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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]

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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

http://www.prisma-statement.org/

http://www.gradeworkinggroup.org/





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.


dopamine receptor occupancy in the

striatum of people with schizophrenia varies

according to treatment with first or second

generation antipsychotics.


no differences in D2/D3 receptor availability

in the substantia nigra of unmedicated

people with schizophrenia compared to

controls.





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;


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

http://schizophreniabulletin.oxfordjournals.org/content/early/2009/07/24/schbul.sbp073





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


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.


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


Comparison Grey matter volume in people with schizophrenia vs. healthy

http://ajp.psychiatryonline.org/cgi/content/abstract/appi.ajp.2008.07101562v1

http://linkinghub.elsevier.com/retrieve/pii/S0920996409006136





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.


Meta-analysis was performed using Activation Likelihood Estimate (ALE) analysis on Voxel-Based Morphometry MRI studies.

FWHM 7mm, FDR corrected at p <0.05


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




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


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.

http://www.ncbi.nlm.nih.gov/pubmed/17223194





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.




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


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.


Meta-analysis was performed using ALE analysis on Voxel-Based Morphometry MRI studies.

FWHM 12mm, FDR corrected at p < 0.05


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






Basal ganglia




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


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.


https://www.ncbi.nlm.nih.gov/pubmed/25029687





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


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.


12 studies, N unclear

Increased volume was observed in the caudate, putamen, and globus pallidus.




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


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

http://www3.interscience.wiley.com/journal/118844309/abstract?CRETRY=1&SRETRY=0

http://schizophreniabulletin.oxfordjournals.org/content/early/2009/09/16/schbul.sbp099.abstract





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.


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


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;


Left caudate: Talairach coordinates (0, 12, 4), cluster 360mm3, ALE 0.0276

Left caudate: Talairach coordinates (-12, 6, 0), cluster 264mm3, ALE 0.0095



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



Comparison Functional activation in first-degree relatives of people with schizophrenia vs. healthy controls.






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




Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC





Basal ganglia

Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia

Archives of General Psychiatry 2009; 66(8): 811-822


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.


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




Navari S, Dazzan P

Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.






Basal ganglia

Psychological Medicine 2009; 39(11): 1763-1777


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.


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.






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.


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


Comparison Progressive changes in grey matter volume in people with schizophrenia vs. healthy controls.

http://pubget.com/paper/21457946





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.


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


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


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.

http://www.ingentaconnect.com/content/ben/cpd/2009/00000015/00000022/art00002





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.



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





Basal ganglia

Neuropsychopharmacology 2005; 30(11): 1949-1962


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)



Caudate nucleus



Putamen



Striatum (caudate+putamen)

1 study considers NAA, N unclear


Consistency in results Inconsistent - significant heterogeneity reported, p < 0.0001.



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






Basal ganglia

and PET in vivo receptor imaging literature



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





Basal ganglia

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


Precision in results CIs not reported for all outcomes, precise for subgroup analyses 4

and 5.


Taylor H, Ricciardi A, Dazzan P

A review of caudate nucleus volume in first episode psychosis

Clinical Neuropsychiatry 2007; 4(5-6): 191-198


Comparison 1 Cross-sectional comparison of caudate nucleus volume in antipsychotic naive first episode psychosis patients vs. healthy controls.

http://www.clinicalneuropsychiatry.org/pdf/03%20taylor.pdf





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.




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.


4 studies, N = 428

4 of 4 studies reported no significant difference in bilateral caudate nucleus volume.




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)





Basal ganglia

suggests no significant difference in bilateral caudate volume over time in medicated first episode psychosis patients compared to healthy controls.


6 studies, N = 548

6 of 6 studies reported no significant difference in overall bilateral caudate nucleus volume.




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


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.


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

http://ajp.psychiatryonline.org/cgi/content/abstract/157/1/16





Basal ganglia

No effect, average volume of schizophrenia putamen 104% of control volume, 95%CI 99% to 110%;


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%;


Right globus pallidus

Large effect size – average volume of schizophrenia globus pallidus 121% of control volume, 95%CI 109% to 135%;


Consistency in results Consistent

Precision in results Precise (95%CIs do not exceed 10% in either direction) for all except Globus pallidus.


Explanation of acronyms





Basal ganglia

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





Basal ganglia

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





Basal ganglia

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.





Basal ganglia

References

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2. GRADEWorkingGroup. Grading quality of evidence and strength of recommendations. British Medical Journal. 2004; 328: 1490.

3. 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): 420-9.

4. 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): 774-81.

5. Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E. The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. American Journal of Psychiatry. 2008; 165(8): 1015-23.

6. 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): 465-84.

7. 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): 140-7.

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9. 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. Neuropsychopharmacology. 2005; 30(11): 1949-62.

10. Taylor H, Ricciardi A, Dazzan P. A review of caudate nucleus volume in first episode psychosis. Clinical Neuropsychiatry. 2007; 4(5-6): 191-8.

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13. MacDonald AW, 3rd, 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): 1142-62.

14. 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 and PET in vivo receptor imaging literature. Schizophrenia Bulletin. 2009; 35(4): 789-97.

15. Ellison-Wright I, Bullmore E. Anatomy of bipolar disorder and schizophrenia: A meta-analysis. Schizophrenia Research. 2010; 117: 1-12.

16. Chan RCK, Di X, McAlonan GM, Gong Q-y. Brain Anatomical Abnormalities in High-Risk Individuals, First-Episode, and Chronic Schizophrenia: An Activation Likelihood Estimation Meta-analysis of Illness Progression. Schizophrenia Bulletin. 2009.

17. 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. 2009.

18. Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, Radue EW, McGuire PK, Riecher-Rossler A, Borgwardt SJ. The Effects of Antipsychotics on the Brain: What Have We Learnt





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from Structural Imaging of Schizophrenia? - A Systematic Review. Current Pharmaceutical Design. 2009; 15(22): 2535-49.

19. 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.

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22. GRADEpro. [Computer program]. Jan Brozek, Andrew Oxman, Holger Schünemann. Version 32 for Windows. 2008.

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