Conditioned respiratory threat in the subdivisions of the human periaqueductal gray
- University of Oxford, United Kingdom
Figures
Figure 1
Targeted PAG columnar analysis.
Left: Schematic representation of the columns of the midbrain periaqueductal gray (PAG), which almost surrounds the aqueduct. Middle: Ventrolateral PAG (vlPAG) activation during anticipation of resistance contrasted with anticipation of no resistance. Right: Lateral PAG (lPAG) deactivation during inspiratory resistance. Statistics are small-volume-corrected for multiple comparisons using highlighted PAG column masks, adapted from Ezra et al. (2015), and the images consist of a colour-rendered statistical map superimposed on a standard (MNI 1 mm3) brain. Line drawing originally published in Ezra et al., 2015.
Figure 2
Periaqueductal gray (PAG) analysis.
Left: 3D representation of the PAG activations on the right. Top row sagittal view, bottom row axial view of activation in the vlPAG during anticipation of certain resistance (against baseline: p=0.021) and deactivation during inspiratory resistance in bilateral lPAG (p=0.007). The key on the right shows location of PAG mask and orientation of displayed slices. Statistics are small-volume-corrected for multiple comparisons using highlighted PAG mask, and the images consist of a colour-rendered statistical map superimposed on a standard (MNI 1 mm3) brain.
Figure 3
Scaled BOLD activity during 100% certain anticipation with intensity and anxiety.
Right: Positive correlation in the lPAG with intensity ratings (green uncorrected Z score, red/yellow TFCE-corrected for lPAG activity, PAG displayed in light grey) but not anxiety. Top: Cortical correlations with average intensity score. Bottom: Cortical correlations with anxiety score for certain anticipation. Images consist of a colour-rendered statistical map superimposed on a standard (MNI 1 mm3) brain.
Figure 4
vlPAG activation with 100% certainty of resistance.
vlPAG activations during uncertain (A) and certain (B) anticipation of impending breathlessness. Uncertain anticipation produces subthreshold vlPAG activation in a consistent area to the certain condition. PAG mask displayed by light grey region. Images consist of a colour-rendered statistical map superimposed on a standard (MNI 1 mm3) brain. Orientations marked on the image.
Figure 5
Cortical activity with functional tasks.
Mean cortical activations and deactivations identified during inspiratory resistance, 100% certain anticipation, 50% uncertain anticipation and finger opposition. The images consist of a colour-rendered statistical map superimposed on a standard (MNI 1 mm3) brain. The bright grey region represents the coverage of the coronal-oblique functional scan. Significant regions are displayed with a threshold Z>2.3, with a cluster probability threshold of p<0.05 (corrected for multiple comparisons). Abbreviations: VPL, ventral posterior lateral nucleus (thalamus); M1, primary motor cortex; S1, primary sensory cortex; CN, caudate nucleus; Put, putamen; Hipp, hippocampus; STN, subthalamic nucleus; PCC, posterior cingulate cortex; MCC, middle cingulate cortex; p-In, posterior insular; m-In, middle insular; OP, operculum; SMC, supplementary motor cortex; PCG, paracingulate gyrus; PN, posterior nuclei of the thalamus; PAG, periaqueductal gray; M, solitary nucleus of the medulla; Cu, cuneate nucleus (medulla); I-IV, I-IV cerebellar lobe; IX, IX cerebellar lobe. Source files providing peak voxel locations are provided (Figure 5—source data 1–3).
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Figure 5—source data 1
Co-ordinates of local maxima of significant increases (activations) and decreases (deactivations) in the BOLD response to inspiratory loading.
Values derived from cluster-based analysis. The most significant maximum is listed for each anatomical location. Co-ordinates are in mm in standard space of MNI (1 mm3). x, distance right (+) or left (-) of the mid saggital line; y, distance anterior (+) or posterior (-) from a vertical plane through the anterior commissure; z, distance above (+) or below (-) the intercommisurial plane. Abbreviations: VPL, ventroposterolateral nucleus of the thalamus.
- https://doi.org/10.7554/eLife.12047.010
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Figure 5—source data 2
Co-ordinates of local maxima of significant increases (activations) and decreases (deactivations) in the BOLD response during certain and uncertain anticipation of inspiratory loading.
Values derived from cluster-based analysis. The most significant maximum is listed for each anatomical location. Co-ordinates are in mm in standard space of MNI (1 mm3). x, distance right (+) or left (-) of the mid saggital line; y, distance anterior (+) or posterior (-) from a vertical plane through the anterior commissure; z, distance above (+) or below(-) the intercommisurial plane.
- https://doi.org/10.7554/eLife.12047.011
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Figure 5—source data 3
Co-ordinates of local maxima of significant increases (activations) and decreases (deactivations) in the BOLD response to a finger opposition task.
Values derived from cluster-based analysis. The most significant maximum is listed for each anatomical location. Co-ordinates are in mm in standard space of MNI (1 mm3). x, distance right (+) or left (-) of the mid saggital line; y, distance anterior (+) or posterior (-) from a vertical plane through the anterior commissure; z, distance above (+) or below (-) the intercommisurial plane. Abbreviations: VPL, ventroposterolateral nucleus of the thalamus.
- https://doi.org/10.7554/eLife.12047.012
Figure 6
Regression of end tidal carbon dioxide effects.
Global BOLD signal change correlating with changes in end tidal carbon dioxide (PETCO2). The image on the right is a zoom to show signal changes within the PAG (outlined in black). Small hypercapnic challenges were administered during rest periods to dissociate hypercapnic effects from respiratory stimuli, and a carbon dioxide (CO2) trace was created by extrapolating between end-tidal CO2 peaks. The images consist of a colour-rendered statistical map superimposed on a standard (MNI 1 mm3) brain. Significant regions are displayed with a threshold Z>2.3, with a cluster probability threshold of p<0.05 (corrected for multiple comparisons).
Figure 7
Finger opposition functional localiser.
Demonstration of the use of finger opposition as a functional localiser in brainstem FMRI in the current study compared to previous results, displaying hypothesised activation in the ipsilateral cuneate nucleus of the medulla (z -54). The 7 T 1 mm3 voxel data is derived from previously-published results (Faull et al., 2015) (14 repeats of 15 sec finger opposition, 1 mm3 voxels and TR=5 s), while the 1.5 mm3 voxel data is from the current study (10 repeats of 15 sec finger opposition, 1.5 mm3 voxels and TR=3.11 s). This technique provides confidence in the analysis model and registration accuracy of the current 7 T study. The images consist of a colour-rendered statistical map superimposed on a standard (MNI 1 mm3) brain. Significant regions are displayed with a threshold Z>2.3, with a cluster probability threshold of p<0.05 (corrected for multiple comparisons). The sagittal image on the right displays the position of slices, for clarity only displayed from the 7 T 1 mm3 acquisition. Abbreviations: R, raphe nuclei; ret, nuclei reticularis; VII, facial nucleus; Amb, nucleus ambiguous; IX, glossopharyngeal nucleus; NTS, nucleus tractus solitaries; GC, gracile (medial) and cuneate (lateral) nuclei (in blue). R (right) and L (left) indicate image orientation. Original line drawings adapted from Duvernoy, 1995.
Figure 8
Breathing system.
Schematic diagram of breathing system that allows remote administrations of inspiratory resistance. Medical air is supplied to the subject, with a reservoir of 2 L. Excess flow and expiration escapes through the one-way expiratory valve, close to the mouth to minimise rebreathing (inspiratory and expiratory valves: Hans Rudolf, Kansas City, MO, USA). Resistive loading is induced by discontinuing the delivery of medical air, forcing the subject to draw air through the resistor (porous glass disc). A diving mouthpiece (Scubapro UK Ltd, Mitcham, UK) connects to a bacterial and viral filter (GVS, Lancashire, UK), sampling lines (Vygon SA, Ecouen, France), connect to a pressure transducer (MP 45, ± 50 cmH2O, Validyne Corp., Northridge, CA, USA) and amplifier (Pressure transducer indicator, PK Morgan Ltd, Kent, UK) for inspiratory pressure readings, and to a gas analyser (Gas Analyser; ADInstruments Ltd, Oxford, United Kingdom) for respiratory gases. A mildly hyperoxic state was achieved through a constant administration of oxygen at a rate of 0.5 L/min. Periodically throughout scanning carbon dioxide challenges were administered to raise PETCO2 to match the PETCO2 rise during inspiratory loading periods.
Figure 9
Experimental protocol.
Study overview (top) and example four minutes of the experimental protocol (bottom), repeated throughout the conditioning and fMRI scanning sessions. Anticipation periods were 5–15 s duration, and resistance periods 15–25 s, and there were 10 repeats of each stimulus.
Tables
Table 1
Mean ( ± SD) anxiety and intensity ratings to the conditioned respiratory tasks.
| No impending resistance | Uncertain impending resistance | Certain impending resistance | |
|---|---|---|---|
| Anxiety (%) | 4.3 (5.1) | 36.7 (22.3)* | 48 (26.7)** |
| Intensity (%) | 4.7 (3.1) | 55.5 (20.9)* | 62.9 (21.5)** |
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*Significantly (p<0.05) different from ‘no impending resistance’ condition;
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**Significantly (p<0.05) different from ‘no impending resistance’ and ‘uncertain impending resistance’.
Table 2
Mean ( ± SD) physiological variables across conditioned respiratory tasks.
| Anticipation | Resistance | ||||
|---|---|---|---|---|---|
| No impending resistance | Uncertain impending resistance | Certain impending resistance | Average | Peak | |
| Pressure (cmH2O) | -0.14 (0.11) | -0.17 (0.12) | -0.18 (0.24) | -5.80 (3.64)* | -14.67 (8.28)* |
| PETCO2 (%) | 4.41 (0.71) | 4.41 (0.67) | 4.32 (0.68)* | 4.46 (0.67) | 4.62 (0.66)* |
| PETO2 (%) | 18.1 (1.0) | 18.1 (1.0) | 18.3 (1.1)* | 18.5 (1.0)* | 18.9 (1.0)* |
| Respiratory rate (min-1) | 12.8 (3.7) | 12.5 (3.8) | 12.4 (3.6) | 11.2 (4.6) | 13.8 (5.9) |
| RVT increase (%) | -4.4 (7.4) | 7.8 (19.6)* | 11.0 (23.0)* | -16.1 (21.6)* | 16.6 (28.5)* |
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*Significantly (p<0.05) different from ‘no impending resistance’ condition.
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Abbreviations: Pressure, average mouth pressure across all ventilatory cycles; PETCO2, pressure of end-tidal carbon dioxide; PETO2, pressure of end-tidal oxygen; RVT, respiratory volume per unit time.
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Conditioned respiratory threat in the subdivisions of the human periaqueductal gray
eLife 5:e12047.
https://doi.org/10.7554/eLife.12047
