferior frontal gyrus.

    “Their patients demonstrated subnormal temporoparietal FC linking to the right IFG.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Vercammen, 2010, Auditory hallucinations in schizophrenia are associated with reduced functional connectivity of the temporo-parietal area, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The putamen and thalamus are involved in initiating and organizing language representations and have been shown to be activated coincident with AVH occurrences.

    “The first two were in the putamen and thalamus, which are involved in initiating and organizing language representations ordinarily (56–58), and have been shown to be activated coincident with AVH occurrences in two reports (26,59).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [56] Booth, 2007, The role of the basal ganglia and cerebellum in language processing, Brain Res source

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    • cites [57] Bhatnagar, 2005, Effects of intralaminar thalamic stimulation on language functions, Brain Lang source

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    • cites [58] Price, 2010, The anatomy of language: A review of 100 fMRI studies published in 2009, Ann N Y Acad Sci source

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    • cites [26] Shergill, 2000, Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging, Arch Gen Psychiatry source

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    • cites [59] Silbersweig, 1995, A functional neuroanatomy of hallucinations in schizophrenia, Nature source

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  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Nonhallucinating patients and healthy controls were instructed to press a button at random intervals approximating rates and durations of hallucinating patients to control for motor effects of button pressing during scanning.

    “In order to control for effects of motorically depressing a button during scanning, some nonhallucinating patients (N=9) and normal control subjects (N=11) were instructed to depress a button spontaneously at random intervals approximating button depression rates and durations generated by hallucinating patients.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The putamen plays a critical role in initiating language representations.

    “Insofar as the putamen plays a critical role in initiating language representations (58)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Price, 2010, The anatomy of language: A review of 100 fMRI studies published in 2009, Ann N Y Acad Sci source

      Not checked in the free run.

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

    Study design and conductown data

    Approximately normal distributions for the FC variables were confirmed using normal probability plots and Kolmogorov-Smirnov test statistics.

    “Prior to group comparisons, approximately normal distributions for the FC variables described above were confirmed using normal probability plots and Kolmogorov-Smirnov test statistics.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Intensive learning can enhance inter-region functional connectivity.

    “First, intensive learning can enhance inter-region FC (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Lewis, 2009, Learning sculpts the spontaneous activity of the resting human brain, Proc Natl Acad Sci U S A source

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    Premisecitation

    Raij et al. reported that subjective ratings of the reality of auditory/verbal hallucinations were positively correlated with enhanced coupling linking left inferior frontal gyrus to bilateral auditory cortices and posterior temporal lobes elicited by auditory/verbal hallucinations.

    “Raij et al. reported that subjective ratings of the reality of AVHs were positively correlated with enhanced coupling linking left IFG to bilateral auditory cortices and posterior temporal lobes elicited by AVHs (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Raij, 2009, Reality of auditory verbal hallucinations, Brain source

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  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Conclusions based on the equivalence of functional connectivity observed for the button-pressing versus non-button-pressing hallucinators must remain tentative.

    “Therefore conclusions based on the equivalence of FC observed for the button-pressing vs. non-button-pressing hallucinators must remain tentative.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Higher levels of functional coordination, if mediated by excitatory inter-region projections, could lead to episodic coactivation that further increases functional connectivity.

    “Higher levels of functional coordination, if mediated by excitatory inter-region projections, could lead to episodic coactivation that further increases FC.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Instructing patients to signal hallucinations with button-presses could have introduced a bias unique to that group since there is no comparable internal monitoring condition for nonhallucinating subjects.

    “To do so could have introduced a bias unique to that group since there is no comparable internal monitoring condition for nonhallucinating subjects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is no comparable internal monitoring condition for nonhallucinating subjects.

  • May combine two claims. The quote only partly states this claim.

    Interpretationown data

    The positive non-significant correlation between hallucination frequency and corticostriatal functional connectivity is consistent with the hypothesis that higher corticostriatal functional connectivity increases hallucination vulnerability.

    “This finding is consistent with the hypothesis that higher corticostriatal FC increases hallucination vulnerability.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The positive non-significant correlation between hallucination frequency and corticostriatal functional connectivity could also reflect the impact of heightened coactivation due to hallucination events themselves that enhances inter-regional correlations.

    “However, this finding could also reflect the impact of heightened coactivation due to hallucination events themselves that enhances inter-regional correlations.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    The possibility that some patients with low-frequency hallucinations outside the scanner experienced higher hallucination rates during scanning cannot be ruled out because many hallucinating patients were not instructed to signal hallucinations with button-presses during scanning.

    “This possibility cannot be ruled out since many hallucinating patients were not instructed to signal hallucinations with button-presses during scanning.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The method for computing functional connectivity does not specify whether lower functional connectivity values are due to absent positive BOLD correlations versus greater BOLD anti-correlation, which may have different physiological origins.

    “Second, our method for computing FC does not specify whether lower FC values are due to absent positive BOLD correlations versus greater BOLD anti-correlation, which may have different physiological origins.”
    Quote in the paperNot a substantial claim
37 of 37

  • The paper relies on this without support.

    Summing functional connectivity between the Wernicke’s seed, left IFG seed, and putamen indexes a functional corticostriatal loop relevant to AVHs.

    “IFG-seeded FC with the putamen, Wernicke’s-seeded FC with the putamen, and Wernicke’s-seeded FC with the IFG seed region were summed together to trace a corticostriatal loop (Figure S1 in the Supplement).”
    “To delineate a functional loop possibly underlying AVHs, a second seed region was defined as the left IFG cluster showing greater FC relative to the Wernicke’s seed region comparing hallucinators with non-hallucinating patients at an uncorrected cut-off level of p=0.005 (Figure 1B).”

  • The paper relies on this without support.

    Most patients do not hallucinate at a frequency range that permits patient-specific delineation of regional fMRI activation coincident with these experiences.

    “since most patients do not hallucinate at a frequency range that permits patient-specific delineation of regional fMRI activation coincident with these experiences.”

  • The paper relies on this without support.

    There is no comparable internal monitoring condition for nonhallucinating subjects.

    “since there is no comparable internal monitoring condition for nonhallucinating subjects.”
3 of 3

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?

  • Potential pathways suggested by MRI studies of hallucinations include right hemisphere homologues of language areas, hippocampal cortex, and subcortical structures.

    “Potential pathways suggested by MRI studies of hallucinations include right hemisphere homologues of language areas (Sommer et al., 2008), hippocampal cortex (Diederen, Neggers et al., 2010), and subcortical structures (Hoffman, Fernandez, Pittman, & Hampson, 2011).”

    From Inner Speech: Development, Cognitive Functions, Phenomenology, and Neurobiology (2015) · cites this paper as Hoffman, Fernandez, Pittman, & Hampson, 2011

  • A better model to explain AVHs involves the surfacing of 'unbidden thoughts' into consciousness, through a hyperconnected corticostriatal loop involving Wernicke's area and its right homologue, the left inferior frontal gyrus, and the putamen bilaterally.

    “Hoffman et al. (2011) have argued that a better model to explain AVHs involves the surfacing of ‘unbidden thoughts’ into consciousness, through a hyperconnected corticostriatal loop involving Wernicke's area and its right homologue, the left inferior frontal gyrus, and the putamen bilaterally.”

    From Auditory verbal hallucinations as atypical inner speech monitoring, and the potential of neurostimulation as a treatment option (2013) · cites this paper as Hoffman et al., 2011

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(2, 76) = 5.04reported p = .009 · recomputed p = .009

    “F(2,76) = 5.04, p = .009”

  • ConsistentF(3, 76) = 15.08reported p < .0001 · recomputed p < .001

    “F(3,76)=15.08, p < .0001”

  • ConsistentF(6, 76) = 2.87reported p = .014 · recomputed p = .014

    “F(6,76)=2.87, p = .014”

  • ConsistentF(2, 53) = 4.4reported p = .018 · recomputed p = .017

    “F(2,53)=4.4, p = .018”

  • ConsistentF(2, 53) = 7.6reported p = .001 · recomputed p = .001

    “F(2,53)=7.6, p = .001”

  • Consistentt(52) = 2.7reported p = .009 · recomputed p = .009

    “t(52) = 2.7, p = .009”

  • ConsistentF(2, 76) = 9.84reported p = .0002 · recomputed p < .001

    “F(2,76)=9.84, p = .0002”

  • ConsistentF(1, 51) = 18.9reported p = .00007 · recomputed p < .001

    “F(1,51)=18.9, p = .00007”

  • ConsistentF(1, 51) = 12.9reported p = .001 · recomputed p < .001

    “F(1,51)=12.9, p = .001”

  • ConsistentF(2, 65) = 7.54reported p = .001 · recomputed p = .001

    “F(2,65) = 7.54, p = .001”

  • ConsistentF(2, 73) = 9.9reported p = .0002 · recomputed p < .001

    “F(2,73) = 9.9, p = .0002”

  • ConsistentF(1, 73) = 2.61reported p = .11 · recomputed p = .111

    “F(1,73)=2.61, p = .11”

  • ConsistentF(2, 73) = 2.55reported p = .085 · recomputed p = .085

    “F(2,73)=2.55, p = .085”

13 of 13

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Sergent, 2004, Neural processes underlying conscious perception: Experimental findings and a global neuronal workspace framework, J Physiol Paris, 98, 374, 10.1016/j.jphysparis.2005.09.006 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Hoffman, R. E., Fernandez, T., Pittman, B., & Hampson, M.
Affiliations
Yale University (US)
Corresponding author
Hoffman, Ralph E.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2011-03
Volume
69
Issue
5
Pages
407-414
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2010.09.050
PMC
PMC3039042
OpenAlex
W2067271714
Cited by
156
References
69
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 11 · 2020: 10 · 2019: 7 · 2018: 15 · 2017: 14 · 2016: 12 · 2015: 18 · 2014: 14 · 2013: 11 · 2012: 18
FWCI
6.21
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R01MH067073)
  • Dana Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • Peterson 50th Anniversary Research Partner
  • Department of Mental Health and Addiction Services of the State of Connecticut
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Hallucinations in medical conditions
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
auditory verbal hallucinations, schizophrenia, functional connectivity, Wernicke's area, inferior frontal gyrus, putamen, thalamus, midbrain, conscious perception
MeSH terms
Adult, Algorithms, Cerebral Cortex, Female, Frontal Lobe, Hallucinations, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Neural Pathways, Neuropsychological Tests, Putamen, Schizophrenia, Schizophrenic Psychology, Socioeconomic Factors, Temporal Lobe, Antipsychotic Agents, Verbal Behavior, Neostriatum, Diagnostic and Statistical Manual of Mental Disorders

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 2026-10-10.

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

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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