Table 2 Habenula measures in clinical cases of depression.
Author | Region | Sex | Analysis of Sex as a biological variable | Age | Sample | Medication use | Methods | Findings |
|---|---|---|---|---|---|---|---|---|
Connectivity | ||||||||
Amiri et al. [94] | Lateral Hb | M/F | Yes | 35.7 ± 9.1 (TRD), 31.7 ± 6.1 (CON) | Treatment resistant depression (TRD) (n = 31, M = 10, F = 21) or CON (n = 29, M = 11, F = 18) | nil at time of study | fMRI (resting-state, 3T scanner) | ↑ Left LHb node degree (MDD male and female vs CON male and female) ≈ Right LHb node degree (MDD male and female vs CON male and female) ↑ Left node degree (MDD female vs MDD male) |
Amiri et al. [95] | Lateral Hb | M/F | Yes | 34.6 ± 8.8 (TRD) 31.4 ± 6.3 (CON) | TRD (n = 33, M = 12, F = 21) or CON (n = 29, M = 13, F = 16) | nil at time of study | fMRI (resting-state, 3T scanner) followed by dynamic casual modelling analysis | ↑ Excitatory effective connectivity between left subcallosal cingulate gyrus and left Hb and in TRD compared to CON. ↑ Inhibitory effective connectivity between the right Hb and right NAc and right ventral caudate in TRD compared to CON ↑ Excitatory effective connectivity between the right ventral caudate and the right Hb in TRD compared to CON ↑ Excitatory effective connectivity between left LHb and left NAc (female TRD compared to female CON) ↑ Inhibitory effective connectivity between left LHb and left mPFC (female TRD compared to female CON) ↑ Inhibitory effective connectivity between right LHb and right NAc (male TRD compared to male CON) |
Barreiros et al. [93] | Whole Hb | M/F | No | 42.3 ± 14.1 (TRD), 37.2 ± 11.0 (TSD), 47.1 ± 14.3 (CON) | TRD (n = 35, M = 14, F = 21) or treatment sensitive MDD (TSD) (n = 35, M = 17, F = 18) or CON (n = 38, M = 17, F = 21) | Unknown | fMRI (resting-state, 3T scanner) | ↑ Functional connectivity between left Hb and left precuneus cortex (TRD vs TSD) ↑ Functional connectivity between left Hb and right precuneus cortex (TRD vs TSD and CON) ↓ Functional connectivity between left Hb and left and right precuneus cortex (TSD vs CON) |
Cho et al. [107] | Whole Hb | M/F | No | 40.71 ± 13.97 (MDD), 35.65 ± 12.19 (CON) | MDD (n = 34, M = 8, F = 26) or CON (n = 37, M = 12, F = 25) | Yes, not specified | DTI-MRI (3T scanner) | ↑ Tract fibre density from right Hb to left mediodorsal thalamus (MDD vs CON) |
Chen et al. [89] | Whole Hb | M/F | No | 67.67 ± 7.36 (suicidal ideation) 67.64 ± 7.00 (non-suicidal ideation) 66.83 ± 5.86 (CON) | Late-life depression with suicidal ideation (n = 51, M = 7, F = 44) or no suicidal ideation (n = 76, M = 19, F = 57) or CON (n = 75, M = 24, F = 51) | Unknown | fMRI (resting-state, 3T scanner) | ↑ dynamic functional connectivity between right Hb and left orbito-frontal cortex in late-life depression without suicidal ideation compared to CON ↑ dynamic functional connectivity between right Hb and left orbito-frontal cortex in late-life depression with suicidal ideation compared to late life depression without suicidal ideation and CON |
Roiser et al. [117] | Whole Hb | M/F | No | 32.4 ± 9.8 (MDD), 30.5 ± 7.3 (CON) | remitted MDD (n = 23, M = 6, F = 17), CON (n = 20, M = 7, F = 13) | nil at time of study | fMRI (emotional processing task, 3T scanner) | ↑ Left Hb blood-flow in remitted MDD compared to CON following tryptophan depletion during emotional processing task |
Furman and Gotlib [97] | Whole Hb | ns | No | 31.1 ± 6.9 (MDD) 27.3 ± 7.0 (CON) | MDD (n = 15), CON (n = 13) | Adderall (n = 1), Lorazepam (n = 1), Bupropion (n = 1), Venlafaxine (n = 1), Unknown ADD (n = 1) | fMRI (reward learning task, 3T scanner) | ↑ Right Hb activation following negative outcome (CON and MDD) Left habenula activation following negative outcome (CON) ≈ Left habenula activation following negative outcome (MDD) |
Jung et al. [92] | Whole Hb | M/F | No | 38.3 ± 12.5 (MDD), 37.1 ± 13.0 (CON) | MDD (n = 46, F = 35, M = 11) or CON (n = 38, F = 26, M = 12) | SSRI (n = 23), SNRI (n = 6), vortioxetine (n = 3), mirtazapine (n = 3), agomelatine (n = 3), bupropion (n = 2) | fMRI (resting-state, 3T scanner) | ↓ Functional connectivity between the left Hb and cerebellum (MDD)≈ Functional connectivity between right Hb and cerebellum (MDD) |
Lawson et al. [98] | Whole Hb | M/F | No | 27.76 ± 9.01 (MDD), 27.44 ± 8.75 (CON) | MDD (n = 25, M = 15, F = 10), CON (n = 25, M = 14, F = 11) | nil at time of study | fMRI (reward learning task, 3T scanner) | ↑ Hb activation following negatively conditioned stimuli (CON) ↓ Hb activation following negatively conditioned stimuli (MDD) ≈ Total Hb volume in MDD compared to CON |
Su et al. [88] | Whole Hb | M/F | No | 67.65 ± 7.00 (late-life depression), 66.83 ± 5.86 (CON) | Late-life depression (n = 127, M = 26, F = 101) or CON (n = 75, M = 24, F = 51) | Unknown | fMRI (resting-state, 3T scanner) | ↓ Functional connectivity (static) between right Hb and left and right inferior frontal gyrus (late life depression) ↓ Functional connectivity (static) between right Hb and inferior frontal gyrus was associated with severity in depressive symptoms and cognitive impairment |
Willinger et al. [99] | Whole Hb | M/F | No | 16.1 ± 1.4 (MDD), 16.2 ± 1.9 (CON) | MDD (n = 30, M = 10, F = 20) or CON (n = 33, M = 10, F = 23) | SSRI (n = 18), SNRI (n = 2), norepinephrine reuptake inhibitor (n = 2) antipsychotic ns (n = 2), methylphenidate (n = 2) | fMRI (error prediction learning task, 3T scanner) | ↓ Loss-related prediction error signalling in Hb (MDD) correlated with anhedonia scores |
Wu et al. [87] | Whole Hb | M/F | No | 36.00 ± 10.37 (MDD), 39.0 (23.0–46.5) (CON) | MDD (n = 28, M = 11, F = 17) or CON (n = 22, M = 9, F = 13) (* From initial MDD cohort (n = 28) only n = 23 completed fMRI, sex and age of this sub cohort not reported) | Unknown | fMRI (resting-state, 3T scanner) | ↓ Functional connectivity between Hb and right anterior cingulate cortex (MDD vs CON) |
Yang et al. [90] | Posterior parietal thalamus (containing Hb) | M/F | No | 21.13 ± 6.17 (MDD), 19.65 ± 1.77 (subclinical), 19.24 ± 0.94 (CON) | MDD (n = 38, M = 11, F = 27), subclinical depression (n = 26 M = 10, F = 16), CON (n = 33, M = 16, F = 17) | Unknown | fMRI (resting-state, 3T scanner) | ↑ Functional connectivity between posterior parietal thalamus and left inferior temporal gyrus (MDD vs subclinical) ↑ Functional connectivity between posterior parietal thalamus and right inferior temporal gyrus (subclinical vs CON) ↓ Functional connectivity between posterior parietal thalamus and middle frontal gyrus (MDD vs subclinical and MDD vs CON) |
Zhu et al. [96] | Whole Hb | M/F | No | 19.91 ± 1.64 (subclinical), 19.70 ± 0.85 (CON) | Subclinical depression (n = 34, M = 11, F = 23), CON (n = 40, M = 21, F = 19) | nil at time of study | fMRI (resting-state, 3T scanner) | ↓ Node degree in right Hb (Subclinical depression) |
Zhu et al. [91] | Whole Hb | M/F | No | 32.04 ± 10.01 (MDD) 28.94 ± 10.89 (CON) | MDD (n = 51, M = 22, F = 31), CON (n = 47, M = 20, F = 27) | SSRI (n = 40), antipsychotic (n = 13), other [5] | fMRI (resting- state, 3T scanner) | ↑ Functional connectivity between left Hb and right inferior temporal gyrus (MDD vs CON) ↑ Functional connectivity between left Hb and left superior frontal gyrus positively correlated with attention related cognitive deficits (MDD) ↓ Functional connectivity between left Hb and right calcarine gyrus (MDD vs CON) |
Volumetric changes | ||||||||
Carceller-Sindreu et al. [101] | Whole Hb | M/F | Yes | 44.4 ± 6.7 (first episode MDD) 47.1 ± 8.2 (remitted-recurrent MDD), 48.6 ± 8.0 (chronic MDD), 47.9 ± 8.1 (CON) | MDD first episode (n = 21, M = 7, F = 14) or MDD remitted/recurrent (n = 20, M = 2, F = 18) or MDD chronic (n = 20, M = 4, F = 16) or CON (n = 34, M = 10, F = 24) | Yes, not specified | MRI (structural, 3T scanner) | ≈ Total Hb volume (MDD vs CON), independent of sex ≈ Hb grey matter volume (MDD vs CON), independent of sex ↑ Hb white matter volume (MDD first episode female only) vs MDD treatment resistant female and CON female |
Kyruragi et al. [100] | Whole Hb | M/F | Yes | 42.9 ± 14.1 (mild depression) 45.7 ± 13.9 (moderate depression), 57.7 ± 17.0 (severe depression), 42.2 ± 12.9 (CON) | Depression (MDD and persistent depressive disorder) mild (n = 92, M = 44, F = 50) or moderate (n = 31, M = 17, F = 14) or severe (n = 29, M = 11, F = 18) or CON (n = 92, M = 34, F = 58) | Unknown | MRI (structural, 3T and 7T scanner) | ≈ Total Hb volume (depression vs CON irrespective of sex) (trend towards lower) ↓ Total Hb volume as depression severity increased (females only) |
Liu et al.[102] | Whole Hb | M/F | No | 30.7 ± 8.9 (MDD), 28.3 ± 5.2 (CON) | MDD (n = 21, M = 9, F = 12), CON (n = 17, M = 7, F = 10) | nil at time of study | fMRI (reward learning task, 3T scanner) | ↑ Total Hb volume associated with severity of anhedonic symptoms (MDD) ↑ left Hb activation following negative stimuli (CON) ≈ left Hb activation following negative stimuli (MDD) |
Ranft et al. [103] | Whole Hb | M/F | No | 48.6 ± 12.2 (MDD), 52.9 ± 7.6 (schizophrenia), 55.9 ± 8.9 (CON) | Post-mortem depression (n = 14, M = 6, F = 8) schizophrenia (n = 17, M = 8, F = 9), CON (n = 13, M = 8, F = 5) | Antidepressant, not specified (n = 14), lithium (n = 7), antipsychotic ns (n = 17) | fixed formaldehyde, Nissl stain | ↓Total Hb volume (depression) ↓ Neuronal cell number and cell area in right Hb (depression) ≈ Total Hb volume (schizophrenia) |
Savitz et al. [104] | Whole Hb | M/F | Yes | 34.4 ± 6.7 (unmedicated BD), 45.1 ± 9.1 (medicated BD), 43.9 ± 11.5 (MDD), 41.3 ± 13.3 (remitted MDD), 37.1 ± 11.9 (CON) | Unmediated BD (n = 22, M = 7, F = 15) medicated BD (n = 15, M = 5, F = 10), MDD (n = 28, M = 13, F = 15), remitted MDD (n = 32, M = 8, F = 24), CON (n = 74, M = 29, F = 45) | lithium (n = 8), divalproex (n = 6), chlorpromazine (n = 1) | MRI (structural, 3T scanner) | ↓ Total habenula volume (unmedicated BD compared to CON), independent of sex ↓ Total habenula volume (MDD female only compared to CON) |
Schmidt et al. [105] | Whole Hb | M/F | Yes | 36.20 ± 12.83 (unmedicated MDD) 40.60 ± 12.11 (medicated MDD), 36.45 ± 13.16 (CON) | MDD unmedicated, early stage (n = 20, M = 8, F = 12) or MDD medicated (n = 20, M = 7, F = 13) or CON (n = 20, M = 8, F = 12) | Yes, not specified (medicated MDD cohort only) | T7-MRI (structural) | ≈ Total Hb volume (MDD medicated vs MDD unmedicated vs CON), independent of sex Significant positive correlation between total Hb volume and disease severity in unmedicated, early stage MDD but not medicated MDD. Independent of sex. |
Molecular analyses | ||||||||
Han et al. [79] | Whole Hb | M | – | 41.5 ± 4.02 (MDD), 44 ± 3.04 (CON) | MDD died by suicide (n = 12) or CON (n = 11) | Unknown | qRT-PCR | ↓ CHT, CHRNB3 mRNA (MDD) ≈ CHAT, VACHT, CHRNA3, CHRNB4 (all trend towards reduced expression) (MDD) |
Kim et al. [106] | Whole Hb | M | – | 40.50 ± 4.35 (MDD), 44.20 ± 3.35 (CON) | MDD died by suicide (n = 10) or CON (n = 10) | Unknown | microarray and gene enrichment analyses | 251 differential expressed genes in Hb tissue of MDD vs CON: genes affected primarily endothelial cell-enriched genes encoding cell-cell junction complex and plasma membrane associated protein |
Lin et al. [82] | Lateral Hb | M/F | No | 54.27 ± 3.8 (MDD), 55.2 ± 5.1 (CON) | MDD died by suicide (n = 15, M = 10, F = 5) vs non-depressed CON (n = 15, M = 10, F = 5) | n = 8 had presence of psychotropic drugs at time of death | Small RNA sequencing analysis, qPCR | ↑ SNOR54, SNORA80E, SNORA26, SNORA69 (small RNA seq) (MDD) ↑SNORA69 and SNORA54 (qPCR validation) (MDD) ≈ SNORA80E, SNORA26 (qPCR validation) (MDD) |
