Functional and Structural Correlates of Aggression and Impulsivity in Schizophrenia

Matthew J. Hoptman, PhDNathan Kline Institute

NYU School of MedicineDepartment of Psychiatry

Outline• MR measures of brain connectivity

– Structural connectivity (DTI)– Functional connectivity (fMRI)

• Aggression as related to brain disconnection• Structural connectivity and aggression in schizophrenia• Functional connectivity and aggression in schizophrenia

Violence in Schizophrenia• Key brain regions implicated in impulsive

aggression include the amygdala and inferior frontal regions– For example, we found (Hoptman et al., 2005) that more

aggressive patients with schizophrenia had larger orbitofrontal cortex volumes (as have others)

• These regions are connected via the uncinatefasciculus

• It has been postulated that impulsive aggression may entail a disconnection between these regions

Early Models of Brain Connectivity

Modern MRI Methods

• In the last 15 years it has become possible to image both structural and functional connectivity in the human brain

• These methods are rapidly developing and improving

Structural Connectivity (DTI)

• White matter organization can be measured using diffusion tensor imaging (DTI)

• DTI examines the degree to which water in the brain diffuses in one direction only (anisotropic) or all directions equally (isotropic)

• Fractional anisotropy (FA) is a quantitative measure of this property

Diffusion• Water self-diffusion - random

Brownian movement of water molecules

• Diffusion equal in all directions• Isotropic Diffusion

• Structural limitation to self-diffusion

• Self-diffusion higher in X than Y axis

• Anisotropic Diffusion

Directional Dependence of Diffusion

II

ADC = 1.5 x 10-5 cm2/sII

ADC = 0.15 x 10-5 cm2/s

The ADC is Anisotropic

DTI Reveals White Matter Structure

G

P

C

Tractography

Tractography

Jones et al., 2006

Limitations• Not a measure of white matter per se

• Probably more influenced by factors like condition of axonal membrane (Beaulieu et al., 1994)

• Tractography is based on fairly low resolution images (2 mm3 is lower limit these days)

• In each voxel, there are probably 1000s of fibers• We only see the average across them in DTI• In some voxels, fibers cross, so which way should tractography program choose?

Functional Connectivity

• Correlation of brain activity in separate regions over time

• Can be measured while the subject relaxes in the scanner

• Appears to be stable over time• Might represent some sort of baseline of

brain functioning or “default state”(Raichle, 2001)

From Task to RestRest

Biswal BB et al., 1995

Finger-Tapping

BA

r=0.; p<0.01Functional Connectivity between (L) ACC and (R) ACC

-3.00000

-2.00000

-1.00000

.00000

1.00000

2.00000

3.00000

4.00000

Time (ms)

Z-Sco

res

ACC (L)

ACC (R)

r =.75, p < .01

Advantages of Resting State

• Easy to collect• Every subject can do it• See similar patterns with varying levels of

consciousness• No performance confounds• Reliable with large effect sizes

Disadvantages

• Unconstrained nature• Possible vascular contributions

– Tested by doing fast scanning (TR = 250ms)– Covariance analyses show at least some signal

remains even if control for respiration/CO2 levels

Many Different Functional Networks

Raichle et al., 2006

DeLuca et al., 2006

Relevance to Psychiatric Disorders• Schizophrenia may entail disrupted connectivity

among brain regions (Friston, 1995)• Some studies have found reductions in white

matter volume in schizophrenia (see e.g., Shenton, 2001)

• Hakak et al. (2001) have found dysregulation of myelin-related genes in schizophrenia

• Functional connectivity is abnormal in schizophrenia (Garrity et al., 2007)

• Many DTI studies have found reduced FA in schizophrenia

Application in Schizophrenia

• Group differences found in multiple regions implicated in the pathophysiology of schizophrenia (Ardekani et al., 2003)

• Abnormalities in FA are also seen in first episode patients (Kumra et al., 2003) and in individuals at high genetic risk for schizophrenia (Hoptman et al., 2008)

Aggression in Schizophrenia

• Lesion Studies

• DTI Studies

Phineas Gage – 1848

Methods

• 14 men with schizophrenia

• DTI acquired using 6 directions

• Patients assessed using the Buss-DurkeeHostility Inventory, Life History of Aggression (LHA) and Barratt Impulsivity Scale (BIS)

• No rule out for substance abuse history

• Region of Interest approach

Regions of Interest – Inferior Frontal Lobe

Hoptman et al., 2002

DTI in Impulsivity

Hoptman et al, 2002

DTI in Aggression

Hoptman et al., 2002

Open Questions

• Used only questionnaire measures• No data on healthy controls• Confounding role of substance abuse

– Cocaine dependent patients show reduced FA in similar regions

– In our own sample, patients with comorbidsubstance abuse diagnoses have reduced FA in that region

New study

• 45+ Patients• New DTI sequence• No subjects with substance dependence or

substance abuse in last 6 months• Urine tox screens to verify abstinence• Patients assessed with LHA and Buss Perry

Aggression Questionnaire (BPAQ)

Voxelwise Analyses

• Entails intersubject registration of scans to a target that is in standard space

• Permits examination of group differences across the entire brain

• Useful in hypothesis generation• Analyses corrected for False Discovery

Rate (q = .05)

Quality of Registrations

• Issue of quality of registrations• Linear vs. Nonlinear (nonlinear is better)• Better registrations give rise to more

activations (Ardekani et al., 2005)• Our registration software is state-of-the-art

(Klein et al., 2009)

FA in inferior frontal white matter negatively correlated with

aggression

BPAQ LHA

Caveats

• Other areas involved• Self-report measures used• Better scans available now

Aggression and Functional Connectivity

• Ventromedial prefrontal and limbic regions abnormalities are seen in social cognitive dysfunction and aggression

• Reduced white matter integrity in right inferior frontal regions was associated with higher levels of aggression (Hoptman et al., 2002)

• We used resting state functional MRI to examine amygdala/ventral prefrontal (vPFC) functional connectivity (FC) and its relation to aggression in patients with schizophrenia

Methods• 21 healthy controls and 25 patients with

schizophrenia or schizoaffective disorder• Aggression was measured using the BPAQ and

LHA• Resting state fMRI was acquired in a six-minute

scan. • Seeds derived from an anatomically-validated

study of effective connectivity in amygdala (Stein et al., 2007)

Results

• Patients showed significant reductions in FC between amygdala and vPFC regions

• Lower FC was associated with higher levels of self-rated aggression

Controls Patients Difference

Hoptman et al, in press

Decreased AmygdalofrontalFC in schizophrenia

Hoptman et al, in press

Hoptman et al, in press

Reduced FC between amygdala and vPFC inschizophrenia is associated with aggression

Conclusions

• White matter structural connectivity is compromised in more aggressive patients with schizophrenia

• Amygdala/vPFC FC is compromised in schizophrenia

• This compromise is associated with increased levels of aggression

• Adds to literature suggesting brain disconnectivity in schizophrenia

Future Directions

• Better understanding of mechanisms• More diffusion directions (current data used 8)

– now using 30– Probabalistic tractography – allows us to account for

error in tracts

• Higher field strength – Need for parallel imaging• Combined fMRI/DTI studies

– Methods in development• e.g., Greicius et al., 2008

– Our own methods

AcknowledgmentsNKI• Babak A. Ardekani, PhD• Karen A. Nolan, PhD• Jan Hrabe, PhD• Jan Volavka, MD, PhD• Daniel C. Javitt, MD, PhD• Debra D’Angelo, BA

University of Minnesota• Kelvin O. Lim, MD

New York University• Glyn Johnson, PhDNYU CSC• Mike Milham, MD/PHD• Xavier Castellanos, MD

FundingR01 MH064783 (Hoptman)NARSAD (Hoptman)

R01 MH066374 (Butler)Whitaker Foundation (Ardekani)