Prefrontal cortex and depression

In the paper

“studies of the neurobiology of reward processing have highlighted the variety of distinct pathways involved in its different aspects resulting in the recognition of separate subtypes of anhedonia, including consummatory, anticipatory, motivational and decisional [20,21].”

What the sources say

• Partly supported

  The Research Highlights (section 6; page unavailable) propose motivational and consummatory anhedonia and introduce decisional anhedonia. Section 2.2 discusses anticipatory pleasure but says it is unclear whether that is the same construct as reward motivation; the paper does not establish anticipatory anhedonia as a fourth separate subtype. (LLM, conf=0.88)

  cites [20] Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35:537–55. sourceExperimental — accuracy not yet measured
• Disputed

  The Concluding Remarks distinguish consummatory and anticipatory anhedonia, but recommend limiting the term “anhedonia” to deficits in hedonic capacity. They treat motivation and decision-making as other reward-related processes, not as additional subtypes of anhedonia. (LLM, conf=0.87)

  Checked by a reasoning model — may be wrong.

  cites [21] Der-Avakian A, Markou A. The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci. 2012;35:68–77. sourceExperimental — accuracy not yet measured

In the paper

“An early meta-analysis (64 structural MRI studies) reported that frontal regions showed the largest volumetric reductions in MDD [78], particularly in the ACC and bilateral OFC, although distinct subregions were not investigated (see also [79]).”

What the sources say

• Supported

  The Abstract describes a meta-analysis of 64 MRI studies and reports large volume reductions in frontal regions, especially the anterior cingulate and orbitofrontal cortex. Table II in “Areas in the Frontal Lobe” reports reduced orbitofrontal volume on both the left and right; that section identifies the anterior cingulate as having the largest effect. Page numbers are not available in our copy. (LLM, conf=0.94)

  cites [78] Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol HE, Kahn RS. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp. 2009;30:3719–35. source
• Disputed

  The Results report 97 studies, not 64 structural MRI studies. The Results section on all patients says the gray-matter-volume analysis found no significant region of convergent abnormality, rather than the largest reductions occurring in frontal regions. The Discussion identifies a subgenual anterior cingulate abnormality in the multimodal analysis, but does not report the claimed bilateral orbitofrontal volumetric reductions. Page numbers were not available in our copy. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [79] Gray JP, Müller VI, Eickhoff SB, Fox PT. Multimodal abnormalities of brain structure and function in major depressive disorder: a meta-analysis of neuroimaging studies. Am J Psychiatry. 2020;177:422–34. sourceExperimental — accuracy not yet measured

In the paper

“Similarly, adolescents with MDD (N = 213) had lower cortical thickness in the medial OFC/vmPFC and superior frontal gyrus than adolescents without MDD history (N = 294) [81].”

What the sources say

• Disputed

  The Results (Adolescents) report the stated sample sizes and reduced surface area in the left medial OFC and right superior frontal gyrus, but explicitly say no cortical thickness differences were detected between adolescent patients and controls. The claim incorrectly describes the surface-area finding as a cortical-thickness finding. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  cites [81] Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22:900–9. sourceExperimental — accuracy not yet measured

In the paper

“Whereas amygdalar hyper-activation to negative faces was reported in a similar offspring sample (mean age: 14 years) [186], the PFC findings contrast with reports of blunted dlPFC activation (and normative amygdalar responses) to fearful faces [187] and a sad mood induction [188] among asymptomatic offspring of MDD patients (16-21 years old and 9-14 years old, respectively).”

What the sources say

• Disputed

  The Abstract and Discussion (page not available in our copy) report greater, not normative, amygdala activation in high-risk girls after sad mood induction. They report lower dlPFC activation during the subsequent mood-regulation task, not during induction. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [188] Joormann J, Cooney RE, Henry ML, Gotlib IH. Neural correlates of automatic mood regulation in girls at high risk for depression. J Abnorm Psychol. 2012;121:61–72. sourceExperimental — accuracy not yet measured

In the paper

“Among MDD subjects, a failure to deactivate the pgACC (and adjacent dmPFC) during cognitive or emotional processing tasks correlated with more depression severity and feelings of hopelessness [181, 182].”

What the sources say

• Disputed

  The Results section, “Correlation of fMRI With Symptom Severity, Behavioral Data and Across Tasks” (page unavailable), explicitly reports that dmPFC activation patterns did not correlate significantly with current depression severity. The Discussion describes possible failure to deactivate the ACC during cognitive tasks, but the claimed severity correlation is contrary to the reported result; the cited passages do not establish a correlation with hopelessness. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  cites [181] Korgaonkar MS, Grieve SM, Etkin A, Koslow SH, Williams LM. Using standardized fMRI protocols to identify patterns of prefrontal circuit dysregulation that are common and specific to cognitive and emotional tasks in major depressive disorder: first wave results from the iSPOT-D study. Neuropsychopharmacology. 2013;38:863–71. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [182] Grimm S, Boesiger P, Beck J, Schuepbach D, Bermpohl F, Walter M, et al. Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology. 2009;34:843–932. source

In the paper

“in a task that manipulated the perception of control over monetary rewards or losses, unlike controls, depressed individuals failed to show greater striatal activation to self-attributed vs. externally attributed monetary gains [210].”

What the sources say

• Disputed

  The Discussion (p. 5) says the altered putamen response in patients concerned self-attributed versus externally attributed losses, and explicitly reports no evidence of an altered ventral striatal response to gains. The simple-effects analysis (p. 5) likewise found no between-group effect for the gains contrast, contrary to the claimed difference from controls for monetary gains. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [210] Späti J, Chumbley J, Doerig N, Brakowski J, Grosse Holtforth M, Seifritz E, et al. Valence and agency influence striatal response to feedback in patients with major depressive disorder. J Psychiatry Neurosci. 2015;40:394–400. sourceExperimental — accuracy not yet measured

In the paper

“Specifically, ketamine infusion reduced (1) hyperactivation in the sgACC (BA25) to positive feedback [121], (2) FC between the pgACC and dACC [199], and (3) FC between the sgACC and limbic regions (e.g., hippocampus) [121].”

What the sources say

• Disputed

  The Effects of ketamine section explicitly reports no significant change in hippocampus–sgACC connectivity before versus after ketamine (p > 0.05). The Discussion mentions reduced connectivity in a previous study of healthy men, but that is not the finding of this paper’s ketamine cohort. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [121] Morris LS, Costi S, Tan A, Stern ER, Charney DS, Murrough JW. Ketamine normalizes subgenual cingulate cortex hyper-activity in depression. Neuropsychopharmacology. 2020;45:975–81. sourceExperimental — accuracy not yet measured

In the paper

“one study employing acute restraint stress to induce a negative bias revealed that the effectiveness of systemic ketamine to reduce such a bias in the ambiguous cue test was dependent upon the mPFC [45]”

What the sources say

• Disputed

  The Results (Behavioural results, Fig. 2; page unavailable) report that acute restraint stress did not induce a negative judgement bias: it had no effect on any behavioural measure. The paper tested FG7142 as its acute drug manipulation, not systemic ketamine, and the retrieved passages do not report an mPFC-dependent ketamine effect. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [45] Hales CA, Robinson ESJ, Houghton CJ. Diffusion modelling reveals the decision making processes underlying negative judgement bias in rats. PLoS One. 2016;11:e0152592. sourceExperimental — accuracy not yet measured

In the paper

“Compared to controls, individuals with MDD showed increased ALFF in a region spanning the medial orbitofrontal cortex (OFC) and perigenual ACC (pgACC).”

What the sources say

• Partly supported

  The Results (ALFF differences of the main meta-analysis; page unavailable) report increased ALFF in MDD versus healthy controls in a cluster including the medial orbitofrontal cortex and anterior cingulate cortex. Table 1 places anterior cingulate/paracingulate areas in that cluster, but the paper does not identify them specifically as perigenual ACC. (LLM, conf=0.83)

  cites [70] Gong J, Wang J, Qiu S, Chen P, Luo Z, Wang J, et al. Common and distinct patterns of intrinsic brain activity alterations in major depression and bipolar disorder: voxel-based meta-analysis. Transl Psychiatry. 2020;10:353. https://doi.org/10.1038/s41398-020-01036-5. sourceExperimental — accuracy not yet measured

In the paper

“In a coordinate-based meta-analysis [69], increased rsFC in the pgACC predicted response to a variety of treatments (e.g., repetitive transcranial magnetic stimulation (rTMS), pharmacotherapy, cognitive behavior therapy, electroconvulsive therapy (ECT)) (see also [16]).”

What the sources say

• ?Not checked — no full text of the sourcecites [69] Long Z, Du L, Zhao J, Wu S, Zheng Q, Lei X. Prediction on treatment improvement in depression with resting state connectivity: a coordinate-based meta-analysis. J Affect Disord. 2020;276:62–68. source
• Partly supported

  The meta-analysis Results report that higher pretreatment rostral ACC activity predicted better response across several treatments, including drugs and rTMS. They do not establish that increased resting-state functional connectivity predicted response; the paper discusses connectivity as a treatment-associated change instead. The Results also explicitly except ECT from the positive prediction finding and report no pretreatment rACC difference between CBT responders and nonresponders in the cited CBT study. (LLM, conf=0.90)

  cites [16] Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36:183–206. sourceExperimental — accuracy not yet measured

In the paper

“Indeed, even for those regions where greater anatomical similarity exists (e.g., mPFC/ACC), the extent to which anatomical similarity reflects functional homology or analogy is unclear [9,18].”

What the sources say

• Supported

  The Cross-Species Homology section describes similar structural organization of the ACC across humans, monkeys, and rodents, then asks how functionally homologous their PFC/ACC regions will prove to be. It also cautions that similar behavioral effects across species need not establish functional homology. Page numbers are not available in the supplied passages. (LLM, conf=0.91)

  cites [9] Roberts A. Prefrontal regulation of threat-elicited behaviors: a pathway to translation. Annu Rev Psychol. 2020;71:357–87. source
• Supported

  The Anatomical Considerations section says that comparable anatomy may suggest homology while primate PFC and ACC may have different neurobiological processes from their rodent counterparts. Reconciling the Differences also describes functional overlaps and inconsistencies between putative anatomical homologs. Together, these support the claim that anatomical similarity does not establish functional homology. (LLM, conf=0.92)

  cites [18] Roberts AC, Clarke HF. Why we need nonhuman primates to study the role of ventromedial prefrontal cortex in the regulation of threat- And reward-elicited responses. PNAS. 2019;116:26297–304. source

In the paper

“Moreover, increases in escape behavior, hypothesized to reflect an antidepressant effect, may reflect instead an increase in anxiety [55].”

What the sources say

• Supported

  In the paper’s discussion of the forced swim test, the authors argue that antidepressant-induced anxiety drives increased escape-directed behavior, rather than that behavior necessarily reflecting an antidepressant effect. The citing sentence preserves this proposed reinterpretation. (LLM, conf=0.94)

  cites [55] Anyan J, Amir S. Too depressed to swim or too afraid to stop? A reinterpretation of the forced swim test as a measure of anxiety-like behavior. Neuropsychopharmacology. 2018;43:931–3. source

In the paper

“Thus, relative to healthy children (8-17 years old), children at increased vulnerability due to parental MDD history (as well as children with current MDD) had lower rsFC between the right dlPFC (BA6/8/9) and the amygdala [74]”

What the sources say

• Partly supported

  The Results (Group Differences in Amygdala RSFC; page unavailable) report reduced negative amygdala–right frontal connectivity in both the at-risk and depressed groups relative to healthy youth. However, the measured frontal cluster included the superior and middle frontal gyri and frontal pole (BAs 6, 8, 9, and 32), rather than being identified solely as the right dlPFC. The Participants and Participant Characteristics sections also show that the depressed group included youth with dysthymia or unspecified MDD, so the result was not reported specifically for children with current MDD. (LLM, conf=0.88)

  cites [74] Singh MK, Leslie SM, Packer MM, Weisman EF, Gotlib IH. Limbic intrinsic connectivity in depressed and high-risk youth. J Am Acad Child Adolesc Psychiatry. 2018;57:775–785.e3. sourceExperimental — accuracy not yet measured

In the paper

“However, current MDD was uniquely characterized by abnormal rsFC between various orbital and mPFC sub-regions (pgACC, dACC, lateral and central OFC) and PFC (dlPFC), subcortical (e.g., dorsal striatum), as well as cortical (e.g., precuneus, inferior temporal lobes) regions.”

What the sources say

• Supported

  The Results (Neuroimaging Analysis; page not provided) report connectivity changes unique to current major depression across medial and orbital prefrontal fields, including connections with dorsolateral PFC, caudate, precuneus, and inferior temporal cortex. The Abstract Results likewise describe abnormalities involving the dorsal striatum and these cortical regions. (LLM, conf=0.93)

  cites [73] Samara Z, Evers EAT, Peeters F, Uylings HBM, Rajkowska G, Ramaekers JG, et al. Orbital and medial prefrontal cortex functional connectivity of major depression vulnerability and disease. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:348–57. source

In the paper

“this has been re-assessed due to evidence indicating preserved consummatory reward in functionally analogous tests (e.g., sweet taste test) in MDD [25,26].”

What the sources say

• Supported

  The Discussion reports no difference between adults with MDD and controls in sweet-taste hedonic response, sucrose sensitivity, or sweet-liking status. It concludes that MDD may not affect responses to sweet tastes, supporting the claim of preserved consummatory reward in this test. (LLM, conf=0.92)

  cites [25] Dichter GS, Smoski MJ, Kampov-Polevoy AB, Gallop R, Garbutt JC. Unipolar depression does not moderate responses to the Sweet Taste Test. Depress Anxiety. 2010;27:859–63. source
• ?Not checked — no full text of the sourcecites [26] Berlin I, Givry-Steiner L, Lecrubier Y, Puech AJ. Measures of anhedonia and hedonic responses to sucrose in depressive and schizophrenic patients in comparison with healthy subjects. Eur Psychiatry. 1998;13:303–9. source

In the paper

“Current MDD and increased risk for MDD shared several abnormalities, including dysregulated coupling involving the pgACC, dmPFC and dorsal ACC (dACC) to other cortical regions (Fig. 4a).”

What the sources say

• Supported

  The Results (Neuroimaging Analysis) explicitly state that patients with current major depression and at-risk individuals shared functional-connectivity abnormalities in pregenual area p32, dorsal area d32, and dorsomedial frontal area BA9. The same passage describes altered coupling between those regions and other cortical areas. (LLM, conf=0.94)

  cites [73] Samara Z, Evers EAT, Peeters F, Uylings HBM, Rajkowska G, Ramaekers JG, et al. Orbital and medial prefrontal cortex functional connectivity of major depression vulnerability and disease. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:348–57. source

In the paper

“Treatment-resistant depression (TRD) was characterized by decreased global connectivity within the right dlPFC and bilateral dmPFC (including the dACC) [76].”

What the sources say

• Partly supported

  The Results section (“GBCr in TRD & Post-ketamine”; page unavailable) reports significantly lower global brain connectivity in bilateral dorsomedial and right dorsolateral prefrontal clusters in TRD patients than in healthy controls. It does not identify the dorsal anterior cingulate cortex as part of those clusters, so the parenthetical detail is not established by our copy. (LLM, conf=0.86)

  cites [76] Abdallah CG, Averill CL, Salas R, Averill LA, Baldwin PR, Krystal JH, et al. Prefrontal connectivity and glutamate transmission: relevance to depression pathophysiology and ketamine treatment. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:566–74. sourceExperimental — accuracy not yet measured

In the paper

“Notably, ketamine infusion increased global connectivity in all three regions.”

What the sources say

• Partly supported

  The Results section, “GBCr in TRD & Post-ketamine” (page unavailable), identifies three clusters in the bilateral dorsomedial and right dorsolateral prefrontal cortex, but reports a significant increase in their average connectivity 24 hours after treatment—not an increase in each cluster during infusion. The Results section, “GBCr & Glutamate Modulators” (page unavailable), reports increases during infusion in two clusters, in the bilateral dorsomedial and left frontolateral prefrontal cortex. (LLM, conf=0.88)

  cites [76] Abdallah CG, Averill CL, Salas R, Averill LA, Baldwin PR, Krystal JH, et al. Prefrontal connectivity and glutamate transmission: relevance to depression pathophysiology and ketamine treatment. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:566–74. sourceExperimental — accuracy not yet measured

In the paper

“Across studies, over-recruitment of PFC regions (mPFC, dlPFC) during reward processing has been interpreted as suggesting over-compensation for reduced striatal responses to rewards [104, 111, 112].”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [104] O’Callaghan G, Stringaris A. Reward processing in adolescent depression across neuroimaging modalities: a review. Z Kinder Jugendpsychiatr Psychother. 2019;47:535–41. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [111] Forbes EE, Hariri AR, Martin SL, Silk JS, Moyles DL, Fisher PM, et al. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatry. 2009;166:64–73. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [112] Pan PM, Sato JR, Salum GA, Rohde LA, Gadelha A, Zugman A, et al. Ventral striatum functional connectivity as a predictor of adolescent depressive disorder in a longitudinal community-based sample. Am J Psychiatry. 2017;174:1112–9. sourceExperimental — accuracy not yet measured

In the paper

“First, recent meta-analyses have yielded surprisingly few structural abnormalities linked to MDD [79].”

What the sources say

• Supported

  The Discussion reports no brain regions with significant convergence in the meta-analysis of gray matter atrophy in major depression versus controls. The Results add that the primary analyses detected no convergence, while secondary pooled structure–function analyses identified a few regions. This supports the claim that meta-analyses have yielded few robust structural abnormalities linked to MDD. (LLM, conf=0.91)

  cites [79] Gray JP, Müller VI, Eickhoff SB, Fox PT. Multimodal abnormalities of brain structure and function in major depressive disorder: a meta-analysis of neuroimaging studies. Am J Psychiatry. 2020;177:422–34. source

In the paper

“In some studies, blunted ventral striatal activation to rewards correlated with anhedonic symptoms [102].”

What the sources say

• Supported

  In Results > Reward liking, the review reports that ventral striatal hypoactivation correlated with anhedonia levels in some studies, while another study found no such correlation. The reported responses were to positive words and happy stimuli, rather than necessarily to monetary rewards. (LLM, conf=0.92)

  cites [102] Borsini A, Wallis ASJ, Zunszain P, Pariante CM, Kempton MJ. Characterizing anhedonia: a systematic review of neuroimaging across the subtypes of reward processing deficits in depression. Cogn Affect Behav Neurosci. 2020;20:816–41. source

In the paper

“Thus, relative to healthy children, children (7-12 years) with a history of preschool-onset depression (age of onset: 3-6 years) had thinner right sgACC cortical thickness [85].”

What the sources say

• Partly supported

  The Methods report imaging at ages 7–12, and the Results (Specificity to PO-MDD) find significantly thinner right VMPFC in children with preschool-onset depression than in healthy children. The Introduction describes the subgenual region as one component of the VMPFC, but the reported thickness result is for the VMPFC as a whole, not specifically the right sgACC. (LLM, conf=0.88)

  cites [85] Marrus N, Belden A, Nishino T, Handler T, Tilak Ratnanather J, Miller M, et al. Ventromedial prefrontal cortex thinning in preschool-onset depression. J Affect Disord. 2015;180:79–86. sourceExperimental — accuracy not yet measured

In the paper

“Specifically, lower cortical thickness in the right medial OFC/vmPFC (but larger pgACC cortical thickness) emerged as two of the top three neural features predicting the first episode of MDD [87].”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [87] Foland-Ross LC, Sacchet MD, Prasad G, Gilbert B, Thompson PM, Gotlib IH. Cortical thickness predicts the first onset of major depression in adolescence. Int J Dev Neurosci. 2015;46:125–31. sourceExperimental — accuracy not yet measured

In the paper

“Accompanying these behavioral changes are marked physiological and structural alterations, not only in the amygdala and hippocampus but, importantly, the PFC [98,99], that are similar to those seen in MDD.”

What the sources say

• Partly supported

  The “Effects of Stress on Prefrontal Cortex” section says repeated stress causes functional and structural changes in the PFC, amygdala, and hippocampus. “Relevance to human vulnerabilities and potential for brain plasticity” describes frontal-cortex and hippocampal changes in depressed individuals, but does not establish that the alterations across all three regions are similar to those in MDD. (LLM, conf=0.85)

  cites [98] McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79:16–29. sourceExperimental — accuracy not yet measured
• Partly supported

  The section on sex differences after puberty reports depressive-like behavior alongside chronic-stress-induced remodeling of the hippocampus, PFC, and amygdala; the PFC section also describes structural remodeling after chronic stress. The copy discusses findings in depressed people for the hippocampus, but the passages do not establish that the alterations across all three regions are similar to those seen in MDD. Page numbers were not available in the indexed passages. (LLM, conf=0.82)

  cites [99] McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology. 2016;41:3–23. sourceExperimental — accuracy not yet measured

In the paper

“Similarly, ECT treatment was associated with increased cortical thickness across PFC (dlPFC) and dACC [89].”

What the sources say

• Supported

  The Discussion (page not provided) explicitly reports increased cortical thickness across prefrontal regions, including the DLPFC, and the ACC during ECT. The Results > Effects of ECT reports increases in bilateral ACC thickness, and the Discussion identifies the dorsal ACC in its account of these findings. (LLM, conf=0.91)

  cites [89] Pirnia T, Joshi SH, Leaver AM, Vasavada M, Njau S, Woods RP, et al. Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex. Transl Psychiatry. 2016;6:e832. https://doi.org/10.1038/tp.2016.102. source

In the paper

“Chronic stress (e.g., social defeat, restraint stress, unpredictable mild stress) over a period of days to weeks induces a variety of depression-related symptoms (Fig. 3, top right-hand panel), including behavioral despair, blunted reward-related behaviors, negative biases and cognitive dysfunction [67,92].”

What the sources say

• ?Not checked — no full text of the sourcecites [67] Gururajan A, Reif A, Cryan JF, Slattery DA. The future of rodent models in depression research. Nat Rev Neurosci. 2019;20:686–701. source
• Partly supported

  The Introduction reports that unpredictable mild stress in rats and mice reduces reward-related behavior over weeks, and the Validity section reports cognitive impairments following CMS. The paper does not establish negative biases or behavioral despair as outcomes, and its account of CMS does not support the sentence’s broader grouping of social defeat and restraint stress with unpredictable mild stress. (LLM, conf=0.87)

  cites [92] Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. 2017;6:78–93. sourceExperimental — accuracy not yet measured

In the paper

“In the largest ever conducted structural MRI study, relative to controls (N = 7658), adults with MDD (N = 1902) showed thinner cortical gray matter in the ACC (with reduction spanning subgenual, perigenual and dorsal regions) and OFC/ vmPFC [81].”

What the sources say

• Partly supported

  The Results (Adults; page unavailable) report thinner cortex in 1,902 adults with MDD than in 7,658 controls, including the medial OFC, rostral ACC and right caudal ACC. The Discussion (Cortical thickness; page unavailable) says the medial OFC atlas region contains the subgenual ACC, but does not establish thinning separately across subgenual, perigenual and dorsal ACC regions as the claim states. (LLM, conf=0.84)

  cites [81] Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22:900–9. sourceExperimental — accuracy not yet measured

In the paper

“Importantly, decreased right sgACC cortical thickness at age 7-12 was predicted by depression severity at age 3-6 (and age 7-12).”

What the sources say

• Partly supported

  The Results (PO-MDD Severity in Relation to VMPFC Thickness; page unavailable) report that preschool depression severity predicted thinner right ventromedial prefrontal cortex (VMPFC) at school age. School-age severity was associated with thickness when tested without preschool severity, but was not a significant predictor when both were included. The paper measured the broader VMPFC, not cortical thickness specifically in the subgenual anterior cingulate cortex. (LLM, conf=0.91)

  cites [85] Marrus N, Belden A, Nishino T, Handler T, Tilak Ratnanather J, Miller M, et al. Ventromedial prefrontal cortex thinning in preschool-onset depression. J Affect Disord. 2015;180:79–86. sourceExperimental — accuracy not yet measured

In the paper

“Fitting this, in the UK Biobank sample, polygenic risk for anhedonia was linked to smaller OFC volumes [84].”

What the sources say

• Supported

  The Results section (‘PRS and brain MRI structural and functional outcomes’) reports that greater polygenic risk for anhedonia was associated with smaller orbitofrontal cortex volume. The Methods section (‘UK Biobank sample’) identifies the cohort as UK Biobank. (LLM, conf=0.95)

  cites [84] Ward J, Lyall LM, Bethlehem RAI, Ferguson A, Strawbridge RJ, Lyall DM, et al. Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure. Transl Psychiatry. 2019;9:327. https://doi.org/10.1038/s41398-019-0635-y. source

In the paper

“In general, blunted striatal activation coupled with over-recruitment of PFC regionsincluding the dlPFC during reward outcomehas emerged [104].”

What the sources say

• Supported

  The Functional MRI Findings report blunted caudate activation in depressed adolescents during reward outcome and greater prefrontal BOLD signals, including in the DLPFC, during reward outcome. These findings support the cited summary. (LLM, conf=0.91)

  cites [104] O’Callaghan G, Stringaris A. Reward processing in adolescent depression across neuroimaging modalities: a review. Z Kinder Jugendpsychiatr Psychother. 2019;47:535–41. source

In the paper

“Finally, reduction in depressive symptoms after left dlPFC rTMS treatment was associated with increases in pgACC thickness (Fig. 4b) [90].”

What the sources say

• Supported

  The Methods describe participants receiving left dorsolateral prefrontal cortex rTMS for depression. The Results (Main Analysis and Region-of-Interest Analyses; page not available in our copy) report that greater clinical improvement was associated with increased thickness in the left rostral anterior cingulate cortex, the region described in the claim as perigenual ACC. (LLM, conf=0.89)

  cites [90] Boes AD, Uitermarkt BD, Albazron FM, Lan MJ, Liston C, Pascual-Leone A, et al. Rostral anterior cingulate cortex is a structural correlate of repetitive TMS treatment response in depression. Brain Stimul. 2018;11:575–81. source

In the paper

“These studies have generally linked MDD to blunted RPE in the ventral and dorsal striatum [122-124] (but see [125,126] for important lack of replication), pgACC [127] and medial OFC [126], and greater RPE in the ventral striatum predicted reductions in anhedonia 6 months later [128].”

What the sources say

• ?Not checked — no full text of the sourcecites [122] Kumar P, Waiter G, Ahearn T, Milders M, Reid I, Steele JD. Abnormal temporal difference reward-learning signals in major depression. Brain. 2008;131:2084–93. source
• Partly supported

  The Results (ROI analyses; page unavailable) report blunted RPE in the right striatum of unmedicated participants with MDD, but not in the left striatum. The whole-brain analyses identify RPE signals in the right putamen and nucleus accumbens in controls, but do not establish separate group differences for dorsal and ventral striatum. Thus the source supports the broad striatal claim, not the claim at that anatomical specificity. (LLM, conf=0.83)

  cites [123] Kumar P, Goer F, Murray L, Dillon DG, Beltzer ML, Cohen AL, et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology. 2018;43:1581–8. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [124] Gradin VB, Kumar P, Waiter G, Ahearn T, Stickle C, Milders M, et al. Expected value and prediction error abnormalities in depression and schizophrenia. Brain. 2011;134:1751–64. source

In the paper

“Of relevance, disrupted coupling within reward-related corticostriatal pathways has emerged also from resting state studies, with reports of increased rsFC between (1) vlPFC and dorsal striatum [135], and (2) dmPFC and various striatal regions [136].”

What the sources say

• Supported

  The Results (Between-group; page unavailable) report increased resting-state functional connectivity between the dorsal caudate and bilateral ventrolateral prefrontal cortex in depressed patients compared with healthy controls. The dorsal caudate is the dorsal striatal region supporting the cited claim. (LLM, conf=0.94)

  cites [135] Kerestes R, Harrison BJ, Dandash O, Stephanou K, Whittle S, Pujol J, et al. Specific functional connectivity alterations of the dorsal striatum in young people with depression. NeuroImage Clin. 2015;7:266–72. source

In the paper

“Finally, among TRD patients, sgACC hyper-activation to positive feedback correlated with more anticipatory anhedonia (but not anxiety symptoms) [121].”

What the sources say

• Partly supported

  The Participants results report that sgACC activation to positive feedback correlated with worse anticipatory anhedonia, but not anxiety. However, the correlation was calculated across the full sample of depressed patients and healthy controls, not specifically among TRD patients. The Participants and procedures section does not establish treatment resistance as a criterion for that cohort. (LLM, conf=0.90)

  cites [121] Morris LS, Costi S, Tan A, Stern ER, Charney DS, Murrough JW. Ketamine normalizes subgenual cingulate cortex hyper-activity in depression. Neuropsychopharmacology. 2020;45:975–81. sourceExperimental — accuracy not yet measured

In the paper

“These studies have generally linked MDD to blunted RPE in the ventral and dorsal striatum [122-124] (but see [125,126] for important lack of replication), pgACC [127] and medial OFC [126], and greater RPE in the ventral striatum predicted reductions in anhedonia 6 months later [128].”

What the sources say

• Supported

  The Results section reports that greater left ventral striatal activation to reward prediction error predicted greater improvement in self-reported anhedonia over six months. This supports the cited claim; the paper specifies the left ventral striatum. (LLM, conf=0.94)

  cites [128] Eckstrand KL, Forbes EE, Bertocci MA, Chase HW, Greenberg T, Lockovich J, et al. Anhedonia reduction and the association between left ventral striatal reward response and 6-month improvement in life satisfaction among young adults. JAMA Psychiatry. 2019;76:958–65. source

In the paper

“In MDD, reduced approach-related dlPFC activation correlated with increasing perceived stress.”

What the sources say

• Partly supported

  The Discussion reports reduced approach-related DLPFC activation in MDD. However, the correlation with higher perceived stress is reported for DLPFC activation during non-conflict trials, not specifically for approach-related activation (Results, Imaging Results; page not provided). (LLM, conf=0.88)

  cites [42] Ironside M, Amemori KI, McGrath CL, Pedersen ML, Kang MS, Amemori S, et al. Approach-avoidance conflict in major depressive disorder: congruent neural findings in humans and nonhuman primates. Biol Psychiatry. 2020;87:399–408. sourceExperimental — accuracy not yet measured

In the paper

“Consistent with the latter, NMDA infusions into ILc reduced spontaneous firing of DA neurons in the medial VTA [139].”

What the sources say

• Supported

  The ILPFC Activation results report that NMDA infusion reduced the number of spontaneously active dopamine neurons in the medial VTA. The paper calls this reduced population activity; it explicitly says the average firing rate of active neurons did not change. (LLM, conf=0.88)

  cites [139] Moreines JL, Owrutsky ZL, Grace AA. Involvement of infralimbic prefrontal cortex but not lateral habenula in dopamine attenuation after chronic mild stress. Neuropsychopharmacology. 2017;42:904–13. source

In the paper

“In studies using a “wheel-offortune” task, which involves making choices about varying amounts of monetary rewards with varying levels of risk, adults with MDD showed greater left OFC activation but reduced pgACC activation during the selection phase relative to controls; in addition, they showed greater activation to wins in the left inferior frontal gyrus (BA9/45) than controls [132].”

What the sources say

• Supported

  The Introduction identifies the task as a Wheel of Fortune task involving adults with MDD and matched adult controls. The Results (Imaging Data, Reward Outcomes) report greater left inferior frontal gyrus (BA 9/45) activation in the MDD group than in controls for the Win > Control contrast. (LLM, conf=0.94)

  cites [132] Smoski MJ, Felder J, Bizzell J, Green SR, Ernst M, Lynch TR, et al. fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder. J Affect Disord. 2009;118:69–78. source

In the paper

“In contrast, prolonged ILc pyramidal stimulation for 60 min mirrored the putative antidepressant effects of ketamine on sucrose preference, while neuronal silencing of ILc (and not PLc), using the GABA-A agonist, muscimol, blocked the actions of ketamine, 24 h later [63].”

What the sources say

• Partly supported

  Methods and Materials specify 60 minutes of optical stimulation, and the Fig. 4 caption reports a significant sucrose-preference effect. The Optogenetic Stimulation results qualify that finding: the increase was small and occurred with bilateral IL-PFC stimulation, not unilateral stimulation. The Neuronal Inactivation results also support the citing sentence’s separate point that IL, but not PrL, muscimol infusion blocked ketamine’s behavioral effects assessed 24 hours later. (LLM, conf=0.86)

  cites [63] Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Natl Acad Sci USA. 2015;112:8106–8111. sourceExperimental — accuracy not yet measured

In the paper

“Importantly, sgACC hyper-activation to positive (but not negative) incentives was normalized (decreased) by a single ketamine infusion.”

What the sources say

• Supported

  The Abstract describes a second cohort scanned before and after a single ketamine infusion and reports reduced sgACC hyper-activation to positive, but not negative, incentives. The Discussion likewise states that ketamine blunted hyper-activation to positive feedback but not negative feedback. (LLM, conf=0.94)

  cites [121] Morris LS, Costi S, Tan A, Stern ER, Charney DS, Murrough JW. Ketamine normalizes subgenual cingulate cortex hyper-activity in depression. Neuropsychopharmacology. 2020;45:975–81. source

In the paper

“Moreover, in a community-based sample (N = 475) tested with a probabilistic reward learning task, increasing depressive symptoms were related to blunted (1) directional connectivity from the mPFC to the striatum, (2) RPE in the dACC, and (3) reward signal magnitude in the nucleus accumbens and caudal vmPFC [129].”

What the sources say

• Partly supported

  The Results (General linear model voxel-based functional MRI analyses; page unavailable) link higher depressive symptoms to reduced reward activation in the striatum, supporting the nucleus accumbens portion. They report vmPFC reward activation across participants, but do not report a depressive-symptom-related reduction in reward signal magnitude in the caudal vmPFC; the separate mPFC finding concerns RPE encoding. (LLM, conf=0.87)

  cites [129] Rupprechter S, Romaniuk L, Series P, Hirose Y, Hawkins E, Sandu AL, et al. Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression. Brain. 2020;143:1946–56. sourceExperimental — accuracy not yet measured

In the paper

“Moreover, in a community-based sample (N = 475) tested with a probabilistic reward learning task, increasing depressive symptoms were related to blunted (1) directional connectivity from the mPFC to the striatum, (2) RPE in the dACC, and (3) reward signal magnitude in the nucleus accumbens and caudal vmPFC [129].”

What the sources say

• Supported

  The Results section (Dynamic causal modelling of event-related effective connectivity; page not supplied) reports that higher depression scores were associated with decreased directed influence from the mPFC to the ventral striatum. The Discussion identifies the sample as community-based. (LLM, conf=0.94)

  cites [129] Rupprechter S, Romaniuk L, Series P, Hirose Y, Hawkins E, Sandu AL, et al. Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression. Brain. 2020;143:1946–56. source

In the paper

“Of relevance, disrupted coupling within reward-related corticostriatal pathways has emerged also from resting state studies, with reports of increased rsFC between (1) vlPFC and dorsal striatum [135], and (2) dmPFC and various striatal regions [136].”

What the sources say

• Supported

  The Results (Primary Hypothesis Testing: Striatal iFC Group Comparisons; page unavailable) report increased resting-state intrinsic functional connectivity between striatal seeds and the dmPFC in adolescents with MDD compared with healthy controls. The Abstract Results specify that this finding involved all striatal regions bilaterally, supporting the citing sentence’s reference to various striatal regions. (LLM, conf=0.94)

  cites [136] Gabbay V, Ely BA, Li Q, Bangaru SD, Panzer AM, Alonso CM, et al. Striatum-based circuitry of adolescent depression and anhedonia. J Am Acad Child Adolesc Psychiatry. 2013;52:628–.e13. source

In the paper

“Critically, in a community-based sample of 6-12 years children (N = 637), rsFC strength between the ventral striatum and other reward-related regions (vmPFC, dACC, VTA) predicted the new onset of depressive disorder 3 years later [112].”

What the sources say

• Supported

  The Method passage (page unavailable) reports 637 children aged 6–12 who underwent resting-state fMRI. The Results and Discussion (pages unavailable) report that left ventral striatum node strength—a measure of connectivity across the reward network—predicted new-onset depressive disorder three years later. The named regions describe that network; the paper does not present each individual connection as a separate predictor. (LLM, conf=0.88)

  cites [112] Pan PM, Sato JR, Salum GA, Rohde LA, Gadelha A, Zugman A, et al. Ventral striatum functional connectivity as a predictor of adolescent depressive disorder in a longitudinal community-based sample. Am J Psychiatry. 2017;174:1112–9. source

In the paper

“In one case of ILc, its inactivation selectively blocked the effects of chronic mild stress on reward-related dopamine activity [139].”

What the sources say

• Supported

  The results section ‘ILPFC but not LHb Inactivation Restores Dopamine Activity in CMS-Exposed Rats’ reports that ILPFC inactivation restored dopamine neuron population activity after chronic mild stress, while LHb inactivation did not. The Discussion identifies the affected medial VTA dopamine neurons as projecting to reward-related regions. Page numbers are not provided in our copy. (LLM, conf=0.91)

  cites [139] Moreines JL, Owrutsky ZL, Grace AA. Involvement of infralimbic prefrontal cortex but not lateral habenula in dopamine attenuation after chronic mild stress. Neuropsychopharmacology. 2017;42:904–13. source

In the paper

“Highlighting specificity, this metric did not predict the emergence of ADHD, anxiety or substance abuse over the same time period.”

What the sources say

• Partly supported

  The Results (Specificity Analyses) report that left ventral striatum node strength was not associated with anxiety disorders, ADHD, or any substance use at the three-year follow-up. The paper measured any reported alcohol, tobacco, or drug use—not a diagnosis of substance abuse—so that part of the claim is more specific than the evidence supports. (LLM, conf=0.88)

  cites [112] Pan PM, Sato JR, Salum GA, Rohde LA, Gadelha A, Zugman A, et al. Ventral striatum functional connectivity as a predictor of adolescent depressive disorder in a longitudinal community-based sample. Am J Psychiatry. 2017;174:1112–9. sourceExperimental — accuracy not yet measured

In the paper

“Relative to controls, unmedicated adults with MDD were less sensitive to reward.”

What the sources say

• Supported

  The Human Participants section identifies the MDD group as 21 unmedicated female adults and the comparison group as 35 healthy female adults. The Human Study Results report that the MDD group was less sensitive to reward than controls on the approach–avoidance task. (LLM, conf=0.94)

  cites [42] Ironside M, Amemori KI, McGrath CL, Pedersen ML, Kang MS, Amemori S, et al. Approach-avoidance conflict in major depressive disorder: congruent neural findings in humans and nonhuman primates. Biol Psychiatry. 2020;87:399–408. source

In the paper

“Moreover, in a community-based sample (N = 475) tested with a probabilistic reward learning task, increasing depressive symptoms were related to blunted (1) directional connectivity from the mPFC to the striatum, (2) RPE in the dACC, and (3) reward signal magnitude in the nucleus accumbens and caudal vmPFC [129].”

What the sources say

• Partly supported

  The Results (General linear model voxel-based functional MRI analyses; page unavailable) link higher depressive symptoms to decreased RPE signal encoding in the midbrain/ventral tegmental area and mPFC. They do not identify the dACC as a region with blunted RPE encoding, so the claimed location is not supported. (LLM, conf=0.84)

  cites [129] Rupprechter S, Romaniuk L, Series P, Hirose Y, Hawkins E, Sandu AL, et al. Blunted medial prefrontal cortico-limbic reward-related effective connectivity and depression. Brain. 2020;143:1946–56. sourceExperimental — accuracy not yet measured

In the paper

“Imaging studies in children and adolescents with MDD have also highlighted blunted ventral striatal activation during reward anticipation, which was often accompanied by over-recruitment of PFC regions (e.g., pgACC/vmPFC) [104].”

What the sources say

• Partly supported

  The Functional MRI Findings section reports reduced caudate activation during reward anticipation in children and adolescents with MDD, as well as greater medial prefrontal activity during anticipation in depressed adolescents. But it says youth findings were primarily in the bilateral caudate, with more ventral reductions seen in adults. It does not establish that pgACC/vmPFC over-recruitment often accompanied the reduced activation in the same young patients (page unavailable in our copy). (LLM, conf=0.87)

  cites [104] O’Callaghan G, Stringaris A. Reward processing in adolescent depression across neuroimaging modalities: a review. Z Kinder Jugendpsychiatr Psychother. 2019;47:535–41. sourceExperimental — accuracy not yet measured

In the paper

“Building on this evidence, the same group recently showed that inhibitory (1 Hz) TMS over the right OFC in TRD was associated with a 30% response rate [118].”

What the sources say

• Supported

  Section 3.3 (page unavailable) reports a 30.0% response rate (9/30) after right OFC-rTMS among patients who had previously failed to respond to DMPFC-rTMS. This is the treatment-resistant subgroup; the response rate across all 42 patients was 35.7%. (LLM, conf=0.91)

  cites [118] Feffer K, Fettes P, Giacobbe P, Daskalakis ZJ, Blumberger DM, Downar J. 1 Hz rTMS of the right orbitofrontal cortex for major depression: Safety, tolerability and clinical outcomes. Eur Neuropsychopharmacol. 2018;28:109–17. source

In the paper

“Of note, deficient recruitment of PFC (particularly, dlPFC) regions has been coupled with hyperactivity in paralimbic (e.g., pgACC, sgACC) and limbic (e.g., amygdala) regions critically implicated in automatic processing of emotional cues (for review, see [16,157]).”

What the sources say

• Supported

  The Functional neuroimaging studies section describes reduced DLPFC recruitment alongside heightened rACC and amygdala responses during emotional tasks, and links these regions to automatic responses to emotional cues. The Introduction identifies rACC as pregenual/perigenual and separately describes subgenual ACC hyperactivity in depression. Page numbers are not available in the supplied copy. (LLM, conf=0.91)

  cites [16] Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36:183–206. source
• Partly supported

  The Results (Connectivity results; page unavailable) report reduced amygdala–DLPFC connectivity, while the Discussion (Abnormal ACC and OFC activity; page unavailable) describes hyperactivation of the subgenual ACC. The review also supports amygdala hyperactivity during negative-face processing, but its Results (Abnormal frontal activity; page unavailable) say DLPFC activation findings are inconsistent, so they do not establish deficient DLPFC recruitment as a general pattern. The supplied passages do not establish hyperactivity of the pgACC. (LLM, conf=0.86)

  cites [157] Stuhrmann A, Suslow T, Dannlowski U. Facial emotion processing in major depression: a systematic review of neuroimaging findings. Biol Mood Anxiety Disord. 2011;1:1–10. sourceExperimental — accuracy not yet measured

In the paper

“Consistent with the latter is the finding that area 25 activity positively correlates with cortisol levels during anxiety-provoking contexts in macaques [143].”

What the sources say

• Supported

  The Results for Experiment 2 report positive correlations between cortisol and metabolic activity in a subgenual prefrontal cluster spanning areas 25/24 across three stress-related contexts. Experiment 1 also found this cluster correlated with cortisol across threat and home-cage conditions, with no consistently negative correlation. The paper measures an area 25/24 cluster rather than area 25 in isolation. (LLM, conf=0.93)

  cites [143] Jahn AL, Fox AS, Abercrombie HC, Shelton SE, Oakes TR, Davidson RJ, et al. Subgenual PFC Activity Predicts Individual Differences in HPA Activity Across Different Contexts. Biol Psychiatry 2010;67:175–81. source

In the paper

“In contrast, consummatory responses, including behavioral and cardiovascular arousal during reward consumption itself and performance on a sucrose preference test remained relatively unaffected.”

What the sources say

• Supported

  The Results report no significant effect of sgACC/25 over-activation on consummatory cardiovascular arousal or food consumption during reward delivery, and no effect on sucrose preference or consumption. The Discussion likewise states that behavioral and cardiovascular consummatory responses in the Pavlovian task and performance on the sucrose preference test were unaffected. The paper uses the more specific term sgACC/25 for the cited area 25 manipulation. (LLM, conf=0.95)

  cites [61] Alexander L, Gaskin PLR, Sawiak SJ, Fryer TD, Hong YT, Cockcroft GJ, et al. Fractionating blunted reward processing characteristic of anhedonia by over-activating primate subgenual anterior cingulate cortex. Neuron. 2019;101:307–320.e6. source

In the paper

“Similarly, hyperactivation of, or a failure to deactivate, the pgACC has been reported in MDD across disparate affective tasks [16,179], including (1) affective evaluation and cognitive reappraisal of negative stimuli; (2) self-referential processing of negative attributes; (3) inhibition of negative words; and in response to (4) sad words and commission errors.”

What the sources say

• Supported

  The Introduction identifies the rACC as the region often called pregenual ACC (pgACC). In “Frontocingulate activation during affective tasks,” the paper reports hyperactivation or reduced deactivation of this region in MDD across the affective tasks listed in the citing sentence. (LLM, conf=0.95)

  cites [16] Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36:183–206. source
• ?Not checked — no full text of the sourcecites [179] Jaworska N, Yang XR, Knott V, Macqueen G. A review of fMRI studies during visual emotive processing in major depressive disorder. World J Biol Psychiatry. 2015;16:448–71. source

In the paper

“Relative to healthy controls, individuals with MDD showed reduced dlPFC activation during tasks involving matching negative facial expressions [159], presenting negative stimuli [156, 160], requiring to ignore negative faces [161], or inducing emotional interference [162].”

What the sources say

• ?Not checked — no full text of the sourcecites [159] Zhong M, Wang X, Xiao J, Yi J, Zhu X, Liao J, et al. Amygdala hyperactivation and prefrontal hypoactivation in subjects with cognitive vulnerability to depression. Biol Psychol. 2011;88:233–42. source
• Partly supported

  The Discussion (page unavailable) identifies the middle frontal gyrus as DLPFC and reports a relative lack of activation during induction of negative affect in patients with MDD. That supports the claim for negative stimuli generally, but the paper does not establish reduced DLPFC activation for each specified task—matching negative facial expressions, ignoring negative faces, or inducing emotional interference. (LLM, conf=0.84)

  cites [156] Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ. A meta-analytic study of changes in brain activation in depression. Hum Brain Mapp. 2008;29:683–95. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (§3.2; page unavailable) report reduced activation to attentional targets and greater deactivation to sad distractors in MDD, including in the middle frontal gyrus, during an emotional-distraction task. But for targets following sad distractors—the comparison that isolates emotional interference—the Results report increased, not reduced, middle frontal gyrus activation in MDD relative to controls. Thus the citation supports the broader task-level finding but not an unqualified reduction during the interference-specific condition. (LLM, conf=0.86)

  cites [160] Wang L, LaBar KS, Smoski M, Rosenthal MZ, Dolcos F, Lynch TR, et al. Prefrontal mechanisms for executive control over emotional distraction are altered in major depression. Psychiatry Res. 2008;163:143–55. sourceExperimental — accuracy not yet measured
• Supported

  Citation [162] supports the emotional-interference part of the sentence. The Discussion reports that, when fearful faces were unattended distractors, controls recruited the right DLPFC but participants with MDD did not. (LLM, conf=0.92)

  cites [161] Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, et al. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. 2008;63:377–84. source

In the paper

“Its over-activation not only blunted appetitive processing but also enhanced responsivity to both uncertain threat and Pavlovian conditioned, certain threat [144], consistent with the high comorbidity of anxiety with MDD [145, 146]; but inconsistent with the role of ILc in inhibiting conditioned fear responses in rats [147].”

What the sources say

• Supported

  The Results report that sgACC/25 over-activation heightened anxiety-like responses to a human intruder and elevated arousal during Pavlovian conditioned-threat tests. The Discussion describes the conditioned-threat effect as generalized across the test session, rather than confined to the conditioned stimulus. (LLM, conf=0.88)

  cites [144] Alexander L, Wood CM, Gaskin PLR, Sawiak SJ, Fryer TD, Hong YT, et al. Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat. Nat Commun 2020;11:1–14. source

In the paper

“Additionally, current MDDbut not familial MDD riskwas associated with potentiated medial OFC activation to negative faces.”

What the sources say

• Supported

  The Results report increased medial OFC activation to negative stimuli in patients with MDD irrespective of familial risk. The Discussion specifies that OFC response to negative faces was associated with depressive symptoms and that no association between familial risk and altered medial OFC signalling was detected. (LLM, conf=0.94)

  cites [163] Opel N, Redlich R, Grotegerd D, Dohm K, Zaremba D, Meinert S, et al. Prefrontal brain responsiveness to negative stimuli distinguishes familial risk for major depression from acute disorder. J Psychiatry Neurosci. 2017;42:343–52. source

In the paper

“Relative to control children (8-14 years), unaffected high-risk children (due to parental depression) showed higher responses to fearful vs. neutral faces in the dlPFC (BA10/46) and amygdala [185].”

What the sources say

• Partly supported

  The Methods (Participants; page unavailable) identify children aged 8–14 with parental depression and age-matched controls. The Results (fMRI results; page unavailable) report greater fearful-versus-neutral activation in the at-risk group, including the amygdala and a middle prefrontal region. Our copy does not identify that prefrontal finding specifically as dlPFC (BA10/46), so that anatomical detail is unsupported. (LLM, conf=0.86)

  cites [185] Chai XJ, Hirshfeld-Becker D, Biederman J, Uchida M, Doehrmann O, Leonard JA, et al. Functional and structural brain correlates of risk for major depression in children with familial depression. NeuroImage Clin. 2015;8:398–407. sourceExperimental — accuracy not yet measured

In the paper

“Reduced FC between dmPFC regions (superior (BA6) and medial (BA10) frontal gyrus) and the amygdala was observed in healthy first-degree relatives of MDD patients during an implicit emotional processing task involving presentation of negative faces (Fig. 4f) [189].”

What the sources say

• Supported

  The Discussion reports reduced amygdala connectivity with dorsomedial prefrontal regions in healthy relatives across task conditions. The group-effects table identifies the superior frontal gyrus as BA6 and the medial frontal gyrus as BA10; the Introduction describes the task as matching angry and fearful faces against shapes. The reduction was measured across conditions, not specifically during face presentation alone. (LLM, conf=0.92)

  cites [189] Wackerhagen C, Wüstenberg T, Mohnke S, Erk S, Veer IM, Kruschwitz JD, et al. Influence of familial risk for depression on cortico-limbic connectivity during implicit emotional processing. Neuropsychopharmacology. 2017;42:1729–38. source

In the paper

“In contrast, prolonged ILc pyramidal stimulation for 60 min mirrored the putative antidepressant effects of ketamine on sucrose preference, while neuronal silencing of ILc (and not PLc), using the GABA-A agonist, muscimol, blocked the actions of ketamine, 24 h later [63].”

What the sources say

• Supported

  The “Neuronal Inactivation of IL-PFC” section reports that muscimol infused into IL before ketamine blocked its antidepressant effect in the forced swim test when behavior was assessed 24 hours later. It also reports that muscimol infused into PrL did not block that response. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [63] Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Natl Acad Sci USA. 2015;112:8106–8111. source

In the paper

“Notably, relative to young adults without a family history of MDD, the high-risk group was also characterized by increased task-related FC between vmPFC regions (sgACC (BA25) and pgACC (BA24/32)) and the amygdala [189].”

What the sources say

• Supported

  The Discussion reports increased amygdala connectivity with the vmPFC regions sgACC and pgACC in unaffected relatives of people with MDD, compared with controls, across task conditions. The Participants section identifies the groups as adults with mean ages of 28.0 and 29.7 years; the connectivity table labels the regions sgACC (BA24/25) and pgACC (BA32/24). The finding is across task conditions, not an increase specific to the emotional-faces condition. (LLM, conf=0.93)

  cites [189] Wackerhagen C, Wüstenberg T, Mohnke S, Erk S, Veer IM, Kruschwitz JD, et al. Influence of familial risk for depression on cortico-limbic connectivity during implicit emotional processing. Neuropsychopharmacology. 2017;42:1729–38. source

In the paper

“In an emotional face-matching paradigm, currently depressed adults (as well as unaffected firstdegree relatives of individuals with MDD) showed reduced dlPFC activation to negative faces compared to controls without familial risk [163].”

What the sources say

• Supported

  The Methods describe an emotional face-matching paradigm comparing acutely depressed patients and healthy first-degree relatives with controls without a family history of depression. The Results report significantly lower DLPFC activation to negative stimuli in both the depressed patients and the healthy participants at familial risk than in controls without familial risk. (LLM, conf=0.95)

  cites [163] Opel N, Redlich R, Grotegerd D, Dohm K, Zaremba D, Meinert S, et al. Prefrontal brain responsiveness to negative stimuli distinguishes familial risk for major depression from acute disorder. J Psychiatry Neurosci. 2017;42:343–52. source

In the paper

“Conversely, area 14 in the medial OFC/caudal vmPFC appears more important for comparing values of alternative options.”

What the sources say

• Partly supported

  The ‘Medial versus lateral orbitofrontal cortex’ section says the medial OFC seems important for choices based on value comparisons, and describes impaired choices after medial OFC lesions. The paper does not specifically assign that function to area 14; its anatomy section identifies area 14 as a subdivision of the OFC without establishing the narrower functional claim. Page numbers were not available in our copy. (LLM, conf=0.82)

  cites [115] Murray EA, Rudebeck PH. Specializations for reward-guided decision-making in the primate ventral prefrontal cortex. Nat Rev Neurosci. 2018;19:404–17. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction’s “Neural correlates of value in the OFC” section describes OFC activity associated with the values of goods on offer. It does not identify area 14 or say that this region is more important for comparing options. The “OFC is required for model-based value computation” section also reports that medial OFC inactivation did not affect choice behavior in well-trained rats. (LLM, conf=0.82)

  cites [150] Zhou J, Gardner MP, Schoenbaum G. Is the core function of orbitofrontal cortex to signal values or make predictions?. Curr Opin Behav Sci. 2021;41:1–9. sourceExperimental — accuracy not yet measured

In the paper

“Temporary infusions of the glutamate transporter blocker, dihydrokainic acid (DHK), which heightens the excitability of neurons, induced the blunting of both anticipatory and motivational arousal when infused into area 25.”

What the sources say

• Supported

  The Results report that DHK infusions into sgACC/25 blunted anticipatory cardiovascular and behavioral arousal in marmosets. A separate Results section reports that DHK-induced over-activation significantly reduced their willingness to work for reward, supporting the claim’s motivational component. The Methods describe the infusions as temporary. (LLM, conf=0.90)

  cites [61] Alexander L, Gaskin PLR, Sawiak SJ, Fryer TD, Hong YT, Cockcroft GJ, et al. Fractionating blunted reward processing characteristic of anhedonia by over-activating primate subgenual anterior cingulate cortex. Neuron. 2019;101:307–320.e6. source

In the paper

“Similarly, in an emotional face-matching paradigm, unaffected first-degree relatives of acutely depressed patients with MDD (as well as individuals with current MDD) had reduced dlPFC activation in response to negative faces compared to healthy controls without familial risk [163].”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [163] Opel N, Redlich R, Grotegerd D, Dohm K, Zaremba D, Meinert S, et al. Prefrontal brain responsiveness to negative stimuli distinguishes familial risk for major depression from acute disorder. J Psychiatry Neurosci. 2017;42:343–52. source

In the paper

“Thus, blunted dlPFC activation has been accompanied by exaggerated amygdalar activation when (1) viewing and reappraising negative pictures [167], (2) processing subliminal negative stimuli [168, 169] (Fig. 4d) and negative words”

What the sources say

• Partly supported

  The Imaging Data section reports greater left-amygdala responses to negative pictures in depressed participants and lower activation in the left dorsal medial prefrontal cortex during viewing. It does not report blunted dorsolateral prefrontal (dlPFC) activation. Figure 2 and the Discussion indicate that the amygdala group difference was found during viewing, not reappraisal. (LLM, conf=0.88)

  cites [167] Sheline YI, Barch DM, Price JL, Rundle MM, Vaishnavi SN, Snyder AZ, et al. The default mode network and self-referential processes in depression. Proc Natl Acad Sci USA. 2009;106:1942–7. sourceExperimental — accuracy not yet measured

In the paper

“The selectivity of these findings was illustrated by the lack of such effects following activation or inactivation of area 32; interestingly, a similar blunting of anticipatory but not consummatory arousal was also seen following over-activation of neighboring area 14 within primate medial OFC/caudal vmPFC [142].”

What the sources say

• Supported

  The Results section, under “sgACC/25 Over-Activation Blunts Anticipatory, but Not Consummatory, Arousal for Reward, whereas pgACC/32 Manipulations Have No Effect,” reports that neither over-activation nor inactivation of pgACC/32 affected anticipatory or consummatory arousal. No page number is provided in our copy. (LLM, conf=0.95)

  cites [61] Alexander L, Gaskin PLR, Sawiak SJ, Fryer TD, Hong YT, Cockcroft GJ, et al. Fractionating blunted reward processing characteristic of anhedonia by over-activating primate subgenual anterior cingulate cortex. Neuron. 2019;101:307–320.e6. source

In the paper

“Greater pgACC (and amygdalar) activation in response to negative stimuli, coupled with reduced activation in bilateral inferior frontal regions, emerged also among women with subthreshold depressive symptoms [180], suggesting that such abnormalities precede the onset of MDD.”

What the sources say

• Supported

  The Discussion reports greater amygdala and rostral ACC activation and less bilateral inferior frontal gyrus recruitment in participants with subthreshold depression, each in a negative-stimulus task contrast. It also states that the study recruited only young women. The paper calls the ACC region “rostral ACC” rather than “pgACC.” (LLM, conf=0.90)

  cites [180] Li H, Wei D, Sun J, Zhang Q, Qiu J. Fronto-limbic alterations in negatively biased attention in young adults with subthreshold depression. Front Psychol. 2017;8:1354. https://doi.org/10.3389/fpsyg.2017.01354. eCollection 2017 source

In the paper

“Thus, blunted dlPFC activation has been accompanied by exaggerated amygdalar activation when (1) viewing and reappraising negative pictures [167], (2) processing subliminal negative stimuli [168, 169] (Fig. 4d) and negative words”

What the sources say

• Partly supported

  The Results (fMRI Results; page not provided) report greater amygdala responses to masked-sad faces in depressed participants than in healthy controls, supporting the subliminal-stimulus portion of the claim. They do not report blunted dlPFC activation accompanying that response; the reported frontal difference concerns unmasked faces. (LLM, conf=0.88)

  cites [168] Victor TA, Furey ML, Fromm SJ, Öhman A, Drevets WC. Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder. Arch Gen Psychiatry. 2010;67:1128–38. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction reports an abnormally increased amygdala response to masked-sad faces in unmedicated depressed participants, supporting the exaggerated-amygdala part of the claim. The fMRI Results and Discussion describe changes in the pgACC, ventrolateral prefrontal cortex and lateral frontal polar cortex, but do not report blunted dlPFC activation accompanying that amygdala response. Passage-level page numbers are unavailable in our copy. (LLM, conf=0.85)

  cites [169] Victor TA, Furey ML, Fromm SJ, Öhman A, Drevets WC. Changes in the neural correlates of implicit emotional face processing during antidepressant treatment in major depressive disorder. Int J Neuropsychopharmacol. 2013;16:2195–208. sourceExperimental — accuracy not yet measured

In the paper

“Among adolescents, blunted dlPFC to negative social status words mediated the relationship between social risk (peer victimization and fear of negative evaluation) and depressive symptoms [164].”

What the sources say

• Supported

  The Results (Mediation Analysis) report significant indirect effects of both peer victimization and fear of negative evaluation on depressive symptoms through late DLPFC activity. The paper states that reduced late DLPFC activity in response to negative social status words accounted for both relationships. (LLM, conf=0.94)

  cites [164] Lee KH, Oppenheimer CW, Siegle GJ, Ladouceur CD, Lee GE, Silk JS, et al. Prefrontal cortical response to negative social words links social risk to depressive symptoms in adolescence. J Res Adolesc. 2018;28:87–102. source

In the paper

“Findings of potentiated pgACC activation to negative cues in MDD are intriguing in light of evidence that, among healthy controls, a negativity bias correlated with pgACC activation for “sad” vs. “happy” choices in response to ambiguous faces [184].”

What the sources say

• Supported

  The Results (Imaging results, Fig. 3) report that bilateral pgACC activation during “sad” versus “happy” choices for ambiguous faces correlated with the measure of negativity bias. The Discussion identifies the participants as healthy individuals and summarizes the association as a preferential pgACC response to sad over happy choices. (LLM, conf=0.94)

  cites [184] Ito T, Yokokawa K, Yahata N, Isato A, Suhara T, Yamada M. Neural basis of negativity bias in the perception of ambiguous facial expression. Sci Rep. 2017;7:420. https://doi.org/10.1038/s41598-017-00502-3. source

In the paper

“Conversely, inactivation of area 11 only induces negative biases based on the memory of those experiences, memories dependent on the OFC's interaction with the amygdala and anterior hippocampus [38].”

What the sources say

• Supported

  The Results identify the targeted anterior OFC as area 11. The Discussion reports that its inactivation produced a bias away from the punished side the following day, not during the punished decision, and that expression of this punishment-memory bias depended on the amygdala–anterior hippocampal circuit. The indexed passages provide no page numbers. (LLM, conf=0.93)

  cites [38] Clarke HF, Horst NK, Roberts AC. Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making. PNAS. 2015;112:4176–81. source

In the paper

“In line with the hypothesis that antidepressant medications might exert their effects by normalizing negative emotional biases before changes in symptoms, eventual week 6 responders showed greater reduction in neural responses to fearful vs. happy faces after 7 days of escitalopram treatment in the pgACC, dACC and amygdala [197].”

What the sources say

• ?Could not verify

  The Methods section describes MRS scans before and after six weeks of escitalopram, and the Discussion compares baseline GABA levels in eventual responders and non-responders. Searches for fearful versus happy faces, seven-day neural responses, and the pgACC, dACC, and amygdala found no passage addressing the claimed result. Page numbers are unavailable in our copy. (LLM, conf=0.76)

  cites [197] Godlewska BR, Near J, Cowen PJ. Neurochemistry of major depression: a study using magnetic resonance spectroscopy. Psychopharmacology. 2015;232:501–7. sourceExperimental — accuracy not yet measured

In the paper

“For example, in an fMRI study comparing never-depressed dizygotic twins with vs. without cotwin with a history of MDD, high-risk twins were characterized by negative functional connectivity between BA10/BA24 and the amygdala [192].”

What the sources say

• Supported

  The Methods (p. 3) describe an fMRI comparison of dizygotic twins with and without a co-twin history of depression, and the Introduction (p. 6) identifies them as never-depressed. The Figure 3 caption (p. 35) reports negative functional connectivity between the left amygdala and both MFG (BA 10) and pgACC (BA 24) in high-risk twins. (LLM, conf=0.95)

  cites [192] Miskowiak KW, Svendsen AMB, Harmer CJ, Elliott R, Macoveanu J, Siebner HR, et al. Differences in neural and cognitive response to emotional faces in middle-aged dizygotic twins at familial risk of depression. Psychol Med. 2017;47:2345–57. source

In the paper

“Excitotoxic lesion studies of area 32 in marmosets [204], similar to lesions of PLc in rodents [205], have implicated this region in the learning, but not expression of action-outcome associations in the appetitive domain, particularly with respect to the contingent relationship between actions and their outcomes.”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports that excitotoxic lesions of marmoset area 32 caused insensitivity to contingency degradation, supporting its involvement in learning about contingencies. But it explicitly says the study cannot determine whether the deficit concerns stimulus–outcome or action–outcome contingencies. The learning-versus-expression distinction is reported there for rodent PL lesions, not established by this marmoset experiment. (LLM, conf=0.87)

  cites [204] Jackson SAW, Horst NK, Pears A, Robbins TW, Roberts AC. Role of the perigenual anterior cingulate and orbitofrontal cortex in contingency learning in the marmoset. Cereb Cortex. 2016;26:3273–84. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [205] Balleine BW, Dickinson A. Goal-directed instrumental action: contingency and incentive learning and their cortical substrates. Neuropharmacology. 1998;37:407–19. source

In the paper

“Akin to microstimulation in pgACC, microstimulation of the caudal OFC in macaques also induces a negative bias [202].”

What the sources say

• Supported

  The Results report that microstimulation at two caudal orbitofrontal cortex (cOFC) sites in monkeys increased avoidance choices relative to adjoining white-matter sites. The authors describe this as a second cortical source of negative bias in decision-making. (LLM, conf=0.93)

  cites [202] Amemori S, Amemori K, Yoshida T, Papageorgiou GK, Xu R, Shimazu H, et al. Microstimulation of primate neocortex targeting striosomes induces negative decision‐making. Eur J Neurosci. 2020;51:731–41. source

In the paper

“More recently, area 24 and projection target region in the caudate nucleus in marmosets have also been implicated in the detection/expression of changes in actionoutcome contingencies for reward [206].”

What the sources say

• ?Could not verify

  The cited paper’s passages on pp. 1–2 discuss SNAP25 mutations and neurotransmitter release, not reward-related action–outcome contingencies. Searches for area 24, the marmoset caudate nucleus, and reward contingencies found no passage in our copy addressing the claim. (LLM, conf=0.78)

  cites [206] Duan LY, Horst NK, Cranmore SAW, Horiguchi N, Cardinal RN, Roberts AC, et al. Controlling one’s world: identification of sub-regions of primate PFC underlying goal-directed behavior. Neuron. 2021;109:1–14. sourceExperimental — accuracy not yet measured

In the paper

“In a study using graph analyses, rsFC strength within a module involving several PFC regions (e.g., dorsal and medial superior frontal gyrus; OFC; middle frontal gyrus, anterior cingulum gyrus) correlated positively with self-reported helplessness in MDD [209].”

What the sources say

• Partly supported

  Results §3.5 reports a positive correlation between intra-module I connectivity and helplessness in MDD (r = 0.54, p < 0.05). However, the Introduction describes the helplessness measure as a clinician-rated HAMD interview, not a self-report. Results §3.2 also places the middle frontal gyrus in module II, rather than the correlated module I, among MDD patients. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites [209] Peng D, Shi F, Shen T, Peng Z, Zhang C, Liu X, et al. Altered brain network modules induce helplessness in major depressive disorder. J Affect Disord. 2014;168:21–29. sourceExperimental — accuracy not yet measured

In the paper

“A region bordering area 32 within the pgACC of macaques [39] has also been implicated in negative bias in decision making using a task subsequently adapted to assess negative biases in MDD [42].”

What the sources say

• Supported

  The Discussion (page unavailable) places the effective pACC zone in the rostral part of area 24 and dorsal part of area 32. It reports that microstimulation of this ventral-bank zone biased macaques toward avoidance, supporting its implication in negative decision-making. (LLM, conf=0.88)

  cites [39] Amemori K, Graybiel AM. Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making. Nat Neurosci. 2012;15:776–85. source
• Supported

  The Discussion (Cross-species function of the ACC; page unavailable) locates the macaque region in the ventral bank of the cingulate sulcus, at the posterior part of area 32 and/or anterior part of area 24, and says it encodes chosen aversiveness. The Introduction also reports that pACC microstimulation can increase avoidance in nonhuman primates, supporting its implication in negatively biased decisions. (LLM, conf=0.90)

  cites [42] Ironside M, Amemori KI, McGrath CL, Pedersen ML, Kang MS, Amemori S, et al. Approach-avoidance conflict in major depressive disorder: congruent neural findings in humans and nonhuman primates. Biol Psychiatry. 2020;87:399–408. source

In the paper

“These findings were complemented by data showing that 8 weeks of sertraline treatment normalized amygdalar hyper-activation to sad faces in MDD [194], replicating prior findings [195,196].”

What the sources say

• ?Could not verify

  The Introduction (page unavailable) discusses citalopram and amygdala–prefrontal connectivity, while the Methods describe a ketamine study in healthy subjects. Searches for sertraline and sad faces found no passage reporting eight weeks of sertraline treatment or normalized amygdala responses to sad faces in MDD. (LLM, conf=0.75)

  cites [194] Scheidegger M, Walter M, Lehmann M, Metzger C, Grimm S, Boeker H, et al. Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action. PLoS One. 2012;7:e44799. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [195] Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001;50:651–8. source
• Partly supported

  The treatment and Effects of Antidepressant Treatment sections (page not provided) support reduced amygdala activation to sad faces after eight weeks in patients with depression. But this paper treated its patients with fluoxetine, not sertraline; it describes an earlier sertraline study as using fearful faces. (LLM, conf=0.90)

  cites [196] Fu CHY, Williams SCR, Cleare AJ, Brammer MJ, Walsh ND, Kim J, et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch Gen Psychiatry. 2004;61:877–89. sourceExperimental — accuracy not yet measured

In the paper

“This effect was attributed to a likely overall enhancement of threat reactivity, consistent with increased activation in this region associated with enhanced negative reactivity in MDD [157,183].”

What the sources say

• Partly supported

  The Results (Differential effects of valence; page unavailable) report exaggerated subgenual cingulate responses to negative facial stimuli in MDD, and the Discussion (Abnormal ACC and OFC activity; page unavailable) describes hyperactivation of the ventral/subgenual ACC. The paper does not identify area 25 specifically or attribute its overactivation to an overall enhancement of threat reactivity. (LLM, conf=0.84)

  cites [157] Stuhrmann A, Suslow T, Dannlowski U. Facial emotion processing in major depression: a systematic review of neuroimaging findings. Biol Mood Anxiety Disord. 2011;1:1–10. sourceExperimental — accuracy not yet measured
• Partly supported

  Table 1 in §3.3.2 reports greater activity in subgenual cingulate area 25 in depressed patients than controls. It lists this as a main effect of group, not an effect specific to fearful stimuli, and the paper does not attribute it to enhanced threat or negative reactivity. The fear-related activation result in that section concerns the amygdala instead. (LLM, conf=0.85)

  cites [183] Fales CL, Barch DM, Rundle MM, Mintun MA, Mathews J, Snyder AZ, et al. Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression. J Affect Disord. 2009;112:206–11. sourceExperimental — accuracy not yet measured

In the paper

“Critically, increased pretreatment FC between the sgACC and amygdala predicted nonresponse to ketamine [200] and reduced dACC-pgACC FC correlated with a reduction in suicidal ideation [199].”

What the sources say

• Supported

  The Results (Imaging results) report that higher baseline right amygdala–sc/sgACC connectivity correlated with less improvement after ketamine and distinguished responders from nonresponders. The Discussion interprets baseline hyperconnectivity as potentially obstructing ketamine’s antidepressant effect in patients with treatment-resistant depression. (LLM, conf=0.92)

  cites [200] Nakamura T, Tomita M, Horikawa N, Ishibashi M, Uematsu K, Hiraki T, et al. Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment‐resistant depression. Neuropsychopharmacol Rep. 2021;npr2:12165. source

In the paper

“Inactivation of more rostral regions of the central OFC (primarily area 11) and vlPFC in marmosets also induce a negative bias in decision making [38], although likely the result of distinct underlying psychological mechanisms.”

What the sources say

• Supported

  The introductory passage identifies anterior OFC as area 11. Figure 2 (Materials and Methods) reports that inactivating either anterior OFC or vlPFC in marmosets induced a negative decision bias, though on different days; the paper also describes distinct underlying mechanisms. (LLM, conf=0.93)

  cites [38] Clarke HF, Horst NK, Roberts AC. Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making. PNAS. 2015;112:4176–81. source

In the paper

“For example, an early study reported that SSRI treatment (sertraline) reduced activation in the pgACC (BA24/32) (as well as left medial OFC and left vlPFC) in response to masked sad vs. happy faces [169].”

What the sources say

• Partly supported

  The fMRI Results report reduced masked-sad versus masked-happy (SN-HN) response in the right pgACC after sertraline treatment. They report reductions in the left medial OFC and left vlPFC for masked-sad versus masked-neutral (SN-NN) faces, not the sad-versus-happy contrast attributed to all three regions. The cited passages do not specify BA24/32 for the pgACC. (LLM, conf=0.90)

  cites [169] Victor TA, Furey ML, Fromm SJ, Öhman A, Drevets WC. Changes in the neural correlates of implicit emotional face processing during antidepressant treatment in major depressive disorder. Int J Neuropsychopharmacol. 2013;16:2195–208. sourceExperimental — accuracy not yet measured

In the paper

“similar bias reductions followed ketamine infusions directly into the mPFC (although PLc or ILc were not distinguished).”

What the sources say

• ?Could not verify

  The Materials and Methods (Experiment 1: Acute induction of negative affective state) describe intraperitoneal FG7142, and the Results (Behavioural results) report a negative judgement bias after that treatment. Searches for ketamine, mPFC, and prefrontal-cortex infusions found no passage addressing the claimed bias reductions. (LLM, conf=0.75)

  cites [45] Hales CA, Robinson ESJ, Houghton CJ. Diffusion modelling reveals the decision making processes underlying negative judgement bias in rats. PLoS One. 2016;11:e0152592. sourceExperimental — accuracy not yet measured

In the paper

“Diener et al. reported that, relative to controls, unmedicated individuals with MDD had potentiated frontal PINV during settings in which control over an aversive outcome was removed and then restored [208].”

What the sources say

• Supported

  The Results (PINV) report enhanced frontal PINV during both loss and restitution of control in depressed participants relative to healthy controls. The Methods (Participants) identify them as medication-free, and the Results (Exclusion of patients with dysthymia) say the PINV findings remained virtually the same after the seven participants with dysthymia were excluded, supporting the claim about MDD. (LLM, conf=0.90)

  cites [208] Diener C, Kuehner C, Brusniak W, Struve M, Flor H. Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression and dysthymia. Psychol Med. 2009;39:77–86. source

In the paper

“stimulation of the striosomes of the striatum to which this region projects also induces a negative bias [202]”

What the sources say

• Partly supported

  The Results report that microstimulation of pACC sites increased avoidance choices and that those sites preferentially projected to striosomes. The paper stimulated the cortex, not the striosomes directly, so it does not establish that stimulation of striosomes induces the negative bias. (LLM, conf=0.87)

  cites [202] Amemori S, Amemori K, Yoshida T, Papageorgiou GK, Xu R, Shimazu H, et al. Microstimulation of primate neocortex targeting striosomes induces negative decision‐making. Eur J Neurosci. 2020;51:731–41. sourceExperimental — accuracy not yet measured

In the paper

“Specifically, ketamine infusion reduced (1) hyperactivation in the sgACC (BA25) to positive feedback [121], (2) FC between the pgACC and dACC [199], and (3) FC between the sgACC and limbic regions (e.g., hippocampus) [121].”

What the sources say

• Partly supported

  The Discussion reports that ketamine reduced sgACC activation to positive feedback in patients with MDD (Fig. 3). However, the BA25-specific analysis in “Subdivisions within sgACC” found only a trend toward reduced hyperactivity (p = 0.062), so the claim states that more specific result more firmly than the paper does. (LLM, conf=0.85)

  cites [121] Morris LS, Costi S, Tan A, Stern ER, Charney DS, Murrough JW. Ketamine normalizes subgenual cingulate cortex hyper-activity in depression. Neuropsychopharmacology. 2020;45:975–81. sourceExperimental — accuracy not yet measured

In the paper

“reduced amPFC deactivation was associated with more rumination [248].”

What the sources say

• Supported

  The Abstract states that diminished DMN deactivation was strongest in the anterior-medial prefrontal cortex (amPFC) and was linked to increased rumination. The Results (Post hoc response style analysis) report a significant association between reduced DMN deactivation and increased rumination in the study of remitted MDD. (LLM, conf=0.93)

  cites [248] Bartova L, Meyer BM, Diers K, Rabl U, Scharinger C, Popovic A, et al. Reduced default mode network suppression during a working memory task in remitted major depression. J Psychiatr Res. 2015;64:9–18. source

In the paper

“the effects of ILc inactivation appear more restricted to social behavior [233].”

What the sources say

• Supported

  The Discussion reports that infralimbic (IL) NMDAR blockade prevented protection of social exploration after stress, whereas only prelimbic (PL) blockade affected shuttlebox escape. This supports the qualified claim that the observed effects of IL inactivation were more restricted to social behavior; the comparison concerns these two outcomes in the paper’s stressor paradigm. (LLM, conf=0.90)

  cites [233] Christianson JP, Flyer-Adams JG, Drugan RC, Amat J, Daut RA, Foilb AR, et al. Learned stressor resistance requires extracellular signal-regulated kinase in the prefrontal cortex. Front Behav Neurosci. 2014;8:348. source

In the paper

“a failure to detect changes in the contingencies between one's actions and their outcome (associated with disrupted function in both areas 32 and 24 in monkeys [206] and PLc in rodents [205,250]) could contribute not only to negative biases in approach-avoidance decision making but also despair/helplessness [232].”

What the sources say

• ?Could not verify

  The cited paper’s discussion of SNAP25 mutations and neurotransmitter release (pp. 1–2) does not address the claim’s proposed link to despair or helplessness. Searches for action–outcome contingencies, approach–avoidance decisions, and areas 32/24 or PLc found no relevant passage in our copy. (LLM, conf=0.77)

  cites [206] Duan LY, Horst NK, Cranmore SAW, Horiguchi N, Cardinal RN, Roberts AC, et al. Controlling one’s world: identification of sub-regions of primate PFC underlying goal-directed behavior. Neuron. 2021;109:1–14. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [205] Balleine BW, Dickinson A. Goal-directed instrumental action: contingency and incentive learning and their cortical substrates. Neuropharmacology. 1998;37:407–19. source
• Supported

  The cited paper’s ‘Neural Substrates of Goal-Directed Learning’ section reports that lesions of the rat prelimbic cortex prevent acquisition of goal-directed learning, as assessed by contingency degradation. This supports the part attributed to this source: disrupted PLc function in rodents is associated with reduced sensitivity to changes in action–outcome contingencies. The monkey-region and despair/helplessness claims have separate citations in the citing sentence. (LLM, conf=0.90)

  cites [250] Balleine BW, O’Doherty JP. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology. 2010;35:48–69. source
• ?Not checked — no full text of the sourcecites [232] Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365–71. source

In the paper

“MDD was associated with reduced recruitment of the dlPFC [160, 161, 170, 244-246] and dACC [160,161,246] in contexts requiring task-irrelevant negative cues to be ignored or behavioral adjustments after errors.”

What the sources say

• Partly supported

  The Results (section 3.2) report reduced ACC engagement in MDD for targets following sad distractors, and the Discussion (section 4) reports reduced activity in executive regions including the middle frontal gyrus during target detection. But the paper identifies the ACC finding as rostral, not dorsal, and does not study behavioral adjustments after errors. It also reports increased middle frontal gyrus activation in MDD for targets following sad distractors, so reduced dlPFC recruitment does not describe that specific contrast. (LLM, conf=0.88)

  cites [160] Wang L, LaBar KS, Smoski M, Rosenthal MZ, Dolcos F, Lynch TR, et al. Prefrontal mechanisms for executive control over emotional distraction are altered in major depression. Psychiatry Res. 2008;163:143–55. sourceExperimental — accuracy not yet measured
• Partly supported

  The Effects of Attended and Unattended Fear section reports reduced right DLPFC recruitment when patients ignored fearful faces and lower activation in a region extending into the lower dorsal ACC. The Posterror Analysis reports that patients failed to increase DLPFC activation after errors. It does not show impaired error-related recruitment of the dorsal ACC: the Error Analysis found that its response to errors did not differ by group. (LLM, conf=0.88)

  cites [161] Fales CL, Barch DM, Rundle MM, Mintun MA, Snyder AZ, Cohen JD, et al. Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psychiatry. 2008;63:377–84. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [170] Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61:198–209. source
• ?Not checked — no full text of the sourcecites [244] Holmes AJ, Pizzagalli DA. Response conflict and frontocingulate dysfunction in unmedicated participants with major depression. Neuropsychologia. 2008;46:2904–13. source
• ?Not checked — no full text of the sourcecites [245] Mitterschiffthaler MT, Williams SC, Walsh ND, Cleare AJ, Donaldson C, Scott J, et al. Neural basis of the emotional Stroop interference effect in major depression. Psychol Med. 2008;38:247–56. source
• ?Not checked — no full text of the sourcecites [246] Wang L, Krishnan KR, Steffens DC, Potter GG, Dolcos F, McCarthy G. Depressive state- and disease-related alterations in neural responses to affective and executive challenges in geriatric depression. Am J Psychiatry. 2008;165:863–71. source

In the paper

“studies have generally shown no or few differences between MDD and healthy groups in emotion regulation tasks that provided clear cognitive reappraisal instructions [253,254].”

What the sources say

• Supported

  The Results (§3.6; page unavailable) report no significant group-by-reappraisal interaction or group effect on brain activation. The Discussion (§4; page unavailable) says participants with MDD could reappraise negative emotions when given detailed instructions and cues. This study supports the cited sentence as an example of few differences under clear instructions, though it does not establish the broader frequency across studies. (LLM, conf=0.90)

  cites [253] Dillon DGDG, Pizzagalli DADA. Evidence of successful modulation of brain activation and subjective experience during reappraisal of negative emotion in unmedicated depression. Psychiatry Res. 2013;212:99–107. source
• Supported

  The Results (Instructed causal attributions; page unavailable) report no significant group-by-condition interaction in emotion ratings. The Discussion (Group differences; page unavailable) says patients and controls could both regulate emotions when instructed to apply causal attributions, with no group differences in brain regions linked to cognitive emotion regulation, although some other differences were observed. (LLM, conf=0.88)

  cites [254] Loeffler LAK, Radke S, Habel U, Ciric R, Satterthwaite TD, Schneider F, et al. The regulation of positive and negative emotions through instructed causal attributions in lifetime depression – a functional magnetic resonance imaging study. NeuroImage Clin. 2018;20:1233–45. source

In the paper

“neuronal silencing of IL (and not PL) blocks the actions of ketamine, 24 h later [63]”

What the sources say

• Supported

  In “Neuronal Inactivation of IL-PFC Blocks the Effects of Systemic Ketamine” (page not provided), the paper reports that silencing IL before ketamine blocked its antidepressant effect in the forced swim test 24 hours after dosing. Silencing PrL before ketamine did not block that response. (LLM, conf=0.94)

  cites [63] Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Natl Acad Sci USA. 2015;112:8106–8111. source

In the paper

“stronger pretreatment dlPFC activationcoupled with weaker dlPFC-amPFC functional connectivitypredicted depression recovery.”

What the sources say

• Supported

  The Abstract reports that strong dlPFC activation and weak dlPFC–amPFC coupling at day 0, before escitalopram treatment, predicted depression recovery. The Results section also identifies strong dlPFC activation and weaker dlPFC functional connectivity as beneficial prognostic predictors. (LLM, conf=0.94)

  cites [247] Meyer BM, Rabl U, Huemer J, Bartova L, Kalcher K, Provenzano J, et al. Prefrontal networks dynamically related to recovery from major depressive disorder: a longitudinal pharmacological fMRI study. Transl Psychiatry. 2019;9:64. https://doi.org/10.1038/s41398-019-0395-8 source

In the paper

“only neurons in the PLc (but not ILc) projecting to the dorsal raphe nucleus show selective activation to escapable stress [234]”

What the sources say

• Supported

  In Results, Experiment 1 (page unavailable), escapable stress increased activation of dorsal raphe nucleus-projecting prelimbic (PL) neurons relative to inescapable stress. Dorsal raphe nucleus-projecting infralimbic (IL) neurons were activated by both stress conditions, with no effect of controllability. This supports the cited PL-versus-IL distinction. (LLM, conf=0.94)

  cites [234] Baratta MV, Zarza CM, Gomez DM, Campeau S, Watkins LR, Maier SF. Selective activation of dorsal raphe nucleus-projecting neurons in the ventral medial prefrontal cortex by controllable stress. Eur J Neurosci. 2009;30:1111–6. source

In the paper

“continuous inactivation of OFC for two weeks using muscimol [231] increased active coping.”

What the sources say

• Supported

  The Methods (Chronic Muscimol Infusion into the OFC; page unavailable) describe continuous muscimol infusion to inhibit OFC activity for approximately two weeks. The Results (Forced Swim Test; page unavailable) report less immobility and more climbing in muscimol-treated rats than in controls, supporting increased active coping in that test. (LLM, conf=0.88)

  cites [231] Kuniishi H, Ichisaka S, Matsuda S, Futora E, Harada R, Hata Y. Chronic inactivation of the orbitofrontal cortex increases anxiety-like behavior and impulsive aggression, but decreases depression-like behavior in rats. Front Behav Neurosci. 2017;10:250. source

In the paper

“Different again may be the contribution of regions within central OFC, with their links to the updating of predictive stimuli which may be involved in the mechanisms by which predictive stimuli can influence goal-directed actions, known as Pavlovian-to-Instrumental transfer [206,235].”

What the sources say

• ?Could not verify

  The cited paper’s discussion of SNAP25 mutations and synaptic transmission (Molecule-to-Circuit Disease Mechanisms of a Synaptic SNAREopathy, pp. 1–2) does not address central OFC, predictive-stimulus updating, or Pavlovian-to-instrumental transfer. Searches for those terms and for goal-directed actions found no relevant passage in our copy. (LLM, conf=0.78)

  cites [206] Duan LY, Horst NK, Cranmore SAW, Horiguchi N, Cardinal RN, Roberts AC, et al. Controlling one’s world: identification of sub-regions of primate PFC underlying goal-directed behavior. Neuron. 2021;109:1–14. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report that post-training OFC lesions abolished outcome-selective Pavlovian-to-instrumental transfer and impaired adjustment to a change in a stimulus’s predictive relationship. The Histological verification section locates the lesions primarily in lateral and ventrolateral orbital regions, not specifically in central OFC; that anatomical attribution is not established by this paper. (LLM, conf=0.83)

  cites [235] Ostlund SB, Balleine BW. Orbitofrontal cortex mediates outcome encoding in pavlovian but not instrumental conditioning. J Neurosci. 2007;27:4819–25. sourceExperimental — accuracy not yet measured