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Gray matter abnormalities in opioid-dependent patients: A neuroimaging
meta-analysis
Scott C. Wollman, MS
a
, Omar M. Alhassoon, PhD
a,b
, Matthew G. Hall, MS
a
, Mark J. Stern, MA
a
, Eric J. Connors,
MA
a
, Christine L. Kimmel, MA
a
, Kenneth E. Allen, PhD
a
, Rick A. Stephan, PhD
a
, and Joaquim Radua, MD, BStat,
PhD
c,d,e
a
California School of Professional Psychology, San Diego, CA, USA;
b
Department of Psychiatry, University of California, San Diego, CA, USA;
c
FIDMAG Germanes Hospitalàries –CIBERSAM, Barcelona, Spain;
d
Institute of Psychiatry, Psychology and Neuroscience, King’s College
London, London, UK;
e
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
ABSTRACT
Background: Prior research utilizing whole-brain neuroimaging techniques has identified structural
differences in graymatter in opioid-dependent individuals. However, the results have been inconsistent.
Objectives: The current study meta-analytically examines the neuroimaging findings of studies published
before 2016 comparing opioid-dependent individuals to drug-naïve controls. Method: Exhaustive search
of five databases yielded 12 studies that met inclusion criteria. Anisotropic Effect-Size Seed-Based d
Mapping (AES-SDM) was used to analyze the data extracted by three independent researchers. Voxel-
based AES-SDM distinguishes increases and decreases in brain matter significant at the whole-brain
level. Results: AES-SDM identified the fronto-temporal region, bilaterally, as being the primary site of gray
matter deficits associated with opioid use. Moderator analysis revealed that length of opioid use was
negatively associated with gray matter in the left cerebellar vermis and the right Rolandic operculum,
including the insula. Meta-regression revealed no remaining significant areas of gray matter reductions,
except in the precuneus, following longer abstinence from opioids. Conclusions: Opioid-dependent
individuals had significantly less gray matter in several regions that play a key role in cognitive and
affective processing. The findings provide evidence that opioid dependence may result in the break-
down of two distinct yet highly overlapping structural and functional systems. These are the fronto-
cerebellar system that might be more responsible for impulsivity, compulsive behaviors, and affective
disturbances and the fronto-insular system that might account more for the cognitive and decision-
making impairments.
ARTICLE HISTORY
Received 28 June 2016
Revised 11 September 2016
Accepted 1 October 2016
KEYWORDS
Neuroimaging; meta-
analysis; opioid dependence;
heroin; insula; seed-based d
mapping; cerebellum;
frontal lobe
Opioids, which include both synthetic and non-syn-
thetic drugs that bind to the opioid receptors, are
highly addictive substances typically abused for their
euphorgenic and analgesic effects. One of the most
commonly abused opioids is heroin. According to the
National Institute on Drug Abuse, approximately 23%
of first-time heroin users become dependent (1).
Opioid dependence is associated with negative conse-
quences for both the individual and society. In 2011,
the Centers for Disease Control estimated over 4000
heroin-related deaths resulting from overdose, reveal-
ing a striking 47% increase from the previous year (2).
In addition to increasing the risk of overdose, repeated
opioid use causes organ damage, disrupts normal blood
pressure, and is correlated with poor health-care out-
comes (2). These harmful effects have become the focus
of national attention because, in the last two decades,
use of these drugs has increased significantly; as a
result, an epidemic of significant proportion has
emerged affecting different segments of society (3,4).
There is evidence that heroin dependence is asso-
ciated with structural changes in the brain (5–7). A
recent neuroimaging meta-analysis demonstrated that
heroin-dependent individuals have significantly com-
promised white matter integrity (8). Extensive reduc-
tions in fractional anisotropy (FA) were observed
bilaterally and included lateral and longitudinal tracts
such as the cingulum, superior longitudinal fasciculus,
and corpus callosum. The authors postulated that her-
oin dependence disrupts circuitry involved in cognitive
and behavioral processing. These disruptions result in
deficits in behavioral inhibition, decision-making abil-
ity, and environmental monitoring (9), which rely lar-
gely on normal insular as well as orbital and inferior
frontal gyri functioning (10,11). Wollman and collea-
gues postulated that white matter injury might lead to
CONTACT Omar M. Alhassoon, PhD oalhassoon@ucsd.edu California School of Professional Psychology, Clinical Psychology PhD Program, 10455
Pomerado Road, San Diego, CA 92131, USA
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/iada
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE
http://dx.doi.org/10.1080/00952990.2016.1245312
© 2016 Taylor & Francis
overall gray matter changes as a result of Wallerian
degeneration (8). Further, chronic opioid use has been
shown to change gray matter rapidly (12), with possible
cell death occurring from persistent hypoxia as a result
of hypoperfusion (13). Taken together, opioid-depen-
dent individuals may have extensive gray matter
changes compared to controls. However, it remains to
be seen whether the specific gray matter changes
observed with opioid dependence in primary studies
are reproducible when these studies are combined
meta-analytically.
Whole-brain neuroimaging techniques have identi-
fied specific structural abnormalities in gray matter
among heroin-dependent individuals, including both
atrophy and hypertrophy (6,14,15). The frontal lobes
appear to be a prominent site for gray matter damage
from heroin, with numerous studies showing an effect
that is correlated with length of use (14–16).
Gray matter deficits have also been identified in the
temporal and parietal lobes as well as multi-specialized
association areas. Specifically, less gray matter in heroin
dependence has been demonstrated bilaterally in the
insula along with lateralized reductions in the right
fusiform gyrus (14,15,17). In the parietal lobes, gray
matter reductions have been found in the inferior par-
ietal lobule and cuneus, as well as areas including the
parieto-occipital junction and precuneus (14,17).
Research has also shown an impact on gray matter in
the cerebellum, with both deficits and excesses in cer-
ebellar gray matter (18).
It is plausible that abstinence from opioids allows for
structural recovery in both gray and white matter (16).
In their sample of 20 heroin users, Wang and colleagues
examined gray matter densities at 3 days post heroin
abstinence and then again at 30 days of abstinence. At
30 days of abstinence, the authors did not detect a pre-
viously observed significant difference in gray matter
density in one area of the superior frontal gyrus, suggest-
ing gray matter atrophy may be reversible in as little as 1
month. Similarly, Wang and colleagues examined gray
matter density in 30 long-term abstinent heroin addicts
with an average of 14 years of prior heroin abuse (19).
Their sample had been abstinent from heroin without
drug substitution therapy for an average of 4.5 years.
Significant gray matter atrophy was only observed in a
posterior region and did not involve other frequently
observed areas such as the frontal and insular cortices.
These results are in contrast to Younger and colleagues,
who demonstrated that opioid-induced gray matter
changes were persistent following approximately 4
months of abstinence (12).
Anisotropic Effect-Size Seed-Based dMapping (AES-
SDM, formerly Effect Size-Signed Differential Mapping),
a new meta-analytic software, provides an updated
method for quantitatively analyzing neuroimaging data
that utilize a whole-brain approach. Peak coordinates
representing both positive and negative changes in gray
matter are overlaid onto a gray matter template signifi-
cantly increasing the accuracy and the ability to detect
true regional differences between groups (20). To explore
potential sources of heterogeneity such as duration of
opioid use and abstinence, AES-SDM also utilizes random
effects general linear modeling for meta-regression ana-
lyses (20). AES-SDM and Signed-Differential Mapping
(SDM) have previously been shown to be effective tools
for investigating structural changes in substance depen-
dence (8,21). The aim of this study is to apply AES-SDM
to structural neuroimaging research that examines voxel-
based morphometry (VBM) changes in opioid users and
provides the first systematic and quantitative review of
gray matter changes associated with opioid use.
The gray matter deficits seen in opioid dependence
appear to be widespread. Opioid receptors are abun-
dant throughout the brain; however, research has high-
lighted specialized opioidergic circuitry (22) with
higher densities of opioid receptors in comparison to
the rest of the brain (23). These regions include cortical
and subcortical gray matter structures involved in both
cognitive and emotional functioning. Following an
acute dose of morphine, functional Magnetic
Resonance Imaging demonstrated that the most signif-
icant activation is localized to highly dense mu opioid
receptor areas such as the cingulate, middle and infer-
ior frontal gyri, insular cortex, precuneus, cerebellum,
middle and superior temporal gyri, caudate, and palla-
dium (23). Further, it is postulated that regions rich
with opioid receptors are susceptible to injury from
opioid toxicity (24). For example, research has shown
that street heroin causes cell death through disrupting
mitochondrial functioning, independent of both gluta-
matergic excitotoxicity or oxidative stress (25). The
majority of VBM neuroimaging studies comparing
opioid-dependent individuals to controls identify cor-
tical regions as most associated with gray matter loss.
To date, there has only been one whole-brain study that
identified gray matter abnormalities in subcortical
structures (26). This may suggest that medial gray
matter structures react to the effects of opioids in a
different way compared to cortical areas.
Overall, there is evidence that opioid-dependent
individuals may have disrupted cognitive (17–19,27)
and emotional processing (18,28–33) because of possi-
ble organic brain changes stemming from heroin toxi-
city. Given the cognitive and affective disturbances, we
speculated that the deficits in opioid-dependent indivi-
duals could represent a breakdown of separate neural
2S. C. WOLLMAN ET AL.
systems. It is hypothesized that opioid-dependent indi-
viduals will exhibit less gray matter in cortical struc-
tures such as the fronto-temporal regions as well as the
cerebellum. Further, since previous studies have shown
a cumulative effect of opioids on gray matter loss, we
expect that longer durations of opioid use will be asso-
ciated with greater gray matter reductions. It is also
expected that with abstinence, gray matter levels may
return to normal.
Method
Data source
This study followed the recommendations set forth by
Meta-Analysis Reporting Standards (34), as well as the
SDM procedures (http://www.sdmproject.com) for con-
ducting a neuroimaging-based meta-analysis as outlined
by Radua and colleagues (20,35–37). Two independent
investigators executed a systematic and comprehensive
search of five databases including PubMed, PsycINFO,
Web of Science, Proquest Dissertation and Thesis data-
base, and Google Scholar. For each database, specific key-
words were combined with controlled vocabulary to
retrieve articles. In addition, reference lists of relevant
articles were also manually searched to identify other
studies. When possible, truncation commands were
paired with Boolean searches to increase the breadth of
the search. Unique terms such as “voxel,” “VBM,” “mor-
phometry,” “whole-brain,” “gray matter,” “opioid,” “her-
oin,” “opium,”or “methadone”were truncated and
combined with other terms. In order to ensure the com-
prehensiveness of the search, an expert database
education specialist at PsycINFO (American
Psychological Association) was also consulted for appro-
priate index terms and fields to search. Following the
initial searches of each database, the results of the two
independent searchers were combined, duplicates were
removed, and the final set of abstracts was sorted by two
other independent researchers into (1) Core (those that
had enough information in abstract and title to indicate
that they would likely be included), (2) Unknown (those
that required the full-text version to decide whether or not
to include), (3) Irrelevant (those that were clearly unre-
lated based on title and abstract), and (4) Review articles
(articles that may be used to mine for more relevant
primary studies). Any disagreement about sorting or
inclusion was resolved by consensus between the two
researchers. The contact author was consulted in cases
where there was irreconcilable difference in opinion in
applying the inclusion/exclusion criteria (Figure 1).
Inclusion/exclusion of studies
Studies were included if they met the following criteria:
(1)opioid users were formally diagnosed and met cri-
teria for opioid dependence, (2) the studies compared
opioid-dependent individuals to drug-naïve controls, (3)
they reported stereotactic coordinates for whole-brain
comparisons of gray matter volume, and (4) they used
whole-brain voxel-wise structural magnetic resonance
imaging analysis. Studies were excluded if (1) they solely
used ROI data collection or analysis, (2) their control
group had current or past substance dependence, (3)
participants had comorbid neurological disease (e.g.,
Hepatitis C, HIV, traumatic brain injury), (4)
Searcher 1:
1007
citations
Searcher 2:
691
citations
Unknown: 2
citations
Excluded from further
analysis: 531 citations
Irrelevant: 515
citations
543 Unique citations
Reviews: 14
citations
Included for Coding: 12
citations
Core: 12
citations
Consensus; 1 author contacted
Figure 1. Flowchart of articles searched, sorted, and coded.
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 3
participants in the opioid group were not currently
dependent on or abusing another substance (except
nicotine), (5) participants in either group were diag-
nosed with any major psychiatric illnesses, or (6) the
studies reported only small volume corrections. Three
independent researchers performed coordinate extrac-
tion separately, and any discrepancy was examined and
corrected by consensus.
Statistical analyses and data preparation
Data preparation and individual analyses have pre-
viously been discussed in detail and will only be
mentioned briefly here (8,21). This meta-analysis
was conducted using Anisotropic Seed-Based d
Mapping AES-SDM v4.31 software (http://www.
sdmproject.com). First, peak coordinates and effect
sizes were used to recreate a map of the effect size
of the gray matter abnormality in each study. Full
effect sizes were assigned to peaks (positive for gray
matter increases and negative for decreases), and
decreasing effect sizes were assigned to voxels less
correlated with the peak (20). Second, a classic
meta-analysis was separately conducted in each
voxel, accounting for sample size, intra-study var-
iance, and between-study heterogeneity. AES-SDM
also assesses for any potential heterogeneity asso-
ciated with the main coordinates. Finally, type I
error was controlled with the following thresholds:
voxel p< .005 (p< .001 for moderator analyses),
cluster extent ≥10, and peak SDM z≥1.76 (8,21).
Jackknife sensitivity analyses were used to assess
for robustness and replicability of the findings (35–
37). Meta-regression analyses were conducted for
length of abstinence, duration of opioid use, age,
and education. Due to predominantly male partici-
pants, a gender analysis was not possible. In order to
assess quality of study, we created an assessment tool
that evaluated the following criteria: (1) group
matching, (2) method of substance use diagnosis,
(3) method used to collect substance use history, (4)
use of toxicology screening, (5) neuroimaging sample
size, (6) sampling method, (7) group matching on
drug use levels (e.g., smoking), and (8) the use of
gray matter covariates. Each of these criteria was
scored independently by two researchers who
assigned a numerical value that ranged from 0 to 2
to indicate quality. The sum was then used in a meta-
regression to examine the moderating effect of qual-
ity. Finally, publication bias was addressed through
the inclusion of gray literature, as well as visual
inspection of funnel plots.
Results
Demographic and clinical characteristics
Thirteen studies initially met inclusion criteria. Author
contact was initiated in order to obtain relevant data
(i.e., maps, coordinates, tor zscores) for 1 of the 13
articles; however, the author was unreachable and
therefore, the study was excluded. Twelve opioid stu-
dies were subsequently eligible for analysis (6,14–
19,26,27,38–40). Included opioid studies yielded 292
opioid-dependent subjects and 286 opioid-naïve con-
trols. Heroin was the most common form of opioid
across studies. Demographic and clinical characteristics
for each study are presented in Table 1. Neuroimaging
characteristics for each study can be found in Table 2.
Regional gray matter alterations
Overall opioid effects
Voxel-based AES-SDM meta-analysis identified the
fronto-temporal region, bilaterally, as being the pri-
mary site of gray matter deficits associated with opioid
use (see Figure 2). Specific regions that exhibited sig-
nificantly less gray matter were the: (1) right Heschl’s
gyrus with atrophy extending into the right insula and
superior temporal gyrus, (2) right gyrus rectus with
extension into bilateral orbital frontal regions, (3)
right middle frontal gyrus, and (4) left temporal pole
with extensions to the bilateral inferior frontal gyri.
Peak coordinates and cluster breakdowns are shown
in Table 3. This analysis did not identify significant
regions of increased gray matter associated with opioid
dependence.
Sensitivity analysis and publication bias
Whole-brain jackknife sensitivity analysis of the opioid
findings revealed that the main results were highly
robust. Heschl’s gyrus and associated regions were iden-
tified in all 12 study sets. The gyrus rectus and its asso-
ciated regions were identified in 11 of the 12. The right
middle frontal gyrus, which included the right inferior
frontal gyrus, also remained significant in 11 out of the
12 study sets. The left temporal pole, which extended to
the left inferior frontal gyrus, was significant in 10 of the
12 combinations of studies. None of the effect size differ-
ences of the peak coordinates revealed significant hetero-
geneity. Quality of study did not impact the results as
indicated by moderator analyses. Finally, visual inspec-
tion of the funnel plots did not reveal any publication
bias (see online supplementary material).
4S. C. WOLLMAN ET AL.
Table 1. Demographic and clinical characteristics of opioid-dependent individuals and healthy controls.
Drug Included study
Opioid
users (n)
Healthy
controls (n)
Age opioid
users
Age healthy
controls
Opioid users
education
Healthy controls
education
Age first
opioid use
Duration of
use (years)
Abstinence
(weeks)
Length of drug
therapy (weeks)
Receiving
drug therapy TOX SMK
Heroin Gardini and
Venneri (2012)
24 20 31.33 33.21 9.62 12.75 NA 11.29 <1 NA No UT NA
Heroin Li et al. (2008)* 13 12 32.17 32.17 NA NA NA NA <2 NA NA NA NA
Heroin Lin et al. (2012) 27 23 36.78 34.04 10.33 15.36 22.9 13.9 0 144.9 Yes UT Yes
Heroin Liu et al. (2009) 15 15 30.47 30.53 10.13 11.73 NA 6.21 0 <1 Yes UT No
Opioid Lyoo et al. (2006) 63 46 38.4 38.4 11.4 15.2 NA NA NA NA Yes NA NA
Codeine Qiu et al. (2014) 30 30 25.07 23.97 13.03 12.07 19.93 5.08 4 NA No UT Yes
Heroin Qiu et al. (2013) 24 24 35.67 35.38 10.79 11.21 NA 10.38 <1 NA No UT Yes
Opioid Reid et al. (2008) 9 21 NA NA NA NA NA NA 0 NA Yes NA NA
Heroin Wang et al. (2016) 30 30 40.7 38.9 9.7 11.6 NA 14.4 254.8 NA No UT No
Heroin Wang et al. (2012) 15 20 29.8 30.2 8.85 9.3 NA 4.35 <1, 4 NA No UT Yes
Heroin Yuan et al. (2010) 13 11 37.2 36.8 10.7 15.1 NA 7.46 0 NA Yes UT Yes
Heroin Yuan et al. (2009) 30 34 25 23.97 9.03 10.24 20.4 4.29 34.51 NA No UT NA
Note. n: Sample size; NA: not available in the primary study; *Gray literature; TOX: Toxicology screen method; UT: Urinalysis Test; SMK: differences in percent smokers between opioid group and controls.
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 5
Meta-regression
Duration of use
Meta-regression analysis revealed an inverse relation-
ship between duration of opioid use and gray matter in
the right Rolandic region as well as the left cerebellum
(see Figure 3). Specifically, longer duration of opioid
use was associated with greater gray matter loss in the
right Rolandic operculum (MNI coordinate 48, −20,16;
221 peak voxels; SDM z=−2.49, p~ .000) and left
cerebellum (MNI coordinate −2, −78, −38; 53 peak
voxels; SDM z=−2.49, p~ .000).
Abstinence
Meta-regression analysis on length of abstinence from
opioids revealed no remaining significant areas of gray
matter reductions in the frontal, temporal, and insular
regions. However, studies with longer abstinence
reported atrophy in the precuneus, bilaterally (MNI
Table 2. Neuroimaging characteristics from included studies.
Study
MRI imaging scanner
(T)
Kernel smoothening (FWHM)
(mm)
Software
package
Statistical
thresholding
Coordinates
extracted
Gardini and Venneri (2012) 3 12 SPM5 p< .05 1
Li et al. (2008)* 1.5 6 SPM5 p< .01 12
Lin et al. (2012) 3 8 SPM5 p< .05 10
Liu et al. (2009) 1.5 8 SPM2 p< .001; k> 200 4
Lyoo et al. (2006) 1.5 8 SPM99 p< .01; k> 100 13
Qiu et al. (2014) 1.5 12 SPM8 p< .05 1
Qiu et al. (2013) 1.5 12 SPM5 p< .05; k> 200 7
Reid et al. (2008) 1.5 N/A SPM2 p< .05 3
Wang et al. (2016) 3 8 SPM8 p< .05 1
Wang et al. (2012) 1.5 6 SPM2 p< .001 5
Yuan et al. (2010) 3 8 SPM5 p< .05 5
Yuan et al. (2009) 3 12 SPM2 p< .001; k> 300 11
Note: *: Gray Literature; T: Tesla; p: = p-value; MRI: magnetic resonance imaging; SPM: = statistical parametric imaging; mm: millimeter; FWHM: full width half
max; k: kernel; N/A: not available.
AB
CD
Figure 2. Regional areas of less gray matter in opioid-dependent individuals compared to controls. Note: A= Right Heschl’s Gyrus; B= Right
Gyrus Rectus; C= Right Middle Frontal Gyrus; D= Left Temporal Pole.
6S. C. WOLLMAN ET AL.
coordinate 2, −64, 20; 187 peak voxels; SDM z=−4.50,
p~ .000). See Figure 4.
Age and education
Meta-regression on age was found to be associated with
gray matter in the right insula (MNI coordinate 36, −16,
20; p~ .000) and left temporal pole (MNI coordinate −34,
16, −24; p~ .001). Education was not associated with gray
matter.
Subgroup analyses
Drug substitution effect
Subgroup analysis examining the effect of drug substi-
tution therapy (methadone) on gray matter, while
Table 3. Gray matter reductions in opioid-dependent individuals as compared to controls.
Region MNI SDM zCluster breakdown Voxels p-Value Studies contributing to region
R- Heschl Gyrus 38, −26, 16 −2.31 R –rolandic operculum 349 0.0000 12/12
R–superior temporal gyrus 138
R–insula 113
R-Gyrus Rectus 2, 46, −18 −2.14 L –left superior frontal gyrus, medial orbital 52 0.0002 11/12
L–gyrus rectus 38
R–superior frontal gyrus, medial orbital 32
R-Middle Frontal Gyrus 46, 48, −2−2.02 R –inferior frontal gyrus 39 0.0007 12/12
L–superior temporal gyrus 48L-Temporal Pole −34, 14, −20 −2.01 0.0007 10/12
L–inferior frontal gyrus 22
Note. MNI: Montreal Neurologic Institute; R: right hemisphere; L: left hemisphere; SDM zSeed-Based dMapping zvalue; p: p-value.
Figure 3. Flowchart of articles searched, sorted, and coded.
Figure 4. Less gray matter bilaterally in the precuneus associated with longer abstinence from opioids when compared to healthy controls.
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 7
controlling for abstinence in the non-treatment group,
revealed that opioid-dependent individuals receiving
drug substitution therapy had more gray matter in the
right precuneus (MNI coordinate 2, −62, 20; 171 peak
voxels; SDM z= 1.00, p~ .000).
Heroin versus other opioids
Subgroup analysis between articles of heroin-dependent
individuals and other opioid-dependent individuals did
not have significant differences.
Discussion
To our knowledge, this is the first voxel-wise meta-
analysis utilizing AES-SDM to quantitatively examine
the long-term effects of opioid dependence on gray
matter structures. Compared to healthy controls,
opioid-dependent individuals have significant reduc-
tions in gray matter. Specifically, less gray matter was
observed in bilateral fronto-temporal regions. These
regions included right Heschl’s gyrus, with atrophy
extending into the right insula and superior temporal
gyrus. Significantly less gray matter was also observed
in the right gyrus rectus with extension into the orbital
regions bilaterally. Lastly, there were significant differ-
ences in the right middle frontal gyrus and the left
temporal pole, with atrophy extending to the inferior
frontal gyri bilaterally. Meta-regression analyses indi-
cated that gray matter changes were negatively asso-
ciated with duration of opioid use, while positively
associated with length of abstinence. Jackknife sensitiv-
ity analysis indicated that these results are highly
robust.
Our finding that opioid-dependent individuals
have atrophy in the right insula is in line with prior
opioid research as well as other substances (18,21,38).
The insula has numerous efferent and afferent con-
nections from posterior, anterior, and medial struc-
tures (38). It directly projects to the brain reward
system via the ventral striatum, an area highly asso-
ciated with problematic behaviors seen in addiction
(38). The right insula projects to several frontal gyri
through fronto-insular tracts. Specifically, direct con-
nections to the orbital, middle, and inferior frontal
gyri have been mapped (41). Primary studies of sub-
stance abuse have reported inconsistent findings
involving structural damage in frontal/posterior
(16,19) and medial/lateral regions (26). However,
since the insula acts as a connecting hub to most of
the regions affected by substance abuse, it tends to be
the area most often identified as affected in neuroi-
maging meta-analyses. The insular cortex serves an
integral role in executive functions, as well as
processing motivational states (9,11). Specifically, it
is involved in error detection (42), cognitive media-
tion (43), and the integration of environmental,
internal, and social information to regulate homeos-
tasis (44). The insula regulates bodily states by first
processing internal and environmental cues to inform
goal-directed behavior. Decision-making is thus
guided by subjective responses to somatic and exter-
nal cues (45). Disruption to this circuitry could
impair the ability to properly weigh risk versus
reward for behavior and could explain their propen-
sity to have more errors and poorer task monitoring
on neuropsychological testing and disrupted cogni-
tive control (46). Among substance users, these def-
icits could potentially lead to continuous problems
with relapse (45).
In addition to the insula findings, opioid-dependent
individuals demonstrated significantly less gray matter
in the right superior temporal gyrus. Gray matter
reductions in the superior temporal lobe have been
previously demonstrated in substance-dependent indi-
viduals (21). Lesions associated with this region can
result in neglect, as well as difficulty with visuospatial
ability (47). The superior temporal gyrus has also been
implicated in drug-related cuing and increased craving
response in substance-dependent individuals (48).
Disrupted gray matter in this region may underlie
abnormally heightened responses, as measured by posi-
tron emission tomography, to drug-related imagery and
memories in opioid-dependent individuals (48).
This study also found significantly less gray matter
bilaterally in the orbitofrontal gyri and in the right middle
frontal gyrus. The orbitofrontal cortex has been associated
with affective decision-making ability as well as beha-
vioral and emotional regulation (49,50). Previous research
has shown that opioid-dependent individuals have signif-
icant deficits in performance on neuropsychological tasks
measuring affective decision-making as well as other tasks
of neurocognitive functioning (51–53), even following
periods of abstinence (54–56). Lower gray matter volumes
in this region could result in high-risk and low-reward
behaviors seen in substance-dependent individuals
(50,54,55). Our findings of less gray matter in the right
middle frontal gyrus are also consistent with previous
opioid research and were evident in studies included in
this analysis (17,40). This region plays an important role
in inhibitory control (57), and its dysfunction may be the
mechanism behind decreased inhibitory ability and high
levels of impulsivity among the opioid-dependent popu-
lation (58). Taken together, damage to the right middle
and orbital frontal gyri may result in potentially poorer
affective self-regulatory behaviors commonly seen in
opioid-dependent individuals (17,18,49,58,59).
8S. C. WOLLMAN ET AL.
Compared to controls, opioid-dependent individuals
were also found to have less gray matter in the left
temporal pole, with atrophy extending into the inferior
frontal gyri bilaterally.
Opioid-dependent individuals have been found to
have decreased verbal learning and memory ability (59),
which has been linked to left temporal regions.
Furthermore, we found less gray matter in the inferior
frontal gyri bilaterally. The left inferior frontal gyrus has
been demonstrated to aid in verbal self-monitoring, while
the right inferior frontal gyrus is involved in the integra-
tion of emotional and environmental information (60).
Disruption to this area, in addition to the orbitofrontal
region, could also result in poor affective decision-making
(54,56) in opioid-dependent individuals marked by the
inability to process and integrate environmental and emo-
tional cues in relation to the self (27,46). Opioid-depen-
dent individuals may incorrectly pursue immediate
reward despite future negative consequences (56,61).
Ultimately, poor learning could potentially lead to adverse
compulsive behaviors despite unfavorable outcomes seen
among opioid-dependent individuals (49,54,56,59).
Moderator analysis revealed that length of opioid use
was negatively associated with gray matter in the left
cerebellar vermis and the right rolandic operculum,
including the insula. That is, greater gray matter loss
is observed as duration of opioid use increases.
Disruption to the right insula has been extensively
documented in the different substance dependence lit-
erature (18,21,38). Further, the current study provides
evidence for a positive relationship between opioid use
and insular injury. Longer duration of opioid use was
also associated with significantly less gray matter in the
left cerebellar vermis. This finding is consistent with
previous finding of white matter changes in the cere-
bellum of opioid-dependent individuals (18,39).
The cerebellum has strong anterior projections. Lesions
to the cerebellum can result in higher order cognitive
deficits such as impulsivity and perseverative tendencies
as well as emotion dysregulation (62,63). The cerebellar
vermis also receives dopaminergic input from the ventral
tegmental area (18). It has been implicated in goal-directed
behavior and reward processing, with heightened sensitiv-
ity to adaptive changes over time (64). Cerebellar white
matter connectivity has also been associated with repetitive
behaviors such as those seen in autism (65). Further, stu-
dies have found cerebellar structural changes to be asso-
ciated with greater emotional disturbances including
depression (18,59). Thus, damage involving the cerebellum
and its anterior projections could increase depressive
symptomatology, as well as drug habit development that
may result in perseverative behavior such as chronic drug
consumption (64).
Our meta-regression findings also indicate possible
structural recovery. Specifically, with increasing length
of abstinence, only the precuneus bilaterally demon-
strated persistent significantly less gray matter in
opioid-dependent individuals. Interestingly, there were
no remaining significant gray matter differences in
frontal, temporal, and insular regions. Similar gray
matter recovery has been shown in stimulant-depen-
dent individuals (21). The precuneus has been shown to
have direct projections to the insula, middle, inferior,
and orbital frontal gyri, as well as connections to the
cerebellum (50). It has been demonstrated to be
involved in craving intensity (66), as well as undergoing
morphological changes both structurally and function-
ally as a result of substance dependence (67). The pre-
cuneus and cuneus are involved in many cognitive
functions including episodic memory, attention, and
visuospatial processing (68). This region is engaged
mainly at rest and is heavily involved in processing
self-reflection as well as self-awareness (69). The pre-
cuneus is also a very important structure of the default
mode network (DMN) (70), which has been found to
be impaired in heroin users (46). In their study, Ma and
colleagues (46) found hyperconnectivity within the
DMN to hippocampal areas. It is postulated that dis-
ruptions to the DMN could alter the ability to exert
attentional control over heightened craving and drug-
related memory processing (46). Disruptions to the
precuneus could potentially alter the ability to utilize
self-reflective processes and impair insight into deficits,
an ability diminished in addiction and other common
neuropsychiatric disorders (71). Since there is signifi-
cantly less gray matter in the precuneus bilaterally even
after years of abstinence, this regional abnormality
might be a preexisting structural weakness. Future
research should explore the role of the precuneus and
cuneus as premorbid structural markers of susceptibil-
ity to addiction.
Subgroup analyses were conducted to compare her-
oin-dependent to other opioid-dependent groups. In
addition, opioid-dependent individuals who were
undergoing drug-substitution therapy were compared
to ones who had reportedly never received this type of
treatment. This study did not identify any differences
among the different opioid-dependent groups. It is
possible that the non-heroin opioid group was too
heterogeneous and small that the effect was not
detectable. Future studies should examine such poten-
tial difference with larger samples. Examining the role
of drug substitution therapy revealed that groups
being treated with methadone had more gray matter
in the right precuneus than the non-methadone group.
Although methadone treatment has been shown to be
THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 9
associated with increased cellular level activity (72), as
well as improved neuropsychological functioning (73),
no study has identified gray matter increases asso-
ciated with methadone treatment that correlate with
positive functional outcomes. Indeed, recent research
suggests that methadone treatment exacerbates struc-
tural damage (74) as well as cognitive dysfunction
(75). Our finding of increased gray matter in the
precuneus following methadone treatment should be
interpreted with caution. Future studies may wish to
clarify the structural changes associated with metha-
done treatment in opioid-dependent individuals.
There are several limitations to be considered when
interpreting the findings of this meta-analysis. The major-
ity of participants included in our study were mainly
heroin-dependent males; therefore, our results should
only be generalized to that group. Additionally, age was
negatively associated with gray matter in the right insula
and left temporal pole and could potentially explain some
of the results. It is possible that older opioid-dependent
patients exhibit more gray matter loss in the main areas
affected by the drug compared to younger patients. A
recent study found that heroin users undergo accelerated
brain aging in both gray and white matter, which corre-
lated with poorer cognitive and behavioral outcomes (76).
Nicotine use is highly comorbid with substance depen-
dence and has been associated with changes in gray mat-
ter (77). Smoking is a potentially important confound in
our study, since many participants in the primary studies
smoked. However, it is important to note that a recent
VBM neuroimaging meta-analysis examining gray matter
deficits associated with chronic cigarette use did not
identify any overlapping areas found in this study (78).
Since this meta-analysis included only a small number of
studies, the results of the moderator analyses and meta-
regression analyses should be considered preliminary.
Implications for treatment and conclusion
Although both hemispheres appear to exhibit gray matter
loss, the right hemisphere might be more impacted by the
effects of opioids. This is an important finding for treat-
ment providers, because damage to the right hemisphere
is associated with impaired self-awareness and insight
into deficits (71). Treatment approaches may benefit
from including components that address insight (71).
Providers may also consider utilizing cognitive rehabilita-
tion techniques to address cognitive deficits, while psy-
chotherapeutic approaches could help address the
affective symptoms. Cognitive behavioral therapy techni-
ques have been shown to produce metabolic changes in
the insula that are associated with reductions in depres-
sive symptomology (79). Also, since the cerebellum plays
a major role in cognition and affect as well as long-term
habit formation, behavioral techniques such as extinction
may be valuable to treat perseverative behaviors asso-
ciated with drug use as well as craving (80).
Future primary studies should further examine the
involvement of the cerebellum, insula, and frontal
regions and explore the possibility that opioid depen-
dence may potentially be the result of two adversely
affected neural circuits with considerable functional
overlap. Each of these circuits might play a relatively
distinct role in the observed maladaptive consequences
of the drug. It is possible that the fronto-cerebellar
damage could be responsible for impulsivity, compul-
sive behaviors, and affective disturbances associated
with opioid dependence (62,63), while the insular and
frontal lobe findings may account for the observable
cognitive and decision-making impairments seen in
opioid-dependent individuals (9,45). Testing the rela-
tionship between structure and function should be con-
sidered high priority of future opioid-focused research.
Disclosure statement
None.
Funding
None.
ORCID
Omar M. Alhassoon http://orcid.org/0000-0003-0596-6085
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