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TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 1
Basal ganglia
Introduction
The basal ganglia are a group of sub-cortical nuclei thought to be involved in motor control and learning. The nuclei comprising the basal ganglia include the caudate, putamen, globus pallidus, the subthalamic nucleus and the substantia nigra. The caudate and putamen together form the striatum, while the globus pallidus (including the ventral pallidum) and the putamen together form the lenticular nucleus.
The striatum is the principal input centre, receiving afferents primarily from the cortex, but also the substantia nigra, thalamus, and external globus pallidus. There are two primary pathways from the striatum through the basal ganglia (‘direct’ and ‘indirect’ pathways) which incorporate different components of the basal ganglia circuitry, and play different roles in controlling and planning movements and cognition.
Schizophrenia has been associated with altered
structure and function of the basal ganglia.
Understanding of brain alterations in people
with schizophrenia may provide insight into
changes in brain development associated with
illness onset or progression. Reviews contained
in this technical summary reflect structural
imaging investigations (MRI), functional
imaging investigations (fMRI, PET, SPECT) as
well as metabolic imaging (MRS) of basal
ganglia function in schizophrenia.
Method
We have included only systematic reviews
(systematic literature search, detailed
methodology with inclusion/exclusion criteria)
published in full text, in English, from the year
2000 that report results separately for people
with a diagnosis of schizophrenia,
schizoaffective disorder, schizophreniform
disorder or first episode schizophrenia.
Reviews were identified by searching the
databases MEDLINE, EMBASE, CINAHL,
Current Contents, PsycINFO and the Cochrane
library. Hand searching reference lists of
identified reviews was also conducted. When
multiple copies of reviews were found, only the
most recent version was included. Reviews with
pooled data are prioritised for inclusion.
Review reporting assessment was guided by
the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA)
checklist, which describes a preferred way to
present a meta-analysis1. Reviews rated as
having less than 50% of items checked have
been excluded from the library. The PRISMA
flow diagram is a suggested way of providing
information about studies included and
excluded with reasons for exclusion. Where no
flow diagram has been presented by individual
reviews, but identified studies have been
described in the text, reviews have been
checked for this item. Note that early reviews
may have been guided by less stringent
reporting checklists than the PRISMA, and that
some reviews may have been limited by journal
guidelines.
Evidence was graded using the Grading of
Recommendations Assessment, Development
and Evaluation (GRADE) Working Group
approach where high quality evidence such as
that gained from randomised controlled trials
(RCTs) may be downgraded to moderate or low
if review and study quality is limited, if there is
inconsistency in results, indirect comparisons,
imprecise or sparse data and high probability of
reporting bias. It may also be downgraded if
risks associated with the intervention or other
matter under review are high. Conversely, low
quality evidence such as that gained from
observational studies may be upgraded if effect
sizes are large, there is a dose dependent
response or if results are reasonably
consistent, precise and direct with low
associated risks (see end of table for an
explanation of these terms)2. The resulting
table represents an objective summary of the
available evidence, although the conclusions
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 2
Basal ganglia
are solely the opinion of staff of NeuRA
(Neuroscience Research Australia).
Results
We found seventeen systematic reviews that
met our inclusion criteria3-19.
Structural changes: MRI and DTI
• High quality evidence suggests increased
grey matter in the caudate, bilateral
putamen, and globus pallidus in people with
schizophrenia compared to healthy controls.
Moderate to low quality evidence suggests
increased volume in these regions in
children with schizophrenia.
• Moderate quality evidence suggests bilateral
caudate nucleus grey matter is significantly
reduced in first episode psychosis patients
(particularly medication naïve patients)
compared to chronic schizophrenia, people
at high risk, and healthy controls.
• High quality evidence suggests a small
effect of greater reductions over time in the
left caudate in people with schizophrenia
compared to healthy controls.
Functional changes: fMRI, PET, MRS and
SPECT
• Moderate quality evidence suggests people
with schizophrenia show reduced activity in
the bilateral claustrum and the right putamen
during executive function tasks.
• Moderate to low quality evidence suggests
no functional abnormality in the basal
ganglia during cognitive control, memory
(long-term and working memory) and
language processing.
• Moderate to low quality evidence suggests
dopamine receptor occupancy in the
striatum of people with schizophrenia varies
according to treatment with first or second
generation antipsychotics.
• Moderate to low quality evidence suggests
no differences in D2/D3 receptor availability
in the substantia nigra of unmedicated
people with schizophrenia compared to
controls.
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 3
Basal ganglia
Chan RCK, Di X, McAlonan GM, Gong Q
Brain Anatomical Abnormalities in High-Risk Individuals, First-Episode, andChronic Schizophrenia: An Activation Likelihood Estimation Meta-analysis of IllnessProgression
Schizophrenia Bulletin 2011; 37(1) 177-188
View review abstract online
Comparison Grey matter volume in people with first episode schizophrenia
vs. healthy controls.
Summary of evidence Moderate quality evidence (large sample size, direct, unable to assess consistency or precision) suggests people with first episode schizophrenia have grey matter reductions in the right caudate nucleus compared to healthy controls, and compared to high risk individuals.
Basal ganglia volume
Meta-analysis was performed using Anatomical Likelihood Estimate (ALE) analysis on Voxel-Based Morphometry MRI studies.
FWHM 10mm, FDR corrected at p < 0.01
14 studies, N = 1082
Right caudate: Talairach coordinates (10, 10, 12), cluster 224mm3, ALE 0.0116
Between group comparisons: subtraction analysis between high risk individuals and first episode schizophrenia
Greater grey matter reduction in first episode group;
Right caudate: Talairach coordinates (10, 8, 14), cluster 224mm3, ALE 0.0104
Left caudate: Talairach coordinates (-12, 6, 12), cluster 192mm3, ALE 0.0099
Consistency in results‡ No measure of consistency is reported.
Precision in results§ No confidence intervals are provided.
Directness of results║ Direct
Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 4
Basal ganglia
The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis
American Journal of Psychiatry, 2008. 165(8): 1015-23
View review abstract online
Comparison Grey matter volume in first episode schizophrenia vs. chronic schizophrenia vs. healthy controls.
Summary of evidence Moderate quality evidence (large sample size, direct, unable to assess consistency or precision) suggests reductions in bilateral caudate head grey matter, which are absent in chronic schizophrenia. Increased grey matter was reported in the putamen.
Basal ganglia volume
N = 1556, 27 studies
First episode reductions
Left caudate head: Talairach coordinates (-12, 6, 12), cluster 528mm3, ALE 0.01, p = 0.0002
Right caudate head: Talairach coordinates (10, 10, 12), cluster 1392mm3, ALE 0.012, p < 0.0002
First episode increases
Left putamen: Talairach coordinates (-22, 0, 12), cluster 1592mm3, ALE 0.008, p < 0.0002
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Ellison-Wright I, Bullmore E
Anatomy of bipolar disorder and schizophrenia: A meta-analysis.
Schizophrenia Research 2010; 117: 1-12
View review abstract online
Comparison Grey matter volume in people with schizophrenia vs. healthy
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 5
Basal ganglia
controls.
Summary of evidence Moderate quality evidence (large sample sizes, direct, unable to
assess consistency or precision) suggests grey matter
increases were reported in the right globus pallidus and left
caudate head in people with schizophrenia.
Basal ganglia volume
Meta-analysis was performed using Activation Likelihood Estimate (ALE) analysis on Voxel-Based Morphometry MRI studies.
FWHM 7mm, FDR corrected at p <0.05
42 studies, N = 4189
Regions of increased grey matter;
Right globus pallidus: Talairach coordinates (16, 0, 4), Sum of ranks = 71.6, p = 0.00005
Left caudate head: Talairach coordinates (-6, 8, 4), Sum of ranks = 67.8, p = 0.00005
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Fusar-Poli P, Perez J, Broome M, Borgwardt S, Placentino A, Caverzasi E, Cortesi M, Veggiotti P, Politi P, Barale F, McGuire P
Neurofunctional correlates of vulnerability to psychosis: A systematic review and meta-analysis
Neuroscience & Biobehavioral Reviews 2007; 31(4): 465-484
View review abstract online
Comparison Functional activation in individuals at high risk of developing schizophrenia vs. healthy controls.
Summary of evidence Low quality evidence (one small observational study per outcome) is unclear as to the direction of the changes in functional activity in the striatum during cognitive tasks in individuals at high risk of developing schizophrenia.
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 6
Basal ganglia
Basal ganglia functional activation
1 observational study, N = 32
Large effect size suggests reduced activation of striatum (d = 1.34) in non-psychotic relatives of schizophrenia patients compared to controls for working memory guided saccades.
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL, Bullmore E, Fox PT
Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis
Biological Psychiatry 2008; 64(9):774-781
View review abstract online
Comparison Grey matter density in people with schizophrenia vs. healthy controls.
Summary of evidence Moderate quality evidence (large sample sizes, direct, unable to assess consistency or precision) suggests schizophrenia is associated with significant increases in grey matter density in the putamen and caudate head in people with schizophrenia.
Basal ganglia volume
Meta-analysis was performed using ALE analysis on Voxel-Based Morphometry MRI studies.
FWHM 12mm, FDR corrected at p < 0.05
13 studies, N = 2457
Regions were much smaller and more discrete;
Left putamen: Talairach coordinates (-38, 0, 16), Voxel cluster size 1248mm3, p < 0.01
Right putamen: Talairach coordinates (28, 6, 2), Voxel cluster size 464mm3, p < 0.01
Right head of caudate: Talairach coordinates (8, 0, 4), Voxel cluster size 424mm3, p < 0.01
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 7
Basal ganglia
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Kambeitz J, Abi-Dargham A, Kapur S, Howes OD
Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: Systematic review and meta-analysis of imaging studies
British Journal of Psychiatry 2014; 204(6): 240-249
View review abstract online
Comparison Cortical and extrastriatal D2/D3 receptor availability (measured by PET or SPECT) in unmedicated people with schizophrenia vs. controls.
Summary of evidence Moderate to low quality evidence (medium-sized samples, inconsistent, imprecise, direct) suggests no differences in D2/D3 receptor availability in the substantia nigra.
D2/D3 receptor availability
Binding potential relative to the non-displaceable compartment
Substantia nigra
No significant differences between groups in D2/D3 receptor availability;
5 studies, N = 143, d = 0.04, 95%CI -0.92 to 0.99, p = 0.90, I2 = 85%
Excluding one study of drug-naïve patients did not substantially change the effect (d = -0.04).
Meta-regression showed no effect of publication year, gender, or age in any analysis.
There was no evidence of publication bias.
Consistency in results Some inconsistency.
Precision in results Some imprecision.
Directness of results Direct
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 8
Basal ganglia
Lahuis B, Kemner C, Van Engeland H
Magnetic resonance imaging studies on autism and childhood-onset schizophrenia in children and adolescents – a review
Acta Neuropsychiatrica 2003; 15(3): 140-147
View review abstract online
Comparison Brain volume in childhood-onset schizophrenia (COS) vs. healthy controls.
Summary of evidence Moderate to low quality evidence suggests child-onset schizophrenia patients exhibit increased volume in the basal ganglia.
Basal ganglia volume
12 studies, N unclear
Increased volume was observed in the caudate, putamen, and globus pallidus.
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Leung M, Cheung C, Yu K, Yip B, Sham P, Li Q, Chua S, McAlonan G
Gray Matter in First-Episode Schizophrenia Before and After Antipsychotic Drug Treatment. Anatomical Likelihood Estimation Meta-analyses With Sample Size Weighting
Schizophrenia Bulletin 2011; 37(1): 199-211
View review abstract online
Comparison Grey matter changes in people with first-episode schizophrenia
(treated and medication naïve) vs. healthy controls.
Summary of evidence Moderate quality evidence (large sample sizes, indirect, unable to
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 9
Basal ganglia
assess consistency or precision) suggests greater reduction in the bilateral caudate in treatment naïve first episode schizophrenia patients compared to healthy controls and treated patients.
Basal ganglia volume
Meta-analysis was performed using Anatomical Likelihood Estimate (ALE) analysis on Voxel-Based Morphometry MRI studies.
FWHM 8mm, FDR corrected at p <0.05
6 studies, N = 327
Treatment naïve first-episode psychosis
Right caudate: Talairach coordinates (10, 10, 12), cluster 1936mm3, ALE 0.0019
Left caudate: Talairach coordinates (0, 12, 4), cluster 1936mm3, ALE 0.0057
Regions where grey matter reductions were larger in magnitude in treatment naïve patients than in
treated patients;
Right caudate: Talairach coordinates (10, 10, 12), cluster 1992mm3, ALE 0.0106
Left caudate: Talairach coordinates (0, 12, 4), cluster 360mm3, ALE 0.0276
Left caudate: Talairach coordinates (-12, 6, 0), cluster 264mm3, ALE 0.0095
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct for within group comparison, indirect for between group
comparison
MacDonald AW, Thermenos HW, Barch DM, Seidman LJ
Imaging genetic liability to schizophrenia: systematic review of FMRI studies of patients' nonpsychotic relatives
Schizophrenia Bulletin 2009; 35(6): 1142-1162
View review abstract online
Comparison Functional activation in first-degree relatives of people with schizophrenia vs. healthy controls.
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 10
Basal ganglia
Summary of evidence Moderate to low quality evidence (large sample size, direct,
unable to assess precision or consistency) suggests no
differences in functional activity during cognitive control tasks,
memory tasks (long term and working) and language
processing.
Cognitive control tasks
7 studies investigated functional activity during cognitive control tasks, N = 308
6 studies investigated the basal ganglia, 2/6 showed reduced activity compared to controls
Working memory tasks
4 studies (5 independent samples) investigated functional activity during working memory tasks, N =
239
2 studies investigated the basal ganglia, 1/2 showed increased activity compared to controls
Long term memory tasks
3 studies investigated functional activity during episodic long term memory tasks, N = 195
3 studies investigated the basal ganglia, 3/3 showed no group differences
1 study investigated functional activity during procedural long term memory tasks, N = 27
Reduced activity in relatives was shown in basal ganglia
Language processing studies
4 studies investigated functional activity during language processing tasks, N = 164
4/4 showed no task-related response in the basal ganglia
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
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Page 11
Basal ganglia
Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia
Archives of General Psychiatry 2009; 66(8): 811-822
View review abstract online
Comparison 1 Functional activation in individuals with schizophrenia vs. healthy controls: ALE analysis
Note – The claustrum is considered by some sources to be a part of the basal ganglia.
Summary of evidence Moderate quality evidence (large sample size, direct, unable to assess precision or consistency) suggests patients with schizophrenia show reduced activity in the bilateral claustrum and the right putamen during executive function tasks
Activation following executive function tasks: where controls have > activity than patients
with schizophrenia
Meta-analysis results reported for 41 studies of either fMRI or PET during executive function tasks.
41 studies, N = 1217
ALE analysis – FWHM 12mm, False Discovery Rate (FDR) corrected model
Significantly reduced activity in schizophrenia patients compared to controls
Right claustrum: Talairach centre of mass (26, 22, 2), cluster volume 1766mm3
Left claustrum: Talairach centre of mass (-28, 24, 0), cluster volume 880mm3
Right putamen: Talairach centre of mass (20, -4, 14), cluster volume 448mm3
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Navari S, Dazzan P
Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 12
Basal ganglia
Psychological Medicine 2009; 39(11): 1763-1777
View review abstract online
Comparison 1 Brain volume in medicated, drug free and drug naïve
schizophrenia patients and healthy controls: cross-sectional
studies.
Summary of evidence Low quality evidence (sample sizes unclear, indirect, unable to
assess consistency or precision) is unclear of the effect of
antipsychotic medications on brain structure.
Volumetry in drug free and drug naïve schizophrenia
1 study, N unclear
Drug free patients showed increased putamen volume and reduced caudate nucleus volume
compared to drug naïve patients and to controls.
Volumetry in schizophrenia medicated in the short term (≤12 weeks)
1 study, N unclear
Patients medicated with typical antipsychotics showed reduced basal ganglia volume compared to
drug free patients.
Volumetry in schizophrenia medicated in the long term (>12 weeks)
2 studies, N unclear
One study reported no difference in basal ganglia and thalamic volume, another reported reduced
basal ganglia and thalamic volume in patients treated with typical antipsychotics
Consistency in results No measure of consistency reported, results appear inconsistent for
long term medication.
Precision in results No confidence intervals are provided.
Directness of results Indirect comparisons of medicated and unmedicated schizophrenia
patients.
Comparison 2 Brain volume in medicated, drug free and drug naïve
schizophrenia patients and healthy controls: longitudinal
studies.
Summary of evidence Low quality evidence is unclear as the effect of antipsychotics
on brain structure over time.
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 13
Basal ganglia
Volumetry in drug free and drug naïve schizophrenia
N unclear, varying follow up (range 4 weeks to 2 years)
One study showed drug naïve patients on a course of atypical antipsychotics with increased
caudate volume identical to controls, another study also showed increased caudate and accumbens
volume with atypical antipsychotics.
One study showed increased striatal volume in drug naïve patients following antipsychotic treatment
(type unspecified).
Volumetry in schizophrenia medicated in the short term (≤12 weeks)
3 studies, N unclear, varying follow up
Three studies reported increased basal ganglia volume following typical medication, a further two
studies reported reduced basal ganglia volume over the treatment period with mostly atypical
medication.
Volumetry in schizophrenia medicated in the long term (>12 weeks)
3 studies, N unclear, varying follow up
Three studies considered the effect of switching from long term typical medication to atypical
medication and reported reduced basal ganglia volume, particularly the caudate. Authors propose
this effect could represent normalization of volumes previously increased by typical medication.
Consistency in results No measure of consistency is provided, results appear inconsistent.
Precision in results No confidence intervals are provided.
Directness of results Indirect comparisons of medicated and unmedicated schizophrenia
patients.
Olabi B, Ellison-Wright I, McIntosh AM, Wood SJ, Bullmore E, Lawrie SM
Are There Progressive Brain Changes in Schizophrenia? A Meta-Analysis of Structural Magnetic Resonance Imaging Studies
Biological Psychiatry 2011; 70(1): 88-96
View review abstract online
Comparison Progressive changes in grey matter volume in people with schizophrenia vs. healthy controls.
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 14
Basal ganglia
Summary of evidence High quality evidence (large sample sizes, consistent, precise, direct) suggests significantly greater reductions over time in the left caudate in people with schizophrenia.
Grey matter volume
Progressive changes in grey matter volume reported across longitudinal MRI scans over 1-10 years.
31 studies, N = 1867
Significant, small effect of greater reductions over time in schizophrenia compared to controls;
Left Caudate: N = 253, 3 studies, d = -0.336, 95%CI -0.60 to -0.07, p = 0.013, I2 = 0%
No differences between groups;
Right Caudate: N = 253, 3 studies, d = -0.132, 95%CI -0.49 to 0.23, p = 0.470, I2 = 41.6%
Consistency in results Consistent
Precision in results Precise
Directness of results Direct
Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, Radue E W, McGuire PK, Riecher-Rossler A, Borgwardt SJ
The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? - A Systematic Review
Current Pharmaceutical Design 2009; 15(22): 2535-2549
View review abstract online
Comparison Grey matter volume changes in cross-sectional and longitudinal
assessments in treated and untreated people with schizophrenia
compared to healthy controls.
Summary of evidence Moderate to low quality evidence (unclear sample size, direct,
unable to assess consistency or precision) is largely unclear as
to the role of medication in mediating structural alterations in
people with schizophrenia.
Atypical antipsychotic medications appear broadly to be
associated with less structural alterations than typical
medications.
TECHNICAL COMMENTARY
NeuRA Basal ganglia March 2017
Margarete Ainsworth Building, Barker Street, Randwick NSW 2031. Phone: 02 9399 1000. Email: [email protected]
To donate, phone 1800 888 019 or visit www.neura.edu.au/donate/schizophrenia
Page 15
Basal ganglia
Changes reported in cross-sectional MRI studies
One study reported treatment with typical antipsychotics was associated with increased basal
ganglia volume in first episode psychosis patients.
Changes reported in longitudinal whole-brain studies
13 studies used VBM methodology to assess structural changes following administration of
antipsychotics.
Basal ganglia increases were reported only for treatment with typical antipsychotics, not for atypical.
Patients treated with haloperidol (typical) showed significant increases in caudate nucleus
compared to patients treated with olanzapine (atypical).
In chronic patients treated with atypical antipsychotics, increased basal ganglia density was
reported.
In early onset patients, atypical treatment was associated with increased caudate volume compared
to healthy controls.
Compared to antipsychotic naïve patients, treated patients (mixed typical and atypical) had
increased caudate.
Changes reported in longitudinal region-of-interest studies
7 studies used region of interest analysis to assess structural changes of the basal ganglia following
administration of antipsychotics.
They reported no significant differences in volume in patients treated with atypical medication,
though small increases were reported with typical.
Consistency in results No measure of consistency is reported, results appear inconsistent.
Precision in results No confidence intervals are provided.
Directness of results Direct
Steen RG, Hamer RM, Lieberman JA
Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis
TECHNICAL COMMENTARY
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Page 16
Basal ganglia
Neuropsychopharmacology 2005; 30(11): 1949-1962
View review abstract online
Comparison Metabolic N-acetylaspartate amino acid (NAA) activity (measured by 1H-MRS) in grey matter regions in people with schizophrenia vs. healthy controls.
Summary of evidence Low quality evidence (sample size unclear, direct inconsistent, unable to assess precision) is unclear of NAA levels in the striatum of people with schizophrenia compared to controls.
NAA levels in grey matter regions
6 studies consider NAA, N unclear
Patient average 98.5% of control levels
Lenticular nucleus (putamen + globus pallidus)
2 studies consider NAA, N unclear
Patient average 104.5% of control levels
Caudate nucleus
3 studies consider NAA, N unclear
Patient average 100.3% of control levels
Putamen
7 studies consider NAA, N unclear
Patient average 100.6% of control levels
Striatum (caudate+putamen)
1 study considers NAA, N unclear
Patient average 112.6% of control levels
Consistency in results Inconsistent - significant heterogeneity reported, p < 0.0001.
Precision in results No confidence intervals are provided.
Directness of results Direct
Stone JM, Davis JM, Leucht S, Pilowsky LS
Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs--an original patient data meta-analysis of the SPECT
TECHNICAL COMMENTARY
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Page 17
Basal ganglia
and PET in vivo receptor imaging literature
Schizophrenia Bulletin 2009; 35(4): 789-797
View review abstract online
Comparison Dopamine D2/D3 receptor occupancy in the striatum and
temporal cortex of schizophrenia patients compared to healthy
controls following first and second generation antipsychotic
administration. Indirectly compared to efficacy measurements of
antipsychotics in separate patient groups.
Summary of evidence Moderate to low quality evidence (direct, small to moderate
sample size, unable to assess precision and consistency)
suggests dopamine receptor occupancy may be different
depending on first or second generation antipsychotic
treatment.
Low quality evidence (indirect, unable to assess sample size,
precision and consistency) is unclear about the relationship
between receptor occupancy and drug effectiveness, side
effects or measurement type. Single ligands had significantly
higher occupancy than dual ligands. Significant difference in
occupancy rates between first and second generation
antipsychotics was reported, when controlling for ligand type
and modelling method.
D2/D3 receptor occupancy
Fifteen studies were pooled to estimate the dopamine receptor occupancy.
Striatal occupancy following first generation antipsychotic administration: N = 28, 74% ± 12%
Striatal occupancy following second generation antipsychotic administration: N = 115, 49% ± 21%
t = 8.8, p < 4x10-13
Ratio of striatal/temporal occupancy for first generation antipsychotics: 96 ± 24%
Ratio of striatal/temporal occupancy for second generation antipsychotics: 74 ± 35%
t = 3.7, p < 0.001
Subgroup analysis 1: correlation to clinical efficacy
Indirect comparison using dose-response curve calculated from separate efficacy studies into first
and second generation antipsychotics.
Occupancy correlated with drug effectiveness for striatal D2/D3: r = 0.76, p = 0.046
Subgroup analysis 2: correlation to extrapyramidal side effects
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Indirect comparison using dose-response curve calculated from separate efficacy studies into first
and second generation antipsychotics.
Dose was correlated linearly with occupancy in the striatum, r = 0.59, p = 0.004
EPSE are known to increase with dose and so are likely to be associated more with striatal
dopamine.
Subgroup analysis 3: controlling for assessment method; Simplified Reference Tissue Modelling vs.
Ratio modelling
No significant difference was found in the occupancy estimates of both methods in the striatum.
The association of measurement method and drug type (typical vs. atypical) was zero for both
regions.
Subgroup analysis 4: single vs. dual ligands
In the striatum, single ligand binding had an 18% lower (95%CI 10 to 25%) occupancy estimate
than dual ligands. F = 22, p = 0.000007
Subgroup analysis 5: ANCOVA with ligand type and modelling method covariates
In the striatum, occupancy was estimated at 74%, 95%CI 66 to 82% for first generation
antipsychotics. For second generation antipsychotics, occupancy was estimated at 47%, 95%CI 44
to 54%
This is a significant difference of 27%, 95%CI 18 to 36% between the two classes of antipsychotics
F = 37, p = 0.00000005
Consistency in results No measure of consistency is reported.
Precision in results CIs not reported for all outcomes, precise for subgroup analyses 4
and 5.
Directness of results Direct
Taylor H, Ricciardi A, Dazzan P
A review of caudate nucleus volume in first episode psychosis
Clinical Neuropsychiatry 2007; 4(5-6): 191-198
View review abstract online
Comparison 1 Cross-sectional comparison of caudate nucleus volume in antipsychotic naive first episode psychosis patients vs. healthy controls.
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Basal ganglia
Summary of evidence Moderate to low quality evidence (direct, unable to fully assess precision or consistency – data appears inconsistent) suggests bilateral caudate nucleus is significantly reduced in drug naive first episode psychosis patients compared to healthy controls.
Bilateral caudate nucleus volume
7 studies, N = 212
4 of 7 studies reported consistently reduced volume in bilateral caudate nucleus in patients.
3 of 7 studies reported no significant difference in caudate nucleus volume, although 2 of the 3 had
methodological limitations.
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Comparison 2 Cross-sectional comparison of medicated first episode psychosis patients (maximum 12 week treatment with first or second generation antipsychotics) compared to healthy controls.
Summary of evidence Moderate quality evidence (large sample size, direct, unable to fully assess precision or consistency – data appears consistent) suggests no significant difference in bilateral caudate volume in medicated first episode psychosis patients compared to healthy controls.
Bilateral caudate nucleus volume
4 studies, N = 428
4 of 4 studies reported no significant difference in bilateral caudate nucleus volume.
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Comparison 3 Longitudinal comparison of medicated first episode psychosis patients compared to healthy controls, measured at several varying time points.
Summary of evidence Moderate quality evidence (large sample size, direct, unable to fully assess precision or consistency – data appears consistent)
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Basal ganglia
suggests no significant difference in bilateral caudate volume over time in medicated first episode psychosis patients compared to healthy controls.
Bilateral caudate nucleus volume
6 studies, N = 548
6 of 6 studies reported no significant difference in overall bilateral caudate nucleus volume.
Consistency in results No measure of consistency is reported.
Precision in results No confidence intervals are provided.
Directness of results Direct
Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET
Meta-analysis of regional brain volumes in schizophrenia
American Journal of Psychiatry 2000; 157(1): 16-25
View review abstract online
Comparison Brain volume in people with schizophrenia vs. healthy controls.
Summary of evidence High quality evidence (large sample size, consistent, precise, direct) suggests increased right caudate, right putamen, and globus pallidus volume in people with schizophrenia compared to healthy controls.
Basal ganglia volume
Left caudate
No effect – average volume of schizophrenia caudate 101% of control volume, 95%CI 97% to 106%;
10 studies, N = 565, d = 0.06, no CIs reported, p = 0.01
Right caudate
Small effect size, average volume of schizophrenia caudate 99% of control volume, 95%CI 95% to 103%;
10 studies, N = 565, d = -0.06, no CIs reported, p = 0.02
Left putamen
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No effect, average volume of schizophrenia putamen 104% of control volume, 95%CI 99% to 110%;
7 studies, N = 255, d = 0.21, no CIs reported, p = 0.14
Right putamen
Small effect size – average volume of schizophrenia putamen 104% of control volume, 95%CI 97% to 110%;
7 studies, N = 255, d = 0.24, no CIs reported, p < 0.01
Left globus pallidus
Large effect size – average volume of schizophrenia globus pallidus 118% of control volume, 95%CI 110% to 126%;
2 studies, N = 84, d = 1.06, no CIs reported, p = 0.03
Right globus pallidus
Large effect size – average volume of schizophrenia globus pallidus 121% of control volume, 95%CI 109% to 135%;
2 studies, N = 84, d = 1.34, no CIs reported, p = 0.03
Consistency in results Consistent
Precision in results Precise (95%CIs do not exceed 10% in either direction) for all except Globus pallidus.
Directness of results Direct
Explanation of acronyms
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ALE = Activation Likelihood Estimate for Gaussian smoothed foci, CI = Confidence Interval, COS =
child-onset schizophrenia, d = Cohen’s d and g = Hedges’ g = standardized mean differences (see
below for interpretation of effect sizes), FDR = False Discovery Rate correction for multiple
comparisons, FWHM = full width at half maximum, applied as a smoothing kernel, fMRI =
Functional Magnetic Resonance Imaging, 1H-MRS = Proton Magnetic Resonance Spectroscopy,
MRI = magnetic resonance imaging, MNI = Montreal Neurological Institute system for stereotactic
space, N = number of participants, NAA = N-acetylaspartate amino acid, p = statistical probability
of obtaining that result (p < 0.05 generally regarded as significant), PET = Positron Emission
Tomography
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Explanation of technical terms
* Bias has the potential to affect reviews of
both RCT and observational studies. Forms of
bias include; reporting bias – selective
reporting of results, publication bias - trials
that are not formally published tend to show
less effect than published trials, further if
there are statistically significant differences
between groups in a trial, these trial results
tend to get published before those of trials
without significant differences; language bias
– only including English language reports;
funding bias - source of funding for the
primary research with selective reporting of
results within primary studies; outcome
variable selection bias; database bias -
including reports from some databases and
not others; citation bias - preferential citation
of authors. Trials can also be subject to bias
when evaluators are not blind to treatment
condition and selection bias of participants if
trial samples are small20.
† Different effect measures are reported by
different reviews.
ALE analysis (Anatomical Likelihood
Estimate) refers to a voxel-based meta-
analytic technique for structural imaging in
which each point of statistically significant
structural difference is spatially smoothed into
Gaussian distribution space, and summed to
create a statistical map estimating the
likelihood of difference in each voxel, as
determined by the entire set of included
studies. Incorporated with the Genome Scan
Meta-analysis (GSMA), the meta-analysis of
coordinates from multiple studies can be
weighted for sample size to create a random
effect analysis. The ALE statistic (if reported)
represents the probability of a group
difference occurring at each voxel included in
the analysis.
Fractional similarity network analysis refers to
a network analysis technique in which
secondary networks are identified within the
larger framework of activity, creating a matrix
for regional co-activity.
Weighted mean difference scores refer to
mean differences between treatment and
comparison groups after treatment (or
occasionally pre to post treatment) and in a
randomised trial there is an assumption that
both groups are comparable on this measure
prior to treatment. Standardised mean
differences are divided by the pooled
standard deviation (or the standard deviation
of one group when groups are homogenous)
which allows results from different scales to
be combined and compared. Each study’s
mean difference is then given a weighting
depending on the size of the sample and the
variability in the data. 0.2 represents a small
effect, 0.5 a medium effect, and 0.8 and over
represents a large effect20.
Odds ratio (OR) or relative risk (RR) refers to
the probability of a reduction (< 1) or an
increase (> 1) in a particular outcome in a
treatment group, or a group exposed to a risk
factor, relative to the comparison group. For
example, a RR of 0.75 translates to a
reduction in risk of an outcome of 25%
relative to those not receiving the treatment or
not exposed to the risk factor. Conversely, a
RR of 1.25 translates to an increased risk of
25% relative to those not receiving treatment
or not having been exposed to a risk factor. A
RR or OR of 1.00 means there is no
difference between groups. A medium effect
is considered if RR > 2 or < 0.5 and a large
effect if RR > 5 or < 0.221. lnOR stands for
logarithmic OR where a lnOR of 0 shows no
difference between groups. Hazard ratios
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measure the effect of an explanatory variable
on the hazard or risk of an event.
Correlation coefficients (eg, r) indicate the
strength of association or relationship
between variables. They are an indication of
prediction, but do not confirm causality due to
possible and often unforseen confounding
variables. An r of 0.10 represents a weak
association, 0.25 a medium association and
0.40 and over represents a strong
association. Unstandardised (b) regression
coefficients indicate the average change in
the dependent variable associated with a 1
unit change in the independent variable,
statistically controlling for the other
independent variables. Standardised
regression coefficients represent the change
being in units of standard deviations to allow
comparison across different scales.Reliability
and validity refers to how accurate the
instrument is. Sensitivity is the proportion of
actual positives which are correctly identified
(100% sensitivity = correct identification of all
actual positives) and specificity is the
proportion of negatives which are correctly
identified (100% specificity = not identifying
anyone as positive if they are truly not).
‡ Inconsistency refers to differing estimates
of treatment effect across studies (i.e.
heterogeneity or variability in results) that
is not explained by subgroup analyses and
therefore reduces confidence in the effect
estimate. I² is the percentage of the variability
in effect estimates that is due to heterogeneity
rather than sampling error (chance) - 0% to
40%: heterogeneity might not be important,
30% to 60%: may represent moderate
heterogeneity, 50% to 90%: may represent
substantial heterogeneity and 75% to 100%:
considerable heterogeneity. I² can be
calculated from Q (chi-square) for the test of
heterogeneity with the following formula;
§ Imprecision refers to wide confidence
intervals indicating a lack of confidence in the
effect estimate. Based on GRADE
recommendations, a result for continuous
data (standardised mean differences, not
weighted mean differences) is considered
imprecise if the upper or lower confidence
limit crosses an effect size of 0.5 in either
direction, and for binary and correlation data,
an effect size of 0.25. GRADE also
recommends downgrading the evidence when
sample size is smaller than 300 (for binary
data) and 400 (for continuous data), although
for some topics, this criteria should be
relaxed22.
║ Indirectness of comparison occurs when a
comparison of intervention A versus B is not
available but A was compared with C and B
was compared with C, which allows
indirectcomparisons of the magnitude of
effect of A versus B. Indirectness of
population, comparator and or outcome can
also occur when the available evidence
regarding a particular population, intervention,
comparator, or outcome is not available so is
inferred from available evidence. These
inferred treatment effect sizes are of lower
quality than those gained from head-to-head
comparisons of A and B.
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Basal ganglia
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