Altered visual cortex excitatory/inhibitory ratio following transient congenital visual deprivation in humans

  1. Rashi Pant  Is a corresponding author
  2. Kabilan Pitchaimuthu
  3. José P Ossandón
  4. Idris Shareef
  5. Sunitha Lingareddy
  6. Jürgen Finsterbusch
  7. Ramesh Kekunnaya
  8. Brigitte Röder
  1. Biological Psychology and Neuropsychology, University of Hamburg, Germany
  2. Department of Medicine and Optometry, Linnaeus University, Sweden
  3. Child Sight Institute, Jasti V Ramanamma Children’s Eye Care Centre, LV Prasad Eye Institute, India
  4. Department of Psychology, University of Nevada, United States
  5. LUCID Medical Diagnostics, India
  6. Institute of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Germany
29 figures, 8 tables and 2 additional files

Figures

Voxel placement for Magnetic Resonance Spectroscopy and electrode placement for Electroencephalography.

(a) Position of the frontal cortex (top) and visual cortex (bottom) voxels in a single subject. Skull-stripped figures output from SPM12. (b) Electrode montage according to the 10/20 electrode system with marked occipital electrodes preselected for analyses, and frontal electrodes used for control analyses.

Edited spectra obtained from Magnetic Resonance Spectroscopy (MRS).

(a) Average edited spectra showing GABA+ and edited Glx peaks in the visual cortices of normally sighted individuals (SC, green) and individuals with reversed congenital cataracts (CC, red) are shown. Edited MRS DIFF spectra are separately displayed for the eyes open (EO), and eyes closed (EC) conditions using dashed and solid lines respectively. The standard error of the mean is shaded. Water-normalized GABA+, water-normalized Glx, and Glx/GABA+ concentration distributions for each group and condition are depicted as violin plots on the right. The solid black lines indicate mean values, and dotted lines indicate median values. The colored lines connect values of individual participants across conditions. (b) Corresponding average edited MRS spectra and water-normalized GABA+, water-normalized Glx and Glx/GABA+ concentration distributions measured from the frontal cortex are displayed. (c) Correlations between visual cortex Glx/GABA+ concentrations in the visual cortex of CC individuals and visual acuity in logMAR units are depicted for the eyes closed (EC, left) and eyes open (EO, right) conditions. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Full spectrum and aperiodic activity of the electroencephalogram (EEG).

(a) EEG spectra across O1 and O2 with the corresponding aperiodic (1 /f) fits for normally sighted individuals (SC, blue, left) and individuals with reversed congenital cataracts (CC, red, right). Spectra of EEG recordings are displayed for the eyes closed (EC) and eyes opened (EO) conditions, as well as while viewing stimuli that changed in luminance (LU). Shaded regions represent the standard error of the mean. (b) Aperiodic intercept (top) and slope (bottom) value distributions for each group and condition are displayed as violin plots. Solid black lines indicate mean values, dotted black lines indicate median values. Colored lines connect values of individual participants across conditions.

Exploratory correlation analyses between the aperiodic intercept (1–20 Hz) and glutamate/glutamine (Glx) concentration in the visual cortex.

Correlations between water-normalized Glx concentration and aperiodic intercept are shown for the eyes closed (EC, left), eyes open (EO, middle) and visual stimulation (LU, right) conditions for sighted controls (SC, green, top) and individuals with reversed congenital cataracts (CC, red, bottom). The reported adjusted p values (p-adj) are Bonferroni corrected for multiple comparisons. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 1
Visual acuity in normally sighted individuals (SC) and congenital cataract-reversal (CC individuals).

Binocularly measured visual acuity distributions in logarithmic of minimum angle of resolution (logMAR) are displayed as violin plots. Solid black lines indicate mean values, dotted black lines indicate median values.

Appendix 1—figure 2
Edited (DIFF) spectrum metabolites quantified via Osprey.

Water-normalized and tissue corrected GABA+, water-normalized and tissue-corrected Glx, and Glx/GABA+ concentration distributions from the visual cortex are depicted as violin plots for each group and condition (left to right). The solid black lines indicate mean values, and dotted lines indicate median values. The colored lines connect values of individual participants across conditions. Results for congenitally cataract-reversal individuals (CC) and for normally sighted controls (SC) are shown in blue and red, respectively. EC = Eyes closed, EO = Eyes open.,

Appendix 1—figure 3
OFF spectrum metabolites quantified via Osprey.

Water-normalized NAA concentration distributions from the visual cortex are depicted as violin plots for each group and condition (left to right). The solid black lines indicate mean values, and dotted lines indicate median values. The colored lines connect values of individual participants across conditions. For abbreviations see Appendix 1—figure 2.

Appendix 1—figure 4
Tissue fractions for Magnetic Resonance Spectroscopy voxels.

The fractions of white matter (yellow), grey matter (grey) and cerebrospinal fluid (blue) are displayed for the eyes open (EO), and eyes closed (EC) conditions in the congenital cataract-reversal group (CC) and the normally sighted control group (SC). Tissue fractions were separately calculated for the visual (left) and frontal (right) cortex voxels.

Appendix 1—figure 5
Cr-normalized edited (DIFF) spectrum metabolites.

Creatine (Cr)-normalized GABA+, Cr-normalized Glx, and Glx/GABA+ concentration distributions from the visual cortex are depicted as violin plots for each group and condition (left to right). The solid black lines indicate mean values, and dotted lines indicate median values. The colored lines connect values of individual participants across conditions.

Appendix 1—figure 6
Phantom testing of GABA concentrations.

Plots depicting the correlation between known and measured concentrations from phantom scans of Gamma-Aminobutyric Acid (GABA; left) and the ratio of GABA to Glutamate/Glutamine (GABA/Glx, right) concentration. In the left panel, previously reported GABA concentration from the visual cortex of congenitally blind individuals (Weaver et al., 2013) is marked with a vertical dotted line.

Appendix 1—figure 7
Edited spectra of participants showing GABA+ and Glx peaks.

Individual participants’ edited spectra and the respective model fits for congenital cataract-reversal (CC, left) and normally sighted control (SC, right) individuals. Spectra are shown as output by GannetFit.m for the eyes closed and eyes open conditions for each subject.

Appendix 1—figure 8
Aperiodic fits for normally sighted control (SC, top) and congenital cataract-reversal (CC, bottom) individuals at occipital electrodes during rest with eyes closed.

Solid black lines indicate the power spectral density, red lines indicate the aperiodic (1 /f) fit in the 1–20 Hz range, excluding alpha frequencies.

Appendix 1—figure 9
Aperiodic fits for normally sighted control (SC, top) and congenital cataract-reversal (CC, bottom) individuals at occipital electrodes during rest with eyes open.

Solid black lines indicate the power spectral density, red lines indicate the aperiodic (1 /f) fit in the 1–20 Hz range, excluding alpha frequencies.

Appendix 1—figure 10
Aperiodic fits for normally sighted control (SC, top) and congenital cataract-reversal (CC, bottom) individuals at occipital electrodes during visual stimulation.

Solid black lines indicate the power spectral density, red lines indicate the aperiodic (1 /f) fit in the 1–20 Hz range, excluding alpha frequencies.

Appendix 1—figure 11
Effect of visual deprivation history on GABA+ concentration.

Correlations between visual cortex GABA+ concentration and chronological age of the congenital cataract-reversal (CC, red) and normally sighted individuals (SC, blue, see left panel). Second to fourth panels depict correlations between visual cortex GABA+ concentration and duration of visual deprivation, time since surgery and visual acuity in the CC individuals, respectively. Correlations were separately calculated for the eyes open (EO, top row) and eyes closed (EC, bottom row) conditions. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 12
Effect of visual deprivation history on Glx concentration.

Correlations between visual cortex Glx concentration and chronological age of the congenital cataract-reversal (CC, red) and normally sighted individuals (SC, blue, see left panel). Second to fourth panels depict correlations between visual cortex Glx concentration and duration of visual deprivation, time since surgery and visual acuity in the CC individuals, respectively. Correlations were separately calculated for the eyes open (EO, top row) and eyes closed (EC, bottom row) conditions. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 13
Effect of visual deprivation history on Glx/GABA concentration.

Correlations between visual cortex Glx/GABA+ concentration and chronological age of the congenital cataract-reversal (CC, red) and normally sighted individuals (SC, blue, see left panel). Second to fourth panels depict correlations between visual cortex Glx/GABA+ concentration and duration of visual deprivation, time since surgery and visual acuity in the CC individuals, respectively. Correlations were separately calculated for the eyes open (EO, top row) and eyes closed (EC, bottom row) conditions. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 14
OFF spectra obtained from Magnetic Resonance Spectroscopy (MRS).

(a) The average spectra show NAA peaks in the visual cortices of normally sighted individuals (SC, green) and individuals with reversed congenital cataracts (CC, red) are shown. Spectra are displayed for the eyes open (EO), and eyes closed (EC) conditions. The standard error of the mean is shaded. NAA concentration distributions for each group and condition are demonstrated as violin plots on the right. The solid black lines indicate mean values, and dotted lines indicate median values. The colored lines connect values of individual participants across conditions. (b) Corresponding average MRS spectra and NAA concentration distributions measured from the frontal cortex are displayed.

Appendix 1—figure 15
Aperiodic intercept (top) and slope (bottom) for congenital cataract-reversal (CC, red) and age-matched normally sighted control (SC, blue) individuals in frontal electrodes.

Distributions of these parameters are displayed as violin plots for three conditions; at rest with eyes closed (EC), at rest with eyes open (EO) and during visual stimulation (LU). Aperiodic parameters were calculated across electrodes Fp1 and Fp2. Solid black lines indicate mean values, dotted black lines indicate median values. Colored lines connect values of individual participants across conditions.

Appendix 1—figure 16
Effect of visual deprivation history on aperiodic intercept.

Correlations between aperiodic intercept at occipital electrodes and chronological age of the congenital cataract-reversal (CC, red) and normally sighted individuals (SC, blue, see left panel). Second to fourth panels depict correlations between aperiodic intercept and duration of visual deprivation, time since surgery and visual acuity in the CC individuals, respectively. Correlations were separately calculated for the aperiodic intercept while participants viewed stimuli that changed in luminance (LU, top row) and the eyes open (EO, middle row) and eyes closed (EC, bottom row) conditions. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 17
Effect of visual deprivation history on aperiodic slope.

Correlations between aperiodic slope across occipital electrodes and chronological age of the congenital cataract-reversal (CC, red) and normally sighted individuals (SC, blue, see left panel). Second to fourth panels depict correlations between aperiodic slope and duration of visual deprivation, time since surgery and visual acuity in the CC individuals, respectively. Correlations separately calculated for the aperiodic slope while participants viewed flickering stimuli (LU, top row) and the eyes open (EO, middle row) and eyes closed (EC, bottom row) conditions. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 18
Correlation between aperiodic slope and Glx/GABA+ concentration.

Correlations between the aperiodic slope and visual cortex Glx/GABA+ concentration measured at rest with eyes closed (EC) (left panels) and eyes open (EO) (middle panels), and the correlation between aperiodic slope measured while subjects viewed flickering stimuli (LU) and visual cortex Glx/GABA+ concentration measured in the EO condition (right panels), are depicted. Correlations were calculated separately for normally sighted control (SC, blue, top row) and congenital cataract-reversal (CC, red, bottom row) individuals. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 19
Correlation between aperiodic intercept and Glx/GABA+ concentration.

Correlations between the aperiodic intercept and visual cortex Glx/GABA+ concentration measured at rest with eyes closed (EC) (left panels) and eyes open (EO) (middle panels), and the correlation between aperiodic intercept measured while subjects viewed flickering stimuli (LU) and visual cortex Glx/GABA+ concentration measured in the EO condition (right panels), are depicted. Correlations were calculated separately for normally sighted control (SC, blue, top row) and congenital cataract-reversal (CC, red, bottom row) individuals. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 20
Correlation between aperiodic slope and GABA+ concentration.

Correlations between the aperiodic slope and visual cortex GABA+ concentration measured at rest with eyes closed (EC) (left panels) and eyes open (EO) (middle panels), and the correlation between aperiodic slope measured while subjects viewed flickering stimuli (LU) and visual cortex GABA+ concentration measured in the EO condition (right panels), are depicted. Correlations were calculated separately for normally sighted control (SC, blue, top row) and congenital cataract-reversal (CC, red, bottom row) individuals. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 21
Correlation between aperiodic intercept and GABA+ concentration.

Correlations between the aperiodic intercept and visual cortex GABA+ concentration measured at rest with eyes closed (EC) (left panels) and eyes open (EO) (middle panels), and the correlation between aperiodic intercept measured while subjects viewed flickering stimuli (LU) and visual cortex GABA+ concentration measured in the EO condition (right panels), are depicted. Correlations were calculated separately for normally sighted control (SC, blue, top row) and congenital cataract-reversal (CC, red, bottom row) individuals. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 22
Correlation between aperiodic slope and Glx concentration.

Correlations between the aperiodic slope and visual cortex Glx concentration measured at rest with eyes closed (EC) (left panels) and eyes open (EO) (middle panels), and the correlation between aperiodic slope measured while subjects viewed flickering stimuli (LU) and visual cortex Glx concentration measured in the EO condition (right panels), are depicted. Correlations were calculated separately for normally sighted control (SC, blue, top row) and congenital cataract-reversal (CC, red, bottom row) individuals. The 95% confidence intervals (CI) of the correlation coefficients (r) are reported.

Appendix 1—figure 23
Aperiodic offset and slope in the 1–20 Hz range from occipital electrodes in congenital cataract reversal (CC) and normally sighted control (SC) individuals of the present study (left) and additional 28 subjects of Ossandón et al., 2023.

Aperiodic intercepts (top) and slope (bottom) distributions for each group and condition are displayed as violin plots. Solid black lines indicate mean values, dotted black lines indicate median values. Colored lines connect values of individual participants across conditions.

Appendix 1—figure 24
Aperiodic-corrected alpha amplitude in congenital cataract-reversal and normally sighted individuals.

Aperiodic-corrected alpha amplitudes (8–14 Hz) distributions for each group and condition are displayed as violin plots. Solid black lines indicate mean values, dotted black lines indicate median values. Colored lines connect values of individual participants across conditions.

Author response image 1
Power spectral density of one congenital cataract-reversal (CC) participant in the visual stimulation condition across all channels.

The reduced power at 30 Hz shows the effects of the anti-aliasing filter applied by EEGLAB’s pop_resample function.

Tables

Table 1
Clinical and demographic information of the participants with a history of dense bilateral congenital cataracts (CC) as well as demographic information and visual acuity of age-matched normally sighted control participants (SC).

NA indicates that patient’s data for the field were not available. FFL: Fixating and Following Light; CF: Counting Fingers; PL: Perceiving Light. Duration of visual deprivation was calculated by subtracting the date of birth from the date of surgery on the first eye (and thus corresponds to the age at surgery). Time since surgery was calculated by subtracting the date of surgery on the first eye from the date of testing. Visual acuity on the date of testing was measured binocularly with the Freiburg Vision Test (FrACT).

GenderAgeVisual acuity on date tested (logMAR)ComorbiditiesVisual acuity pre surgeryDuration of visual deprivation (Years)Time since surgery (Years)Family history
Absorbed lensesStrabismusNystagmusODOS
CC1Male17.00.17NoYesYesFFL -FFL +0.216.8No
CC2Male43.50.9YesYesYes1.18120.822.7Yes
CC3Male18.70.9YesYesYes1.481.7715.63.1No
CC4Male15.20.62YesNAYesCF at 1.5 mCF at 3 m7.08.2No
CC5Male32.40.88NoYesYesNANA14.018.4Yes
CC6Male23.90.78NoYesYesNANA6.017.9Yes
CC7Male13.10.54NoYesYesPL+PL+0.812.4No
CC8Male18.30.66YesNoYes1.21.316.41.9Yes
CC9Male36.91.34NoNAYesNANA6.030.9Yes
CC10Female38.81.04YesYesYes1.481.4831.47.4Yes
SC1Male17.70.2
SC2Male41.9–0.27
SC3Male19.5–0.25
SC4Male16.0–0.11
SC5Male33.3–0.12
SC6Male24.0–0.16
SC7Male12.2–0.25
SC8Female25.1–0.28
SC9Female36.0–0.21
SC10Male37.3–0.22
Table 2
Quality metrics for Magnetic Resonance Spectroscopy data.

Mean quality metrics in each group are reported with the standard deviation in parentheses. The displayed quality metrics for signal-to-noise ratio, full-width half maxima and fit error are those output by Gannet 3.0: signal-to-noise-ratio (SNR), was calculated in GannetFit.m by estimating the noise in the GABA+/Glx/NAA signal across acquisitions and by dividing the absolute peak height of the GABA+/Glx/NAA signal by the estimated noise; full-width-half-maxima (FWHM), is defined as the width of the peak in Hertz (Hz); and fit error, is defined as the standard deviation of the residual of the GABA+/Glx/NAA peak fit. The fit error is expressed as a percentage of the GABA+/Glx peak height. The Cramer-Rao lower bound is reported as output by TARQUIN 4.3.11 for the NAA signal (not calculated for GABA+ or Glx as these metabolites were quantified using Gannet 3.0).

Signal-to-noise ratioCCSC
Visual cortexNAA293.16 (47.50)289.01 (50.91)
GABA+21.53 (3.66)19.08 (3.99)
Glx23.75 (3.75)22.18 (5.26)
Frontal cortexNAA108.37 (21.84)97.20 (28.08)
GABA+10.311 (2.20)8.30 (1.93)
Glx15.82 (4.85)13.58 (3.86)
Full-width-half maximaCCSC
Visual cortexNAA9.04 (0.94)8.69 (0.75)
GABA+19.84 (1.13)19.10 (0.71)
Glx16.62 (1.63)16.46 (1.63)
Frontal cortexNAA19.26 (2.33)21.42 (3.79)
GABA+21.69 (3.15)23.23 (3.41)
Glx27.54 (8.70)30.63 (12.64)
Fit errorCCSC
Visual cortexNAA0.81 (0.20)0.77 (0.15)
GABA+3.42 (0.63)3.68 (0.63)
Glx3.10 (0.58)3.18 (0.47)
Frontal cortexNAA1.33 (0.41)1.70 (0.57)
GABA+6.57 (2.20)8.31 (3.65)
Glx4.44 (1.54)5.15 (1.90)
Cramer-Rao lower boundCCSC
Visual cortexNAA0.13 (0.02)0.14 (0.03)
Frontal cortexNAA0.33 (0.22)0.26 (0.24)
Appendix 1—table 1
ANOVA results for quality metrics on Magnetic Resonance Spectroscopy data.

Quality metrics were compared for each signal (GABA+, Glx and NAA) in a group (congenital cataract-reversal, normally sighted control)-by-region (visual cortex, frontal cortex) ANOVA.

Main effect of groupMain effect of regionGroup-by-region interaction
F(1,39)ηp²pF(1,39)ηp²pF(1,39)ηp²p
Signal-to-noise ratioNAA0.380.0110.539232.000.865<0.0010.080.0020.778
GABA+3.370.0840.080127.120.779<0.0010.01<0.0010.936
Glx0.390.0110.53426.750.426<0.001<0.001<0.0010.989
Full-width half maximaNAA1.530.0410.224247.710.873<0.0012.940.0760.095
GABA+0.090.0020.76521.710.376<0.0010.560.0150.457
Glx0.200.0050.66031.560.467<0.0010.110.0030.743
Fit errorNAA1.970.0520.16838.360.515<0.0013.000.0770.092
GABA+2.780.0700.10469.140.657<0.0011.650.0430.206
Glx0.260.0070.61012.910.264<0.0010.220.0060.643
Cramer-Rao lower boundNAA0.050.0010.8219.340.2060.0040.090.0020.760
Appendix 1—table 2
Results from the Shapiro-Wilk test for normality within each group and Levene’s test for homogeneity of variance across groups, for all dependent variables in the reported analyses.

The assumption of normality or homogeneity of variance was rejected if p was smaller than 0.05.

Dependent variableShapiro-Wilk test for normalityLevene’s Test for homogeneity of variance
CC (W value)CC (p-value)SC (W value)SC (p-value)F(1,18)p-value
Aperiodic intercept (EO)0.860.0760.980.9750.480.499
Aperiodic slope (EO)0.940.5740.920.3630.710.411
Aperiodic intercept (EC)0.840.0500.960.7610.150.700
Aperiodic slope (EC)0.880.1410.930.4310.640.434
Aperiodic intercept (LU)0.940.5260.950.6500.000.993
Aperiodic slope (LU)0.960.8100.880.1210.150.700
GABA+ (EC)0.940.5150.900.2042.270.149
GABA+ (EO)0.970.9130.970.8640.600.450
Glx (EC)0.970.8810.870.1020.690.416
Glx (EO)0.950.7200.970.9063.380.083
GABA+/Glx (EC)0.960.8340.940.5012.070.172
GABA+/Glx (EO)0.920.3470.890.1731.510.235
Appendix 1—table 3
Mean percentage of rejected epochs in each condition for the congenital cataract reversal (CC) and normally sighted control (SC) groups.
GroupEyes openEyes closedVisual stimulation
CC13%3.1%0.2%
SC18.37%2%0.1%
Appendix 1—table 4
Goodness of fit (R2) values for the EEG aperiodic spectrum.

Average R2 values are reported for each group and condition.

Eyes closed (EC)Eyes open (EO)Visual stimulation (LU)
Sighted control (SC)0.960.960.91
Congenital cataract reversal (CC)0.950.980.99
Appendix 1—table 5
Regression summary for the effects of Glutamate/Glutamine (Glx) and age on aperiodic intercept (Visual Stimulation) in the congenital cataract reversal (CC) group in the visual stimulation (LU) condition.
PredictorEstimateSEtp
Model intercept–5.751.71–3.360.012
Age0.0070.0080.820.439
Glx0.810.194.360.003
Appendix 1—table 6
Regression summary for the effects of Glutamate/glutamine (Glx) concentration and age on aperiodic intercept during eye opening at rest (EO) in the congenital cataract reversal (CC) group.
PredictorEstimateSEtp
Model intercept–2.071.11–1.860.106
Age–0.0050.005–0.900.400
Glx0.400.123.350.012

Additional files

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Rashi Pant
  2. Kabilan Pitchaimuthu
  3. José P Ossandón
  4. Idris Shareef
  5. Sunitha Lingareddy
  6. Jürgen Finsterbusch
  7. Ramesh Kekunnaya
  8. Brigitte Röder
(2025)
Altered visual cortex excitatory/inhibitory ratio following transient congenital visual deprivation in humans
eLife 13:RP98143.
https://doi.org/10.7554/eLife.98143.4