Neural Networks in Suicide and Substance Abuse Deborah Yurgelun-Todd, Ph.D.

1. Neural Networks in Suicide and Substance Abuse Deborah Yurgelun-Todd, Ph.D. Assoc. Director, VISN 19 MIRECC Professor of Psychiatry, University of Utah

2. Study Approach Overview • Aim: To clarify the neurobiological and cognitive underpinnings of suicidal ideation and behavior in veterans with TBI. • Hypothesis: a) Disruptions in the functional brain circuitry that support higher-order cognitive processing including mental flexibility, problem solving, inhibitory control and decision making are associated with suicidal risk. b) Higher-order deficits will also result as a consequence of substance abuse. • Methods: MRI, fMRI imaging data and neuropsychological data will be acquired on veterans with TBI, with and without suicidal ideation.

3. Cortico-Limbic Circuits: Top-Down Modulation of Affective Processes

4. Introduction Deficits in decision making and problem solving have been widely implicated in the onset and perpetuation of suicidal ideation and suicide attempts. Deficits reported in substance abuse are similar to those reported in individuals with suicidal ideation with decreased problem solving and decision-making reported as a consequence of using a number of illicit substances. It has been proposed that the orbitofrontal region plays a key role in decision making and behavior planning by taking into account the likely reward value of stimuli.

5. Components of Decision-Making • Selectiveattention and short termstorage of information • Inhibition of response to irrelevant information • Initiation of response to relevant information • Self-monitoring of performance and of changing internal and external contingencies, in order to “stay the course” towards the ultimate goal

6. Working memory ACC Self-Monitoring Conflict Motor Cortex Response Execution Lateral PFC Selective Attention Goal representation Parietal & Association Cortex VTA Reward gating Sensory Input Functional Model of Behavioral Processing

7. Decision Making, Impulsivity and the Orbitofrontal Cortex • The ability to reflect on future outcomes is mediated by orbitofrontal cortex. • The orbitofrontal cortex is critical to appetitive behavior in humans and shows changes in activity that correlate with reward. • We hypothesized that more impulsive individuals may have reduced cortical volume, particularly orbitofrontal volume.

8. Veterans with TBI have complex clinical presentations: Clinical summary for our Pilot Study

9. MRI Data shows that regional cortical thickness is decreased in subjects with TBI compared to controls Medial view Lateral view Left Hemisphere: middle and superior frontal and lingual gyrus Right Hemisphere: middle frontal, lateral occipital, inferior parietal

10. MRI Data shows that regional cortical thickness is decreased in subjects with TBI + Suicidal Ideation compared to TBI alone Medial view Lateral view Left Hemisphere: posterior cingulate, parahippocampus and lingual gyrus Right Hemisphere: superior prefrontal, orbitofrontal and posterior cingulate

11. For TBI subjects brain volume correlated with measures of impulsivity (risk taking). Non-TBI controls did not show this correlation. Task measures: increased number of pumps (p<0.05) and popped balloons (p= 0.05) correlate with decreased overall brain volume.

12. Traumatic Brain Injury and the NeurobiologicalCorrelates for Suicide Risk Veterans with TBI reported more anxious (HAM-A) and depressive symptoms (HAM-D) than HCs. Veterans with TBI reported more overall affective disturbance than HCs (POMS Total Mood Disturbance) and had decreased verbal fluency (FAS TOTAL BRAIN VOLUME: TBIs with suicidal ideation showed reduced cerebral cortex volume compared to TBIs without suicidal ideation.

13. Summary Impulsivity (risk taking) measures appear associated with whole brain volume in TBI subjects but are not associated with brain volume in non-TBI control subjects. Preliminary data on veterans with TBI and suicidal ideation show increased impulsivity compared to veterans with TBI alone. Reduced inferior and middle frontal volume correlated with measures of impulsivity

14. Impulsivity ( BIS) Findings in Cannabis Users • Barratt Impulsivity Scale • 30 item self-report measure • of trait impulsivity • Three dimensions: • Motor • Attention • Non-planning • Cannabis users show decreased future orientation and increased impulsivity as indexed by • the BIS non-planning subscale.

15. Reduced Orbitofrontal Volume in Cannabis Users • Coronal and axial views of two regions of interest (ROIs) • a) lateral orbitofrontal cortex and • b) medial orbitofrontal cortex • Cannabis users show decreased right medial OFC volume compared to healthy controls.

16. Orbitofrontal Volume and Age of Onset of Cannabis Use The earlier the age of onset of cannabis use, the smaller the orbitofrontal volume.

17. Summary • Increased impulsivity and decreased future orientation are seen in cannabis smokers. • Decreased right medial OFC volume is seen in cannabis smokers compared to healthy non-using controls. • Orbitofrontal volume correlated with age of onset of drug use suggesting 1) volume is a risk factor for impulsivity and drug use or 2) orbitofrontal development is altered by drug use.

18. maturation of inhibitory control/emotional regulation Neural Circuitry Mediating Reward PFC ACC OFC VTA SN Nac Ventral Striatum Dorsal Striatum Insula Amygdala Hippocampus BNST mesocortical pathway mesolimbic pathway mesostriatal pathway Lat. Septal Lat. Hypothalamus Silveri, 2007

19. Implications • Veterans with TBI and suicidal ideation show greater levels of impulsivity than veterans with TBI and no suicidal ideation. Impulsivity was correlated with middle frontal volume (OFC). • Heavy marijuana users show Increased impulsivity and decreased orbitofrontal (OFC) volume. • Changes in how the brain evaluates reward influences self-control and/or the ability to inhibit reward seeking and impulsivity. • Prevention models will need to address the dynamic relationship between self-control and reward seeking.