Neural and Cognitive Sequelae of Methamphetamine Abuse

1
Neural and Cognitive Sequelae of Methamphetamine
Abuse
UC Davis T Nordahl, R
Salo, T Natsuaki M Buonocore, M.
Leamon, NM Flynn R
Gibson
Stanford University E.V. Sullivan A.
Pfefferbaum, D.M. Spielman, E.
Adalsteinsson, Haight Ashbury
Clinics G.P. Galloway
2
Methamphetamine Toxicity

• Methamphetamine-induced neurotoxicity
• MA displaces dopamine from vesicular stores
• Other NT systems (Serotonin, NO, glutamate)
  likely involved
• Damage following exposure to methamphetamine
  primarily in dopamine and serotonin axonal
  terminal regions
• Animal (Axt et al. 1999 McCann et al. 1998,
  2000 Woolverton et al. 1989)
• Human (Wilson et al. 1996 Volkow et al. 2001)

3
Methamphetamine Exposure

• Methamphetamine abuse diminishes dopamine and
  serotonin innervation in frontostriatal brain
  regions
• Clinical sequelae include inattention and
  distractibility, suggesting disruption of frontal
  systems

4
Goals of Study

• To assess attentional performance in MD subjects
  using tests that have shown deficits in other
  clinical populations with DA imbalance (PD,
  schizophrenia).
• To identify using two MRI techniques, MRS and
  DTI, areas with findings consistent with damage.
• To correlate cognitive/behavioral results with
  MRS findings.

5
Sample characteristics
Meet DSM-IV Criteria for lifetime
methamphetamine MA dependence Currently MA
Abstinent No dependence on other substances
within the last 5 years No-coexisting Axis I
disorder (non-substance related) No
neurological impairments or chronic medical
conditions
6
Imaging Findings - MRS
7
Imaging Studies of MA Damage

• PET- (Volkow et al 2001)
• Abnormalities in ACC and parietal cortex
• MRS (Nordahl et al 2002 Taylor et al 2000
  Ernst et al 2000 Sekine et al 2002)
  Abnormalities in frontostriatal regions.
• DTI- None published to date.

8
Proton MR Spectroscopy (MRS)

• Method of using data obtained from certain MRI
  pulse sequences to yield chemical spectra
  reflecting relative concentrations of certain
  neurotransmitters or their metabolites of a
  pre-selected voxel of interest, including NAA,
  Cho, Cr, and mI
• Permits noninvasive in vivo detection of
  neurochemical signs of neuronal integrity and
  disruption

9
Metabolites Visible with Proton MRS
NAA N-acetylaspartate Present exclusively in
neurons and axonal and dendritic
processes Levels are thought to reflect cellular
integrity Cho choline Marker of cell membrane
synthesis or degradation Elevated in glial
tissue mI myoinositol Primarily present in
glial tissue Thought to be a glial marker Cr
creatine phosphocreatine High energy
products Often used for normalization of other
metabolite values
10
MRS Short-Echo Single Voxel Protocol
Voxel size 2cm x 2cm in plane x .9cm (3, 3mm
slices) 3.6cm3
Proton spectrum
GE Probe Protocol TR1500ms, TE144ms, 64
averages linear shims
11
Brain Regions Sampled
Anterior Cingulate Cortex target
region Occipital Cortex - control region
12
 
Cingulate Sampling for MRS Study
13
NAA/Cr Regional Ratios
p .005

Ratio
White Matter
Gray Matter
14
Cho/Cr Regional Ratios
p .06 1-tailed
p .04 1-tailed
Ratio
15
Conclusions 4-13 wks clean

• Reduced NAA and elevated Cho in anterior but
  normal posterior brain regions is consistent with
  other animal and imaging studies.
• Anterior cingulum but not the occiput is rich in
  dopamine in monkey Eberling, 2002.
• In animal studies amphetamine exposure results in
  frontal but not occipital axonal sprouting
  Molliver et al., 1990 and may be response to
  neuronal injury.

16
Speculation

• Cognitive deficits in MD subjects are likely to
  reflect damage in anterior brain regions, such as
  anterior cingulum, that could contribute to their
  clinical presentation and to results from
  neuropsychological studies indicating inattention
  and distractibility as features of MD sequelae.
• Preserved priming might reflect sparing in more
  posterior regions such as occipital cortex.

17
Imaging Findings Across Periods of Abstinence1-6
months versus 1 year to 5 years abstinent
18
Correlation between MRS Cognitive Findings
Stroop Priming Task Computerized trial-by-trial
Stroop task with negative and positive priming
sequences.
RED
(Say blue)
19
Sample Trial Sequence Instructions Name the ink
color as quickly and as accurately as you can.

Trial 1 RED
500 msec
Trial 2 XXXX
500 msec
Trial 3 BLUE
20
Stroop InterferenceMA Subjects vs Controls

p.03
Reaction Time Diff (msec)
21
Correlation between levels of NAA and Stroop
Interference in 26 MA Dependent Subjects
P.03
Stroop RT interference
22
MRS Cognitive Study in Controls

• Interesting pattern emerged with low NAA levels
  correlating with poor performance on the Stroop
  Task.

23
Diffusion Tensor Imaging (DTI)
24
Gender Differences in Stimulant Exposure

• Cocaine gt EEG, rCBF abnormalities in males but
  not
• females (King et al. 2000, Levin et al. 1994)
• Methamphetamine induced 74 striatal DA depletion
  in
• male mice but only 56 depletion in female mice
• (Wagner et al. 1993)
• Methamphetamine depletion of 5-HT/DA is modulated
  
• in rats by estrogen (Yu and Liao, 2000)

25
DTI Studies of Substance Abuse

• Cocaine Abuse - Orbital frontal white matter
  abnormalities in fractional anisotropy (FA) in
  cocaine dependent individuals. (Lim et al, 1999).
• Alcoholism - Abnormal Coherence (Ci) only in
  splenium of corpus callosum. Splenium FA
  correlated with working memory. Genu Ci
  correlated with attention (Pfefferbaum et al.
  2000).

26
Diffusion Tensor Imaging (DTI)

• Determines the pattern of neural connectivity by
  examining the restricted flow patterns of water
  molecules.
• Isotropy Random flow of water molecules
• Anisotropy - Constrained flow of water molecules
  (e.g. white matter cell membranes)

27
DTI Protocol and Basics

• Multiple different combinations of gradient coils
  per location (494 images total).
• Each pixel in DTI images represent a voxel, and
  football determined by 3 orthogonal vectors,
  and 3 associated Eigenvectors. Constants, FA and
  CI are calculated based on the footballs.

28
Measurements Obtained with DTI
FA Fractional anisotropy FA is computed on a
voxel to voxel basis and reflects the degree or
fraction of the total anisotropic tensor. Ci
Coherence index Ci represents the coherence
between voxels in the white matter.
29
Rationale for DTI Sampling

• MRS Abnormalities have been observed in Anterior
• Cingulate Cortex (ACC) of MD subjects (Nordahl
  et al,
• 2002 Taylor et al, 2001).
• PET findings- Volkow et al. reported metabolic
• abnormalities in the ACC.
• DTI sampling - anterior callosal white
• matter adjacent to ACC in order to examine
• evidence of damage spreading to adjacent
• white matter tissue.

30
DTI Sampling
31
ROI selection-Brain Segmentation

• Dual-echo (short(PD)/long(T2) echo) based Brain
  Segmentation
• Segmented into WM/GM/CSF by thresholding
• 3 steps 1) skull-brain separation
• 2) CSF-Tissue separation
• 3) WM-GM separation

32
Diffusion Tensor Images
33
DTI Regions of Interest
DTI Regions of Interest (highlighted in white)
Segmented Brain (WMWhite, GMOrange, CSFRed)
34
Coherence Index Group and Gender Interaction
35
Coherence Index Gender difference in Subjects
Interaction Bar Plot for Cimean(fc), Meth
subjects only
Effect Sex
Error Bars 1 Standard Error(s)
850
800
750
700
650
Cell Mean
600
550
500
450
400
Males
Females
36
CONCLUSIONS

• 1. Evidence consistent with damage in ACC and
  adjacent tissue.
• 2. Evidence of abnormal attention as reflected by
  Stroop Interference.
• 3. Stroop abnormalities correlate with ACC
  abnormalities.
• 4. May be partial normalization of ACC
• abnormalities with prolonged remission.