Email

cnievergelt@ucsd.edu

To read the full PDF, click here

Comparing Thalamic Nuclei Volumes Between PTSD Subjects and Controls in the Psychiatry Genetics Consortium (PGC)-PTSD Dataset

A. Research Question, Goal, or Specific Aims

Provide a brief description (e.g., 1 paragraph) describing the aims of the proposal and the research questions to be addressed.

Post-traumatic stress disorder (PTSD) is an illness that has a lifetime prevalence of 6.8% among adult Americans (1). PTSD is present in 4-10 % of OEF/OIF veterans (2) and poses significant burden to society and the health system (2, 3). The neurobiology of PTSD involves (1) abnormal fear learning model, which encompasses altered fear conditioning, fear extinction and fear generalization hypotheses; (2)exaggerated threat detection model which postulates altered attention, anticipation, or “alarm” functions; and (3) a diminished emotional regulation/executive function (EF) model which postulates deficient regulatory capacity of cognitive/executive function regions over emotion generating limbic structures (4).

The thalamus is a subcortical structure situated between the cerebral cortex and midbrain, in the dorsal part of the diencephalon(5). In addition to regulating consciousness and sleep(5, 6), its primary function is to relay sensory and motor information to relevant cortical areas from other subcortical structures(6, 7). It also mediates cognition(8) and pain perception(9).

Role of thalamus in PTSD – Translating from animal studies (10, 11), the thalamus plays a role in fear conditioning in conjunction with the basolateral complex of the amygdala. This has also been shown in human fMRI studies of context based conditioning in virtual reality environments, showing involvement of left medial dorsal thalamus (12), medial thalamic nuclei (13). Its role in fear conditioning has also been shown using MEG (14) and PET imaging(15). Thalamic involvement is also present in fear generalization (16). Resting state functional connectivity studies show altered frontothalamic connectivity in PTSD subjects compared to controls (17).

A meta – analyses of fMRI studies in PTSD showed increased activation of anterior thalamus during fear conditioning, increased activation of thalamus during extinction learning and increased activation of posterior thalamus during extinction recall in trauma exposed healthy controls compared to PTSD subjects(18). Resting state functional connectivity between left thalamus and bilateral dorsal anterior cingulate was also seen to be reduced in subjects with higher early life stress (ELS) scores (19).

Previous studies have used distinct white matter cortical and subcortical connectivity to parcellate thalamic nuclei in vivo (20, 21). Using a more recent segmentation atlas based on histological data, the thalamus has been divided into 26 nuclei (22). The nuclei groups include anterior (anteroventral), lateral (laterodorsal, lateral posterior), ventral (ventral anterior, VA magnocellular, ventral lateral anterior, ventral lateral posterior, ventral posterolateral, ventromedial), intralaminar (central medial, central lateral, paracentral, centromedian, parafascicular, reuniens, mediodorsal medial magnocellular, mediodorsal lateral parvocellular), posterior (lateral geniculate, medial geniculate, suprageniculate, pulvinar anterior, pulvinar medial, pulvinar inferior). A previous study comparing thalamic volumes between PTSD subjects and controls in the PGC dataset showed reduced whole thalamic volumes in PTSD subjects compared to controls(23). However this difference was not significant(23). Hence in this analyses, we propose to compare volumes of distinct thalamic nuclei between PTSD subjects and controls from the PGC dataset.

The neurobiology of PTSD involves sensory hyperactivity and impaired threat perception(24, 25). For this reason we plan to focus on the following nuclei in our analyses: – somatosensory relay (VPL), vision (LGN, PA, PI, PM) and auditory processing (MGN)

B. Analyses Plan

Using data from the PTSD Psychiatric Genetics Consortium (PGC-PTSD) neuroimaging project, we will extract thalamic volumes from subjects across 29 different sites. We have two groups of subjects – controls (trauma exposed or healthy) and subjects with PTSD. Possible covariates for the data include age, gender, childhood trauma score, alcohol use and comorbid MDD.

Primary aims

  1. To compare volumes of thalamic nuclei between subjects with PTSD versus controls (including trauma exposed and healthy) in the PGC-PTSD dataset.
  2. To explore association between PTSD severity scores and thalamic nuclei volumes in PTSD subjects

Primary hypotheses

  1. We hypothesize that thalamic nuclei involved in somatosensory relay (VPL), vision (LGN, PA, PI, PM) and auditory processing (MGN) will show greater volume differences between PTSD subjects and controls.
  2. We also hypothesize a significant association between PTSD symptom severity on CAPS and these nuclei volumes.

Variables to be used in the analysis (the main predictor and outcome variables, and potential covariates must be identified)

Main predictor

  • Diagnosis (PTSD vs healthy controls)

Outcome variables

  • Volume of subnuclei of the thalamus (see below)
  • Total thalamic volume

Covariates

Age

Age2

PTSD x Age

Childhood Trauma (number of categories from CTQ)

PTSD x Childhood Trauma

Gender

ICV

Comorbidity (depression and alcohol use disorder)

Some of the thalamic nuclei defined by Iglesias and colleagues are very small. To minimize floor effects and segmentation failures, we recombine these subnuclei to five larger groups of thalamic subnuclei per hemisphere (see table below).

Nucleus groupNucleus (in Iglesias et al)Definition
AnteriorAnteroventralWell defined nucleus, starting rostrally. Continued by the LD. Small/medium sized neurons. We include the anterior medial and anterior dorsal nuclei into the AV.
LateralLaterodorsalMade up of small cells, pale and homogeneously distributed.
 Lateral posteriorGroup of loosely arranged small and medium neurons. It continues as the ventral lateral nucleus and its posterior part (VLP) caudally, as far as the PuA.
VentralVentral anteriorLocated at the anterior pole of the thalamus, and formed by medium size neurons crossed by bundles of fibres.
 Ventral anterior magnocellularFormed by big and dark neurons, loosely arranged.
 Ventral lateral anteriorFormed by small neurons in clusters, in the dorsolateral part of the nucleus.
 Ventral lateral posteriorMade up of large neurons, loose appearance.
 Ventral posterolateralFormed by small and medium sized neurons from the ventral part of the VLP to the PuI and PuL. The medial portion (ventral posteromedial nucleus) is included in our definition of VPL.
 VentromedialThe neurons are similar to VA neurons, but without bundles of crossing fibres. It lies ventral to VA.
Intralaminar/
medial
Central medialFormed by a compact group of dark neurons, located close to MV-Re and PV.
 Central lateralMade up of big neurons, arranged in clusters. It lies dorsal to the MD, lateral to the MDI and underneath the AV and LD.
 ParacentralLateral to MDI. Medial to VLP. Small and connected islands, loose.
 CentromedianFormed by small, condensed neurons. Fibres of the internal medullary lamina surround it.
 ParafascicularFormed by small and compact neurons. It lies ventral and medial to the CM.
 ParatenialRostro-caudally oriented group of small neurons along the stria medullaris.
 Reuniens (medial ventral)Rostrally situated, it consists of a mix of large and small neurons. Fused with the other side through the adhesion interthalamica. Anteroventral to CM and medial to VA.
 Mediodorsal medial magnocellularMade up of big and darkly stained neurons, sometimes in irregular groups at the ventral part.
 Mediodorsal lateral parvocellularSmaller neurons, which form, varied forms of groupings. Bordered by the Pc, CL and Pf ventrally.
PulvinarPulvinar anteriorGroup of neurons located ventromedially to the LP.
 Pulvinar medialFormed by small and pale neurons of uniform appearance and distribution. It lies at the posterior end of the thalamus.
 Pulvinar lateralLarge in size, it occupies most of the lateral part of the caudal thalamus. Many fibres cross it.
 Pulvinar inferiorLocated ventrally and laterally to the PuM, and formed by small and medium neurons.

Adapted from Iglesias et al. (2018)

C. Investigative Team

  1. Ziv Ben-Zion
  2. Gopalkumar Rakesh
  3. Delin Sun
  4. Emily Clarke
  5. Courtney Haswell
  6. Rajendra Morey
  7. Paul Thompson
  8. Neda Jahanshad
  9. Eugenio Iglesias
  10. Odile van den Heuvel
  11. Chris Vriend
  12. ENIGMA-PTSD Workgroup
  13. PGC-PTSD Neuroimaging Workgroup

D. Resources Needed

Describe the resources needed to achieve the aims of the analysis, including variables needed,

analysis support, and any other issues that may affect the feasibility of the plan.

We will process T1 weighted structural MRI images of all subjects using Freesurfer 7 to segment the thalamus. After this, the add-on thalamic segmentation pipeline (Iglesias et al) (22) will subsegment thalamus into (25 X2) different sub nuclei.  

E. Timeline

6 months

F. Collaboration

The following is the standard PGC policy about secondary analyses. Any deviation from this

policy needs to be described and justified, and could negatively impact the proposal.

PGC investigators who are not named on this proposal but who wish to substantively contribute to the analysis and manuscript may contact the proposing group to discuss joining the proposal.

G. Authorship

We will follow the authorship policy of the PGC-PTSD which can be found at https://pgc-ptsd.com/wp-content/uploads/2017/06/Authorship-Guidelines-PGC-PTSD.pdf

  • are you following the authorship policies of the groups involved? YES see https://pgc-ptsd.com/wp-content/uploads/2017/06/Authorship-Guidelines-PGC-PTSD.pdf
  • will there be a writing group and if so, who will be included? The writing group will be comprised of the investigative team (#1 – #5) listed above.
  • what groups or individuals will be listed as authors? Authors will include the writing group plus individual and group contributors of data and analysis from each site (generally 2-3 co-authors from each site).
  • will PGC members not listed as named authors be listed at the end of the manuscript? All individuals who meet the criteria established in the PGC-PTSD authorship policy will be co-authors. Other PGC members will not be listed at the end of the manuscript.
  • will PGC members or groups be listed as “collaborators” on the PubMed abstract page? All individuals and groups who meet the authorship criteria of the PGC-PTSD authorship policy will be listed as collaborators on the PubMed abstract page. No other individuals or groups will be listed.
  • how will funding sources be handled or acknowledged? All funding sources that supported data collection and analysis will be listed in the manuscript.

References

1.         Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602.

2.         Hoge CW, Auchterlonie JL, Milliken CS. Mental health problems, use of mental health services, and attrition from military service after returning from deployment to Iraq or Afghanistan. JAMA. 2006;295(9):1023-32.

3.         Kessler RC. Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry. 2000;61 Suppl 5:4-12; discussion 3-4.

4.         Liberzon I, Abelson JL. Context Processing and the Neurobiology of Post-Traumatic Stress Disorder. Neuron. 2016;92(1):14-30.

5.         Van der Werf YD, Scheltens P, Lindeboom J, Witter MP, Uylings HB, Jolles J. Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia. 2003;41(10):1330-44.

6.         Sherman SM, Guillery RW. The role of the thalamus in the flow of information to the cortex. Philos Trans R Soc Lond B Biol Sci. 2002;357(1428):1695-708.

7.         Davis KD, Kwan CL, Crawley AP, Mikulis DJ. Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli. J Neurophysiol. 1998;80(3):1533-46.

8.         Fama R, Sullivan EV. Thalamic structures and associated cognitive functions: Relations with age and aging. Neurosci Biobehav Rev. 2015;54:29-37.

9.         Wilcox CE, Mayer AR, Teshiba TM, Ling J, Smith BW, Wilcox GL, et al. The Subjective Experience of Pain: An FMRI Study of Percept-Related Models and Functional Connectivity. Pain Med. 2015;16(11):2121-33.

10.       LeDoux JE, Farb C, Ruggiero DA. Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J Neurosci. 1990;10(4):1043-54.

11.       Ramanathan KR, Jin J, Giustino TF, Payne MR, Maren S. Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction. Nat Commun. 2018;9(1):4527.

12.       Alvarez RP, Biggs A, Chen G, Pine DS, Grillon C. Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J Neurosci. 2008;28(24):6211-9.

13.       Knight DC, Cheng DT, Smith CN, Stein EA, Helmstetter FJ. Neural substrates mediating human delay and trace fear conditioning. J Neurosci. 2004;24(1):218-28.

14.       Lithari C, Moratti S, Weisz N. Thalamocortical interactions underlying visual fear conditioning in humans. Hum Brain Mapp. 2015;36(11):4592-603.

15.       Fischer H, Andersson JL, Furmark T, Fredrikson M. Fear conditioning and brain activity: a positron emission tomography study in humans. Behav Neurosci. 2000;114(4):671-80.

16.       Morey RA, Dunsmoor JE, Haswell CC, Brown VM, Vora A, Weiner J, et al. Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder. Transl Psychiatry. 2015;5:e700.

17.       Jeon S, Lee YJ, Park I, Kim N, Kim S, Jun JY, et al. Resting State Functional Connectivity of the Thalamus in North Korean Refugees with and without Posttraumatic Stress Disorder. Sci Rep. 2020;10(1):3194.

18.       Suarez-Jimenez B, Albajes-Eizagirre A, Lazarov A, Zhu X, Harrison BJ, Radua J, et al. Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies. Psychol Med. 2019:1-10.

19.       Philip NS, Tyrka AR, Albright SE, Sweet LH, Almeida J, Price LH, et al. Early life stress predicts thalamic hyperconnectivity: A transdiagnostic study of global connectivity. J Psychiatr Res. 2016;79:93-100.

20.       Behrens TE, Johansen-Berg H, Woolrich MW, Smith SM, Wheeler-Kingshott CA, Boulby PA, et al. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nat Neurosci. 2003;6(7):750-7.

21.       Johansen-Berg H, Behrens TE, Sillery E, Ciccarelli O, Thompson AJ, Smith SM, et al. Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus. Cereb Cortex. 2005;15(1):31-9.

22.       Iglesias JE, Insausti R, Lerma-Usabiaga G, Bocchetta M, Van Leemput K, Greve DN, et al. A probabilistic atlas of the human thalamic nuclei combining ex vivo MRI and histology. Neuroimage. 2018;183:314-26.

23.       Logue MW, van Rooij SJH, Dennis EL, Davis SL, Hayes JP, Stevens JS, et al. Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia. Biol Psychiatry. 2018;83(3):244-53.

24.       Clancy K, Ding M, Bernat E, Schmidt NB, Li W. Restless ‘rest’: intrinsic sensory hyperactivity and disinhibition in post-traumatic stress disorder. Brain. 2017;140(7):2041-50.

25.       Mueller-Pfeiffer C, Schick M, Schulte-Vels T, O’Gorman R, Michels L, Martin-Soelch C, et al. Atypical visual processing in posttraumatic stress disorder. Neuroimage Clin. 2013;3:531-8.

Recommended Articles

Leave A Comment

Your email address will not be published.