1. Neuroscience

Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours

  1. Flavia Venetucci Gouveia  Is a corresponding author
  2. Jurgen Germann
  3. Gavin JB Elias
  4. Alexandre Boutet
  5. Aaron Loh
  6. Adriana Lucia Lopez Rios
  7. Cristina Torres Diaz
  8. William Omar Contreras Lopez
  9. Raquel Chacon Ruiz Martinez
  10. Erich Talamoni Fonoff
  11. Juan Carlos Benedetti-Isaac
  12. Peter Giacobbe
  13. Pablo M Arango Pava
  14. Han Yan
  15. George M Ibrahim
  16. Nir Lipsman
  17. Andres Lozano
  18. Clement Hamani  Is a corresponding author
  1. Neuroscience and Mental Health, Hospital for Sick Children Research Institute, Canada
  2. Sunnybrook Research Institute, Canada
  3. Division of Neuroscience, Sírio-Libanês Hospital, Brazil
  4. Division of Neurosurgery, Department of Surgery, University Health Network, Canada
  5. Division of Neurosurgery, Department of Surgery, University of Toronto, Canada
  6. Joint Department of Medical Imaging, University of Toronto, Canada
  7. Department of Functional and Stereotactic Neurosurgery, University Hospital San Vicente Fundación, Brazil
  8. Department of Functional and Stereotactic Neurosurgery, San Vicente Fundación, Colombia
  9. Department of Neurosurgery, University Hospital La Princesa, Spain
  10. Nemod Research Group, Universidad Autónoma de Bucaramanga, Colombia
  11. Division of Functional Neurosurgery, Department of Neurosurgery, FOSCAL Clinic, Colombia
  12. LIM 23, Institute of Psychiatry, School of Medicine, University of São Paulo, Brazil
  13. Department of Neurology, Integrated Clinic of Neuroscience, School of Medicine, University of São Paulo, Brazil
  14. Stereotactic and Functional Neurosurgery Division of the International Misericordia Clinic, Canada
  15. Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Canada
  16. Department of Psychiatry, University of Toronto, Canada
  17. Servicio de Neuocirugia Funcional y Esterotaxia, Clinica Comuneros Bucaramanga, Clinica Desa y Clinica Dime Neurocardiovascular de Cali; Clinica Nueva del Lago, Colombia
  18. Division of Neurosurgery, The Hospital for Sick Children, Canada
  19. Institute of Biomedical Engineering, University of Toronto, Canada
  20. Institute of Medical Science, University of Toronto, Canada
https://doi.org/10.7554/eLife.84566
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Cite this article
  1. Flavia Venetucci Gouveia
  2. Jurgen Germann
  3. Gavin JB Elias
  4. Alexandre Boutet
  5. Aaron Loh
  6. Adriana Lucia Lopez Rios
  7. Cristina Torres Diaz
  8. William Omar Contreras Lopez
  9. Raquel Chacon Ruiz Martinez
  10. Erich Talamoni Fonoff
  11. Juan Carlos Benedetti-Isaac
  12. Peter Giacobbe
  13. Pablo M Arango Pava
  14. Han Yan
  15. George M Ibrahim
  16. Nir Lipsman
  17. Andres Lozano
  18. Clement Hamani
(2023)
Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours
eLife 12:e84566.
https://doi.org/10.7554/eLife.84566
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  3. Download .RIS
7 figures, 2 tables and 2 additional files

Figures

Figure 1 with 1 supplement
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Illustration of the methodologies applied in this study.

Preoperative MRI scans were co-registered with the postoperative MRI/CT scan, followed by normalization to standard MNI152 space (https://www.bic.mni.mcgill.ca/ServicesAtlases/ICBM152NLin2009). …

Figure 1—figure supplement 1
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Method of generating functional connectivity maps.

This process involves the localization of the electrodes in each patient’s brain and the estimation of the volume of activated tissue (VAT) based on the stimulation parameters associated with …

Figure 2
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Patient demographics and treatment outcome.

(A) Patients were divided in three main groups according to age: pediatric population (≤17years, 11 out of 33), young adults (18–30years, 14 out of 33) and older adults (31–52years, 8 out of 33). (B)…

Figure 3 with 2 supplements
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Probabilistic Sweet-spot Mapping.

(A) The area of stimulation associated with greater symptomatic improvement (red) was located in the more posterior-inferior-lateral region of the posterior hypothalamic area (from left to right: …

Figure 3—figure supplement 1
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Localization of the probabilistic sweet spot mapping associated with at least 50% improvement in symptoms, in the posterior-inferior-lateral region of the posterior hypothalamic area, and in relation to the red nucleus and the subthalamic nucleus.

Note that a small portion of the map overlaps with the most superior part of the red nucleus, and no overlap with the subthalamic nucleus is observed. The labels for the Subthalamic nucleus and red …

Figure 3—figure supplement 2
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Comparison between two probabilistic sweet-spot maps performed considering amplitude (top panel, original analysis) and amplitude plus pulse width (bottom panel, additional analysis).

Note the striking similarity between maps, with the location and values of the peak corresponding to the most efficacious area for maximal symptom alleviation remaining unaltered, and only a few …

Figure 4 with 1 supplement
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Structural connectivity mapping.

(A) Magnetic resonance imaging (MRI) in the sagittal plane showing the fiber density of streamlines connected to the volumes of activated tissue (VATs) associated with significantly greater …

Figure 4—figure supplement 1
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Structural connectivity mapping.

Magnetic Resonance Imaging (MRI) in the sagittal (A), coronal (B) and axial (C) planes showing the fiber density of streamlines (pink scale) connected to the volumes of activated tissue (VATs) …

Figure 5 with 1 supplement
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Functional connectivity mapping.

Magnetic resonance imaging (MRI) in the axial plane showing areas found to have a positive (warm colors) or a negative (cold colors) correlation between clinical outcome and functional connectivity. …

Figure 5—figure supplement 1
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Threshold-free cluster enhancement functional connectivity mapping.

Magnetic resonance imaging (MRI) in the axial plane (A) and coronal plane (B) showing areas found to have a positive correlation between clinical outcome and functional connectivity (warm colors) or …

Figure 6
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Estimation of clinical outcome.

(A) Location of the peak extracted for each area found to have significant functional connectivity with the volume of activated tissue Illustrated in the coronal plane in MNI152 standard-space (http:…

Figure 7
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Imaging transcriptomics-gene set analysis.

The gene set analysis was performed using the TFCE-corrected distribution of clinically relevant functionally connected areas (qFDR<0.0001) along with whole brain three-dimensional expression …

Tables

Table 1
Demographics.
CaseSexAge rangeImprovement (%)LateralityDBS SystemStimulation Settings
RightLeft
1M31–52100BilateralMedtronic 33871.8V; 180Hz; 60msec1.8V; 180Hz; 60msec
2M≤1797BilateralMedtronic 33872.2V; 200Hz; 90msec2.2V; 200Hz; 90msec
3M≤1798bilateralMedtronic 33872.5V; 180Hz; 90msec2.5V; 180Hz; 90msec
4M≤1789BilateralMedtronic 33875.0V; 210Hz; 90msec5.0V; 210Hz; 90msec
5F≤1793BilateralMedtronic 33872.0V; 200Hz; 90msec2.0V; 200Hz; 90msec
6F≤1785BilateralMedtronic 33874.0V; 180Hz; 90msec4.0V; 180Hz; 90msec
7F≤17100BilateralMedtronic 33873.5V; 180Hz; 90msec3.5V; 180Hz; 90msec
8F31–52100BilateralMedtronic 33875.0V; 200Hz; 100msec5.0V; 200Hz; 100msec
9F18–30100BilateralMedtronic 33872.3V; 200Hz; 120msec2.3V; 200Hz; 120msec
10M≤1785BilateralMedtronic 33872.0V; 130Hz; 60msec2.0V; 130Hz; 130msec
11M18–30100BilateralMedtronic 33873.0V; 180Hz; 90msec3.0V; 180Hz; 90msec
12M≤1789BilateralMedtronic 33875.5V; 185Hz; 130msec5.5V; 185Hz; 130msec
13F18–3047BilateralMedtronic 33877.0V; 250Hz; 120msec7.0V; 250Hz; 120msec
14M18–30100BilateralMedtronic 33875.0V; 210Hz; 130msec5.0V; 210Hz; 130msec
15F18–3090BilateralMedtronic 33873.5V; 180Hz; 90msec3.5V; 180Hz; 90msec
16M18–30100BilateralMedtronic 33875.0V; 200Hz; 100msec5.0V; 200Hz; 100msec
17F≤17100BilateralMedtronic 33873.5V; 180Hz; 90msec3.5V; 180Hz; 90msec
18M≤1797BilateralMedtronic 33874.5V; 180Hz; 90msec4.5V; 180Hz; 90msec
19M31–5288BilateralMedtronic 33893.0V; 180Hz; 90msec3.0V; 180Hz; 90msec
20M≤1791BilateralMedtronic 33893.2V; 180Hz; 90msec3.2V; 180Hz; 90msec
21F18–3018BilateralMedtronic 33893.8V; 180Hz; 90msec3.8V; 180Hz; 90msec
22M31–5289BilateralMedtronic 33893.5V; 180Hz; 90msec3.5V; 180Hz; 90msec
23M31–522BilateralMedtronic 33894.5V; 150Hz; 247msec4.5V; 150Hz; 247msec
24M18–3057UnilateralMedtronic 33890.3V; 150Hz; 450msecNot applicable
25M31–522UnilateralMedtronic 33890.9V; 150Hz; 450msecNot applicable
26F31–5265BilateralMedtronic 33890.1V; 60Hz; 180msec0.1V; 60Hz; 300msec
27M18–3059BilateralMedtronic 33890.7V; 150Hz; 330msec0.5V; 150Hz; 450msec
28F31–5248UnilateralMedtronic 33890.1V; 150Hz; 450msecNot applicable
29M18–30100BilateralMedtronic 33872.0V; 180Hz; 120msec2.0V; 180Hz; 120msec
30M18–3050BilateralBoston, Vercise1.0mA; 185Hz; 90msec1.0mA; 185Hz; 90msec
31F18–3050BilateralBoston, Vercise1.2mA; 113Hz; 120msec1.2mA; 113Hz; 120msec
32M18–3036BilateralBoston, Vercise1.0mA; 170Hz; 70msec1.0mA; 170Hz; 70msec
33M18–3058BilateralBoston, Vercise3mA; 185Hz; 60msec3mA; 185Hz; 60msec
To preserve patients' anonymization, the diagnoses observed in this group are presented as the following list, from more to less frequent. Epilepsy, autism spectrum disorder, tuberous sclerosis, congenital rubella, intermittent explosive disorder, agenesia of the corpus callosum, schizophrenia, obsessive-compulsive disorder, West syndrome, Landau-Kleffner syndrome, Cri-du-chat syndrome, Lennox-Gastaut syndrome, Sotos syndrome, meningoencephalitis, perinatal hypoxia, periventricular leucomalacia, microcephaly, arteriovenous malformation.
Table 2
Estimation of clinical outcome based on functional connectivity map and patient age.
Functionally connected brain areaPeak coordinateRR2p-value
Periaqueductal Grey Matterx=-1 y=-30 z=-100.7250.5251.86e-06
Vermisx=1 y=-49 z=-120.7020.4935.21e-06
Medial Raphe nucleusx=0 y=-25 z=-150.6890.4759.11e-06
Right Subst. Nigra, Subthalamic n., Zona Incertax=16 y=-14 z=-70.6810.4641.28e-05
Left Subst. Nigra, Subthalamic n., Zona Incertax=-14 y=-16 z=-70.6730.4531.77e-05
Left Claustrumx=-30 y=14 z=-20.6720.4511.88e-05
Left Amygdalax=-25 y=-8 z=-270.6720.4511.88e-05
Right Fusiform Gyrusx=37 y=-10 z=-340.6680.4472.14e-05
Left Putamenx=-33 y=-4 z=20.6560.4303.41e-05
Left Dorsal Anterior Cingulate Cortexx=-2 y=25 z=220.6540.4283.65e-05
Right Superior Parietal Lobulex=23 y=-62 z=630.6520.4253.95e-05
Left Transition Orbitofrontal Cortex- Insulax=-24 y=11 z=-180.6450.4165.06e-05
Right Nucleus Accumbensx=11 y=8 z=-70.6450.4165.07e-05
Right Amygdalax=-22 y=-6 z=-260.6450.4165.14e-05
Left Anterior Insulax=-39 y=18 z=-10.6420.4135.59e-05
Right Rostral Anterior Cingulate Cortexx=9 y=40 z=-50.6380.4076.57e-05
Right Bed Nucleus Of The Stria Terminallisx=7 y=8 z=-50.6380.4076.57e-05
Left Bed Nucleus Of The Stria Terminallisx=-6 y=8 z=-50.6380.4076.57e-05
Left Nucleus Acuumbensx=-11 y=8 z=-70.6380.4076.57e-05
Right Transition Orbitofrontal Cortex- Insulax=25 y=10 z=-150.6380.4076.57e-05
Right Hypothalamusx=5 y=-3 z=-110.6310.3988.25e-05
Left Fusiform Gyrusx=-34 y=-12 z=-330.6290.3968.72e-05
Left Hypothalamusx=-4 y=-3 z=-110.6210.3861.13e-04

Additional files

Supplementary file 1

Matrix of the correlations between estimated symptom improvement (i.e. linear model of age and functional connectivity of the two areas) and the measured improvement.

https://cdn.elifesciences.org/articles/84566/elife-84566-supp1-v2.pdf
MDAR checklist
https://cdn.elifesciences.org/articles/84566/elife-84566-mdarchecklist1-v2.pdf

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