Reduced Frontal Lobe Activity in Subjects With High Impulsivity and Alcoholism

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DOI: 10.1111/j.1530-0277.2006.00277.x · Source: PubMed
Abstract
Impulsivity is an important characteristic of many psychiatric disorders, including substance-related disorders. These disinhibitory disorders have a similar underlying genetic diathesis, with each disorder representing a different expression of the same underlying genetic liability. This study assessed whether there is a relationship between impulsivity and alcohol dependence, and their correlations with P3 (P300) amplitude, a proposed endophenotype of alcoholism. Healthy control subjects (n=58) and subjects with DSM-IV diagnosis of alcohol dependence (n=57) were assessed with a visual oddball task. Event-Related Potentials (ERPs) were recorded from 61 scalp electrodes and P3 amplitudes measured. Barratt Impulsiveness Scale (BIS), version 11, was used to evaluate impulsivity. Source localization of P3 was computed using low-resolution brain electromagnetic tomography (LORETA). Alcoholic subjects manifested reductions in target P3 amplitudes (p<0.0001). Using LORETA, significantly reduced activation was mapped in the cingulate, medial, and superior frontal regions in alcoholic subjects and highly impulsive subjects. Alcoholic subjects had significantly higher scores on the BIS (p<0.0001) than nonalcoholic individuals. There were significant negative correlations between total scores on BIS and P3 amplitude (r=-0.274, p=0.003, on Pz; r=-0.250, p=0.007, on Cz). Our results demonstrate a strong frontal focus of reduced activation during processing of visual targets in alcoholic subjects and individuals with higher impulsivity. The findings suggest that impulsivity may be an important factor that underlies the pathogenesis of alcohol dependence. Studies are underway to examine the relationship between impulsivity and ERPs in offspring of alcoholic subjects, and to identify genes associated with the underlying predisposition involved in disinhibitory disorders.
Reduced Frontal Lobe Activity in Subjects With High
Impulsivity and Alcoholism
Andrew C. H. Chen, Bernice Porjesz, Madhavi Rangaswamy, Chella Kamarajan, Yongqiang
Tang, Kevin A. Jones, David B. Chorlian, Arthur T. Stimus, and Henri Begleiter
Objective: Impulsivity is an important characteristic of many psychiatric disorders, including
substance-related disorders. These disinhibitory disorders have a similar underlying genetic diathesis,
with each disorder representing a different expression of the same underlying genetic liability. This
study assessed whether there is a relationship between impulsivity and alcohol dependence, and their
correlations with P3 (P300) amplitude, a proposed endophenotype of alcoholism.
Methods: Healthy control subjects (n 5 58) and subjects with DSM-IV diagnosis of alcohol
dependence (n 5 57) were assessed with a visual oddball task. Event-Related Potentials (ERPs) were
recorded from 61 scalp electrodes and P3 amplitudes measured. Barratt Impulsiveness Scale (BIS),
version 11, was used to evaluate impulsivity. Source localization of P3 was computed using low-reso-
lution brain electromagnetic tomography (LORETA).
Results: Alcoholic subjects manifested reductions in target P3 amplitudes (po0.0001). Using
LORETA, significantly reduced activation was mapped in the cingulate, medial, and superior frontal
regions in alcoholic subjects and highly impulsive subjects. Alcoholic subjects had significantly higher
scores on the BIS (po0.0001) than nonalcoholic individuals. There were significant negative correl-
ations between total scores on BIS and P3 amplitude (r 5 0.274, p 5 0.003, on Pz; r 5 0.250,
p 5 0.007, on Cz).
Conclusions: Our results demonstrate a strong frontal focus of reduced activation during proc-
essing of visual targets in alcoholic subjects and individuals with higher impulsivity. The findings
suggest that impulsivity may be an important factor that underlies the pathogenesis of alcohol
dependence. Studies are underway to examine the relationship between impulsivity and ERPs in off-
spring of alcoholic subjects, and to identify genes associated with the underlying predisposition in-
volved in disinhibitory disorders.
Key Words: P3, Disinhibition, Impulsivity, LORETA, Endophenotype.
A
LCOHOLISM IS A complex and heterogeneous
disorder with both genetic and environmental deter-
minants. In recent decades, research has been directed at
identifying the characteristic traits (i.e., phenotypes) in
affected alcoholic subjects as well as their pedigrees to
understand the factors underlying the pathogenesis of the
disorder. A phenotype represents the observable charac-
teristics of an organism, the joint product of the influences
of genetic and environment factors. However, it became
clear that using ‘‘diagnoses’’ as phenotypes may not be
optimal for genetic disse ction of complex diseases such as
psychiatric diseases because these diseases have complex
genetic underpinnings (Gottesman and Gould, 2003).
Therefore, it is valuable to analyze electrophysiological
data, such as electroencephalograms (EEGs), event-re-
lated potentials (ERPs), and event-related oscillations
(EROs), in alcoholic subjects and their pedigrees to iden-
tify and quantify the endophenotypic markers for studying
the molecular genetics of alcoholism and other coexist-
ing disinhibitory disorders (Begleiter and Porjesz, 1999;
Porjesz et al., 1998). It is believed that these endopheno-
types are closer to gene action than diagnostic categories,
and that they provide a more powerful strategy in search-
ing for genes involved in producing psychiatric diagnoses
(Porjesz et al., 2005).
Measuring ERPs provides a valuable tool for assessing
dynamic brain processes: it is nonin vasive and allows an
exquisite temporal observation of brain signaling and cog-
nition. In addition, the ERP is highly sensi tive to sensory,
cognitive, and motor aspects of information processing
in the brain, and it has been shown to be of great value in
studying the genetics of alcoholism and other psychiatric
From Henri Begleiter Neurodynamics Laboratory, Department of
Psychiatry, SUNY Downstate Medical Center, Brooklyn, New York.
Received for publication July 7, 2006; accepted September 28, 2006.
This work was presented in the scientific meeting of the International
Society for Research on Impulsivity, satellite meeting of the Society for
Neuroscience 35th annual meeting, on November 10, 2005 in Washington,
DC. This study was supported by the NIH grants 5 RO1 AA02686 and 5
RO1 AA05524 from the National Institute of Alcohol Abuse and Alcoholism
(NIAAA).
Reprint requests: Bernice Porjesz, Henri Begleiter Neurodynamics
Laboratory, Department of Psychiatry, SUNY Downstate Medical
Center, Box 1203, 450 Clarkson Ave., Brooklyn, NY 11203; Fax: 718-
270-4081; E-mail: bp@cns.hscbklyn.edu
Copyright r 2006 by the Research Society on Alcoholism.
DOI: 10.1111/j.1530-0277.2006.00277.x
Alcohol Clin Exp Res, Vol 31, No 1, 2007: pp 156–165156
A
LCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 31, No. 1
January 2007
disorders (Porjesz et al., 2005). There is solid evidence for
considering the P3 amplitude of the ERP as an endophe-
notype for the risk of alcoholism (Por jesz et al., 1998,
2005). Of particular note is the initially reported finding by
Begleiter et al. (1984) regarding reduced P3 amplitudes in
the sons of alcoholic fathers, who had no prior exposure to
alcohol. This finding has been replicated in many different
paradigms in both male and female offspring of alcoholic
subjects (e.g., Berman et al., 1993; Ehlers et al., 2003; Van
der Stelt et al., 1998; Whipple et al., 1991). Furthermore,
this reduction in P3 amplitude is not only observed in
alcoholism, but in a spectrum of disinhibitory disorders,
such as conduct disorder (CD), attention-deficit hyper-
activity disorder (ADHD), oppositional defia nt disorder
(ODD), and antisocial personality disorder (ASPD)
(Iacono et al., 2002; Kiehl et al., 1999).
It has been suggested that production of the P3 compo-
nent of the ERP, irrespective of the task and modality,
is associated with an inhibition of neuron assemblies
involved in perceptual processing of the atte nded sensory
input, thereby achieving a ‘‘closure’’ of the cognitive oper-
ations dealing with the cur rently attended sensory input
(Iacono et al., 2002; Nash and Williams, 1982). In addi-
tion, an association of reduced P3 amplitudes with high
sensation-seeking, particularly with high disinhibition, has
been identified in adult children of alcoholic subjects
(Ratsma et al., 2001). Data from the Minnesota Twin
Family Study showed that a low P3 amplitude is associat-
ed with externalizing psychopathology in adolescents
(Carlson et al., 1999). Thus, a low P3 amplitude would
indicate a state of disinhibition (Iacono et al., 2002;
Porjesz et al., 2005; Tomberg and Desmedt, 1998).
Gorenstein and Newman (1980) proposed that behav-
ioral phenomena such as psychopathology, antisocial, and
impulsive traits, and alcoholism should be viewed as vari-
able expression of a generalized disinhibitory complex.
Recently, substance dependence, such as alcohol depend-
ence, has been considered part of the disinhibitory/
externalizing disorder spectrum (Kendler et al., 2003), as
these disorders coexist in their clinical presentation; they
co-occur with externalizi ng traits in both children and
adults (Kuperman et al., 2001; Reebye et al., 1995), and
share similar electrophysiological indices such as a reduced
P3 amplitude (Sher and Trull, 1994). Clinically, altered
impulsiveness is one of the most common manifestations
of these disinhibitory disorders. Impulsivity, which is
mostly defined as action without planning or behavior that
is prematurely executed and has maladaptive consequen-
ces, is a complex behavioral construct (Barratt et al., 1999;
Evenden, 1999; Moeller et al., 2001). It appears to be
associated with a failure of behavioral filtering processes
outside of consciousness and with compromised capacity
to use appropriate judgment to reflect on impending acts
(Moeller et al., 2001). The prevalence of increased impul-
sivity among substance abusers has been widely discussed
or speculated upon. Recent studie s indicate that alcoholic
subjects have higher levels of impulsivity, particularly
those with cluster B personality disord ers (Dom et al.,
2006a) or early-onset type alcoholism (Dom et al., 2006b).
However, an earlier report showed that impulse control
disorders in alcoholic subjects were related only to sensa-
tion seeking but not to impulsivity, as neither the total
score nor the subscale scores on the BIS showed significant
differences between alcohol-dependent subjects (with or
without impulse control disorders) and control subjects
(Lejoyeux et al., 1998).
In the present study, we investigated the correlation
between impulsivity and the phenotypic marker, P3 amp-
litude of the ERP, in control subjects and subjects with al-
cohol dependence. To further study the differences in
source localizations of neuronal activities in the brain dur-
ing processing of visual targets among controls, alcoholic
subjects, and subjects with extreme high or low impulsivity,
we used the recently developed method of low-resolution
electromagnetic tomography (LORETA; Pascual-Marqui
et al., 2002), which overcomes limitations of earlier EEG/
ERP techniques in 3-dimensional distribution of neuronal
electric activity. The LORETA technique is able to com-
pute a functional brain image of source localizations by
incorporating the following neurophysiological obser-
vations: (a) measurable EEG-fields on the scalp reflect
synchronized neuronal mass activity, and (b) close but
opposing sources produce no scalp EEG. Low-resolution
electromagnetic tomography has been applied to study
task-related cognitive processing in normal subjects
(Schairer et al., 2001) and in various disorders (Gallinat
et al., 2002) including alcoholism (Kamarajan et al., 2005b).
It has also been used to examine the phenotype–genotype
relationship of gene variants in association with event-
related activity, and the results have demonstrated good
reliability (Winterer et al ., 2000).
We hypothesize that subjects with alcohol dependence
exhibit increased impulsivity and that this is correlated
with cognitive deficits, as reflected in reduced P3 ampli-
tudes. In addition, we predict that source localization of
P3 (using LORETA) will reveal a lower activation in the
frontal lobes, the brain regions that are thought to be
involved in inhibition, in subjects with alcoholism or high
impulsivity during response inhibition such as processing
target visual signals.
METHODS
Subjects
The sample included the adults who met the Diagnostic and Stat-
istical Manual of Mental Disorders, DSM-IV (American Psychiatric
Association, 1994) criteria for alcohol dependence but no other Axis
I diagnoses (n 5 57) and healthy adult controls (n 5 58). Alcoholic
subjects were recruited from several treatment centers for alcohol
dependence in and around New York City. Before testing, they had
been detoxified in a 30-day treatment program and none of the sub-
jects was in the withdrawal phase. Control subjects were recruited
through newspaper advertisements and notices. Informed consent
157REDUCED FRONTAL LOBE ACTIVITY IN HIGH IMPULSIVITY AND ALCOHOLISM
was obtained from each individual, and the experimental procedures
and ethical guidelines were in accordance with the Institutional
Review Board (IRB).
Subjects, both healthy controls and alcoholic subjects, were ex-
cluded if they manifested any of the following: uncorrected sensory
deficits, hepatic encephalopathy/cirrhosis of the liver, significant
head injury, history of seizures or neurosurgery, other acute/chronic
medical illness, were on medication known to influence brain func-
tioning, or tested positive for HIV. The subjects were also excluded
for their recent (i.e., 5 days) substance and alcohol use, based on self-
report as well as breath analyzer and urine screen. In addition, all
subjects were screened for organicity, using the Mini Mental State
Examination (MMSE, Folstein et al., 1975). The demography of
subjects in this study is shown in Table 1.
Assessment of Impulsivity
Impulsivity was measured using a self-report questionnaire, BIS,
version 11 (Patton et al., 1995). It consists of 30 items measuring 3
aspects of impulsivity: nonplanning (NP, lack of future orientation),
motor impulsivity (MI, impetuous action), and cognitive impulsivity
(CI, attention deficits, rapid, unstable thoughts, and lack of
cognitive patience, or labeled as ‘‘attentional impulsiveness’’). Barr-
att Impulsiveness Scale scores have recently been shown to be
elevated in subjects with cocaine abuse (Moeller et al., 2002) and
alcoholic subjects with cluster B personality disorders (Dom et al.,
2006a).
Event-Related Potential Data Acquisition and Signal Analysis
Details of the visual oddball paradigm used in the present study
have been previously described (Porjesz et al., 1998). It consists of
presentation of 3 types of visual stimuli (n 5 280), 60-ms duration,
subtending a visual angle of 2.51, with an interstimulus interval of
1.625 seconds. The rare target stimulus (n 5 35) was the letter X, to
which the subject was required to press a button as quickly as pos-
sible; the responding hand was alternated across subjects to counter-
balance any laterality effects due to responding. Speed was
emphasized, but not at the cost of accuracy. The frequently occur-
ring nontarget stimuli (n 5 210) were squares, and the novel stimuli
(n 5 35) consisted of colored geometric polygons that were different
on each trial; the subject was not required to respond to the nontar-
get and novel stimuli. The probabilities of occurrence of the
trials were 0.125 for the target trials, 0.75 for the nontarget trials,
and 0.125 for the novel trials. The stimuli were presented pseudo-
randomly with the constraints that neither targets nor novels
could be repeated consecutively.
Subjects were seated in a comfortable chair located in a dimly lit
sound-attenuated RF-shielded room (IAC, Industrial Acoustics,
Bronx, NY) in front of the computer monitor placed 1 m away.
Electroencephalogram activity was recorded on a Neuroscan system
(Version 4.1) (Neurosoft Inc., El Paso, TX) using a 61-channel elec-
trode cap (Electro-cap International Inc., Eaton, OH), which
included 19 electrodes of the 10-20 International System and 42
additional electrode sites (Electrode Position Nomenclature, Amer-
ican Electroencephalographic Association, 1991) as shown previous-
ly (Kamarajan et al., 2005b). The electrodes were referenced to the
tip of the nose and the ground electrode was at the forehead (frontal
midline). A supraorbital vertical lead and a horizontal lead on the
external canthus of the left eye recorded the eye movements. Elec-
trode impedance was maintained below 5 kO. The EEG signals were
recorded continuously with a bandpass at 0.02 to 100 Hz and amp-
lified 10,000 times using a set of amplifiers (Sensorium, Charlotte,
VT).
The continuous EEG was digitally low-pass filtered at 32 Hz and
then segmented into epochs of 100 ms prestimulus to 750 ms post-
stimulus. The mean EEG activity for 100 ms before stimulus onset
served as the prestimulus baseline. All segments exceeding 75 mV
threshold were automatically excluded from further processing.
After correcting eye-movement artifacts, the averaged segments for
each individual were screened visually for further artifact rejection.
The artifact detection was performed on all channels including the
electro-occulogram (EOG) channels. The visual P3 (VP3) amplitude
was measured as the voltage difference between the prestimulus
baseline and the largest positive going peak in the latency window
300 to 600 ms after stimulus onset. For each individual, the ampli-
tude and latency measures were calculated using a semiautomatic
peak-picking program, wherein the time window for each compo-
nent was manually selected in the computer while the peak within the
window was automatically detected, measured, and tabulated for
each channel. However, operator intervention was possible during
the process to ensure that the computer did not make anomalous
peak selections. Each subject had a minimum of 20 good trials in
each condition. The grand averages were computed and plotted to
determine the components and time windows (Kamarajan et al.,
2005a).
LORETA Analyses
The LORETA is a functional source imaging method based on
certain electrophysiological and neuroanatomical constraints
(Pascual-Marqui et al., 2002). The cortex has been modeled as a col-
lection of volume elements (voxels) in the digitized Talairach atlas
provided by the Brain Imaging Center, Montreal Neurological Insti-
tute (Talairach and Tournoux, 1988). The LORETA algorithm
solves the inverse problem by assuming related orientations and
strengths of neighboring neuronal sources (represented by adjacent
voxels). Low-resolution electromagnetic tomography has been iden-
tified as an efficient tool for functional mapping, as it is consistent
with physiology and capable of correct localization. Along with a
comprehensive experimental validation of the initial designers, many
independent studies have replicated the validation of the localization
properties of LORETA (Pascual-Marqui et al., 2002). The version of
LORETA used here to study the current density and source local-
ization (of the generators of ERP components) was made available
at http://www.unizh.ch/keyinst/NewLORETA/LORETA01.htm.
Initially, the voxel-based (2,394 voxels per time frame with a spa-
tial resolution of 7 mm) data were created from the ERP data from
61 scalp electrodes for a single time frame that corresponded to the
peak value of P3 in each group. The current density (at each voxel)
was computed as a linear, weighted sum of the scalp electric poten-
tials scaled to amperes per square meter (A/m
2
). The current density
Table 1. Demography of Subjects Included in the Study (N 5 115)
Controls Alcohol dependence
N (number) 58 57
Gender
a
M/F 29/29 47/10
Age
b
(mean SEM) 23.7 1.0 38.5 0.8
a
Gender is significantly different between groups.
However, among subjects within the same group, there were no signifi-
cant correlations between gender and BIS scores (p 5 0.53, r 5 0.083 in
controls; p 5 0.54, r 5 0.082 in alcoholic subjects, respectively) or P3
amplitudes on the leads we analyzed.
b
Age is also significantly different between groups.
However, among subjects within the same group, there were no signifi-
cant correlations between age and BIS scores (p 5 0.86, r 5 0.023 in
controls; p 5 0.34, r 5 0.13 in alcoholic subjects, respectively). In addi-
tion, age was treated as a covariate in MANOVA and RMANOVA.
BIS, Barratt Impulsiveness Scale; MANOVA, multivariate analysis of
variance; RMANOVA, repeated measures analysis of variance.
158 CHEN ET AL.
data created for each of the individuals in both groups were statis-
tically analyzed using the built-in voxel-wise independent t-tests with
5,000 permutations and corrected for multiple comparisons (Holmes
et al., 1996). The voxels with significant differences (po0.05)
between groups were identified for specific brain regions and Broad-
mann areas (BA) as provided at the website http://www.unizh.ch/
keyinst/NewLORETA/Software/Software.htm.
Statistical Analyses
The demographic data were analyzed using a t-test (e.g., age) or
chi-square test (e.g., gender) when applicable. All 61 electrodes were
grouped into 6 scalp regions for the statistical analyses. Details of the
localization of electrodes and graph were described in our previous
study (Kamarajan et al., 2005a). The grouping of electrodes into 6
scalp regions was based on the lobe-wise divisions of the cerebral
cortex. Several previous studies have used this lobe-wise grouping
(e.g., Cohen et al., 2002; de Bruin et al., 2004), which may help in
interpreting the findings for the functional significance of different
lobes of the cortex. Initially, the repeated measures analysis of vari-
ance (RMANOVA; full-factorial model) was performed on the mean
P3 amplitudes by having regions and electrodes as within-subject
variables and group (diagnosis) as a between-subject variable.
Greenhouse–Geisser correction was carried out for the within-sub-
ject factors and interactions wherever applicable. Only 6 representa-
tive electrodes from each of the regions were taken into analysis as
described previously (Kamarajan et al., 2005a). Having equal num-
bers of electrodes in each region makes the comparisons among
regions more viable and meaningful, and this fits well with the
RMANOVA design. The p-values were adjusted using Bonferroni
correction for multiple comparisons during the region-wise statistic-
al analysis of P3 amplitude. Then, a second stage of analysis was
performed: the mean P3 amplitude values were compared between
the control and alcoholic groups using a multivariate analysis of
variance (MANOVA) for each of the regions separately by including
all the electrodes of the specific region. Age and gender were treated
as covariates in the RMANOVA and MANOVA models for 3 rea-
sons: (1) there were significantly more male subjects in the alcoholic
sample, (2) the alcoholic subjects were significantly older than the
controls in the sample, and (3) age as a factor is known to have an
effect on ERP parameters (Kamarajan et al., 2005a). The behavioral
data (BIS scores) were analyzed using t-tests as well as MANOVA, in
which both age and gender were treated as covariates. The associa-
tion of P3 amplitudes with BIS scores was assessed by the Pearson
2-tailed correlation with the bivariate model.
RESULTS
Target VP3 Amplitudes Are Reduced in Alcoholic subjects
This study replicated previous data showing that alco-
holic subjects had widespread reductions in visual P3
amplitudes during processing of the target stimuli. For
example, the mean P3 amplitudes at the parietal electrode
in the midline (Pz) were 18.43 1.03 (SEM) mV in controls
and 12.85 0.83 (SEM) mV in alcoholic subjects, respect-
ively (po0.0001 by MANOVA); at the frontal electrode in
the midline (Fz), P3 amplitudes were 13.62 0.95 (SEM )
mV in controls and 9.26 0.89 (SEM) mV in alcoholic sub-
jects (po0.001), as shown in Fig. 1. The difference is
statistically more pronounced in the posterior regions
(e.g., po0.0001 at the parietal electrode, Pz; po0.001 at
the frontal electrode, Fz; and F 5 12.044, p 5 0.000018
for the group-by-region 2-way interaction analysis by
RMANOVA).
We also analyzed the VP3 amplitudes elicited by novel
stimuli. Although the novel P3 amplitudes were reduced in
alcoholic subjects, the difference was not statistically sig-
nificant. For example, the mean P3 amplitudes at the
parietal electrode in the midline (Pz) were 11.98 0.76
(SEM) mV in controls and 10.16 0.73 (SEM) mV in alco-
holic subjects, respectively (p 5 0.018 by t-test; p 5 0.285
by MANOVA in which age was treated as a covariate); at
the frontal electrode in the midline (Fz), P3 amplitudes
were 9.95 0.71 (SEM) mV in controls and 8.84 0.88
(SEM) mV in alcoholic subjects (p 5 0.323 by t-test;
p 5 0.184 by MANOVA).
Alcoholic Subjects Show Higher BIS Scores
The BIS scores between controls and subjects with alco-
hol dependence are shown in Fig. 2. Alcoholic subjects had
significantly higher scores on all 3 subscores (nonplanning,
motor impulsivity, cognitive impulsivity) as well as the
Fig. 1. Grand means of the event related potentials in control and
alcoholic subjects at 3 representative (midline) electrodes, Fz, Cz, Pz. Note
the lower P3 amplitude in alcoholic subjects in respon se to target visual
stimuli (in red curves).
159REDUCED FRONTAL LOBE ACTIVITY IN HIGH IMPULSIVITY AND ALCOHOLISM
total score of BIS (po0.0001 by t-test; p 5 0.004 by
MANOVA).
Correlations Between VP3 and Impulsivity
There were significant negative correlations between
VP3 and the total BIS scores for all 115 subjects in this
study (Fig. 3). These correlations varied topographically:
they were statistically more prominent in the posterior/
parietal region (Pz: r 5 0.274, p 5 0.003; Cz: r 5 0.250,
p 5 0.007; Fz: r 5 0.148, p 5 0.115) and at the left tem-
poral lobe (T7: r 5 0.252, p 5 0.007; T8: r 5 0.215,
p 5 0.021).
Functional Image (LORETA) Findings Demonstrate
Reduced VP3 Activity in Both Alcoholic Subjects and
Subjects With High Impulsivity in Similar Areas in the
Frontal Lobe
The LORETA images comparing controls and alcoholic
groups for target visual P3 of ERP are illustrated in Figs.
4A and 4B. Statistical analyses revealed that the alcoholic
group manifested significant (po0.05) reductions in brain
activations in 35 adjacent voxels (777 mm), which
involved 5 specific regions (BA 6, 8, 24, 32, 33) of bilateral
brain exclusively in the frontal lobes, such as bilateral
anterior cingulate, cingulate gyrus, medial frontal gyrus,
and superior frontal gyrus (Table 2).
To further investigate the localization of sources of ac-
tivity that may underlie impulsivity, we compared subjects
with ‘‘high impulsivity,’’ i.e. 30 subjects on the top quartile
of distribution of total BIS scores regardless of diagnoses,
and those with ‘‘low impulsivity,’’ i.e., 33 subjects on the
bottom quartile of the distribution of total BIS scores
regardless of diagnoses, for target visual P3 of the ERP
using LORETA images. Details of the composition of the
subjects are shown in Table 3. Statistical ana lyses demon-
strated that the high-impulsivity group manifested a
significant (po0.05) reduction in brain activations in 49
voxels (777 mm), which involved 5 specific regions (BA
6, 8, 24, 31, 32) of bilateral brain in the frontal lobes com-
prising cingulate gyrus, medial frontal gyrus, and superior
frontal gyrus (Table 4). The regions are similar to those
showing reduced activities in alcoholic subjects (Table 2),
but appear to involve larger areas (49 vs 35 voxels) and are
located more posterior and superior.
DISCUSSION
The present study demonstrated that alcoholic subjects
showed increased impulsivity as evidenced by their signifi-
cantly higher scores on the BIS. This study also replicated
previous data showing that alcoho lic subjects show wide-
spread reductions in P3 amplitudes. Furthermore, there
were significant negative correlations between total scores
in BIS and visual P3 amplitude. Functional imaging of
sources using LORETA showed a significant reduct ion in
activation in both alcoholic subjects and subjects with high
impulsivity in the bilateral frontal lobe areas, such as cin-
gulate gyru s, medial frontal gyrus, and superior frontal
gyrus.
P3 Deficits in Alcoholics and Its Implica tion for Impulsivity
and Disinhibitory Disorders
Studies over the last few decades have replicated that the
P3 (P300) amplitudes in response to task -relevant target
stimuli (e.g., visual stimuli) are significantly lower in absti-
nent alcoholic subjects than controls. The P3 amplitude
decrements are most prominent over the parietal regions,
and do not recover with prolonged abstinence (e.g.,
Barratt Impulsiveness Scores
0
20
40
60
80
***
***
**
***
** P<0.001
*** P<0.0001
compared to Controls
Controls
Alcoholics
NP MI CI Total
Fig. 2. Mean scores on Barratt Impulsiveness Scale in control and alco-
holic subjects. Alcohol-dependent subjects show a significantly increased
overall level of impulsivity trait, as well as for each of the subscales (NP, non-
planning score; MI, motor impulsiveness score; CI, cognitive impulsiveness
score, or attentional impulsiveness).
0 10 20 30 40 50 60 70 80 90 100
0
10
20
30
40
Pz p= 0.003
r= -0.274
Cz p= 0.007
r= -0.250
Total scores on BIS
VP3 Amplitude (µV)
Fig. 3. Figure shows the linear correlation between VP3 amplitudes at Cz
and Pz leads of all subjects and their respective total scores on Barratt Impul-
siveness Scale. Significant negative correlations between VP3 and impulsivity
were found. These correlations varied topographically, and were statistically
more pronounced in the posterior region.
160 CHEN ET AL.
Fig. 4a. Panels show the 2-dimensional low-resolution brain electromagnetic tomography (LORETA) images of 3 orthogonal (axial, saggital, and coronal)
views showing the current density (in amperes per square meter, A/m
2
) during the peaks of the P3 component of event related potential (ERP) in controls (top)
and alcoholic subjects (bottom). Alcoholic subjects showed significantly reduced activation during the processing of the target visual signal in the anterior
cingulate, cingulate gyrus, medial, and superior frontal gyrus in LORETA.
b. Panels (upper: controls, lower: alcoholics) show the 3-dimensional LORETA images during the peaks of P3 component of ERP.
161REDUCED FRONTAL LOBE ACTIVITY IN HIGH IMPULSIVITY AND ALCOHOLISM
Porjesz et al., 1998, 2005). In addition, mean P3 ampli-
tudes are also significantly lower in family members from
densely affected alcoholic families, compared with mean
amplitudes of control family for all comparisons, namely
probands, affected and unaffected individuals, and off-
spring (e.g., Porjesz et al., 1998, 2005). Furthermore,
recent genetic linkage analyses indicate that visual P3
amplitude is a biological phenotypic marker that has
genetic underpinnings (Jones et al., 2004; Porjesz et al.,
2005).
It has been proposed that P3 reflects attentional dis-
tribution and context updating processes of working
memory, cognitive closure, and that it involves inhibitory
processes in specific brain areas (Tomberg and Desmedt,
1998). Production of P3 is believed to be involved in
inhibition of brain activities: the larger the P3 amplitude,
the more the neurophysiological inhibition. Therefore, the
low P3 amplitude in alcoholics is suggestive of a lack of
inhibition, i.e., neurophysiological disinhibition. In the
present study, the findings of increased impulsivity in alco-
holic subjects and significant negative correlations between
VP3 amplitudes and impulsivity provide novel evidence
that links a basic neuro-electric endophenotypic marker to
a multidimensional behavioral construct, impulsivity. To
further substantiate our hypothesis that impulsivity indeed
mediates the relation between alcoholism and the P3 amp-
litudes, we performed an additional MANOVA with a
general linear model where the total BIS score was treated
as a covariate. The results showed that the association
between alcoholism and the reduced P3 amplitudes was no
longer significant (p 5 0.564 at Fz, p 5 0.431 at Cz, and
p 5 0.853 at Pz), indicating that impulsivity indeed
mediates the relationship between alcoholism and P3
amplitude. These data suggest that there is a common
mechanism(s), e.g., genetic control, underlying the expres-
sion of a shared symptom, namely impulsivity, in a class of
disinhibitory disorders. The results also provide evidence to
support our hypothesis that the underlying dysfunc-
tional neural and response inhibition is involved in a
predisposition to alcoholism and other disinhibitory disor-
ders as observed in the reduction in P3 amplitude not only
in alcoholism, but in a spectrum of disinhibitory disorders,
such as CD, ADHD, ODD, and ASPD (Begleiter and
Porjesz, 1999; Kamarajan et al., 2005b; Porjesz et al., 2005).
Frontal Lobe Dysfunction in Alcoholic Subjects and
Subjects With High Impulsivity
Frontal lobe pathology in alcoholism has been well doc-
umented at anatomical, physiological, and neuropsycho-
logical levels, as reviewed by Moselhy et al. (2001).
Moderate neuronal loss in the frontal cortex and in the
cingulate gyrus of alcoholic subjects has been reported (re-
viewed by Harper and Kril, 1994). Functional imaging
studies using positron emission tomography (PET) report
a decrease in glucose utilization, selectively affecting the
bilateral medial frontal lobe such as anterior cingulate in
alcoholic subjects (Gilman et al., 1996). Single photon
Table 3. Composition of the Subjects With ‘‘High Impulsivity’’ or ‘‘Low Impulsivity’’ in this Study
Definition Total score of BIS range Number Controls Alcoholics
High impulsivity Top quartile in total score of BIS of all subjects 69–88 n 5 30 7 (23.3%) 23 (76.7%)
Low impulsivity Bottom quartile in total score of BIS of all subjects 35–54 n 5 33 27 (84.8%) 6 (18.2%)
BIS, Barratt Impulsiveness Scale.
Table 2. Brain Areas Showing Statistical Differences (po0.05) in VP3
Activity Between Controls and Alcoholic Subjects According to Voxel-
by-Voxel Analysis With Low-Resolution Brain Electromagnetic Tomogra-
phy (LORETA)
t-Value x-mm y-mm z-mm Brodmann area Anatomical locations
3.636 4 17 22 Brodmann area 33 Anterior cingulate
3.615 3 17 22 Brodmann area 33 Anterior cingulate
3.5974 4 17 29 Brodmann area 24 Cingulate gyrus
3.5785 3 17 29 Brodmann area 24 Cingulate gyrus
3.5576 4 10 43 Brodmann area 32 Cingulate gyrus
3.5387 11 10 43 Brodmann area 32 Cingulate gyrus
3.5351 3 10 43 Brodmann area 32 Cingulate gyrus
3.5298 11 10 36 Brodmann area 32 Cingulate gyrus
3.5229 4 10 50 Brodmann area 6 Medial frontal gyrus
3.522 4 10 29 Brodmann area 33 Anterior cingulate
3.5168 10 17 29 Brodmann area 32 Cingulate gyrus
3.5059 4 17 43 Brodmann area 32 Cingulate gyrus
3.5054 4 10 36 Brodmann area 24 Cingulate gyrus
3.5043 3 10 50 Brodmann area 6 Medial frontal gyrus
3.4998 4 17 50 Brodmann area 8 Medial frontal gyrus
3.489 3 10 29 Brodmann area 33 Anterior cingulate
3.483 3 17 50 Brodmann area 8 Medial frontal gyrus
3.4772 11 17 36 Brodmann area 32 Cingulate gyrus
3.4761 3 17 43 Brodmann area 32 Cingulate gyrus
3.4744 4 17 36 Brodmann area 32 Cingulate gyrus
3.4743 4 17 57 Brodmann area 8 Superior frontal gyrus
3.4585 3 10 36 Brodmann area 24 Cingulate gyrus
3.4583 3 17 57 Brodmann area 8 Superior frontal gyrus
3.4539 3 17 36 Brodmann area 32 Cingulate gyrus
3.4226 10 17 43 Brodmann area 32 Cingulate gyrus
3.4177 10 10 36 Brodmann area 32 Cingulate gyrus
3.4169 4 3 29 Brodmann area 24 Cingulate gyrus
3.416 10 17 36 Brodmann area 32 Cingulate gyrus
3.3982 4 10 57 Brodmann area 6 Superior frontal gyrus
3.382 4 3 36 Brodmann area 24 Cingulate gyrus
3.3801 11 3 43 Brodmann area 24 Cingulate gyrus
3.3794 3 10 57 Brodmann area 6 Superior frontal gyrus
3.3781 3 3 29 Brodmann area 24 Cingulate gyrus
3.371 4 3 43 Brodmann area 24 Cingulate gyrus
3.371 4 17 64 Brodmann area 6 Superior frontal gyrus
Coordinates are given in millimeters, and the origin is at the anterior
commissure. For x, negative values represent left, positive values repre-
sent right. For y, negative values represent posterior, positive values
represent anterior. For z, negative values represent inferior, positive
values represent superior.
162 CHEN ET AL.
emission computerized tomography (SPECT) studies have
shown a decrease in regional blood flow in the anterior
cingulate and inferior/anterior frontal lobe (Gansler et al.,
2000; O’Carroll et al., 1991). Furthermore, recent PET and
functional magnetic resonance imaging (fMRI) studies
demonstrated similar results of decreased activities in the
frontal lobe in the high-risk offspring of alcoho lic subjects
(Rangaswamy et al., 2004). These findings strongly suggest
that the frontal lobe and the circuitry connections to the
limbic structures are vulnerable substrates in alcoholic
subjects, even before the symptoms emerge, and it may be
one of the indicators of a predisposition to developing
alcoholism.
The impulsivity component of externalizing disorders
has recently gained increas ing attention for research. Im-
aging studies in individuals with high impulsivity, e.g. in
borderline personality disorder, demonstrated similar
findings of a decreased activation in the bilateral medial
frontal lobes during response inhibition (Soloff et al.,
2003). A recent report using diffusion tensor imaging indi-
cated that reduced anterior corpus callosum white matter
integrity is related to increased impulsivity in cocaine-de-
pendent subjects (Moeller et al., 2005). However, there is
no literature on functional brain mapping of impulsivity in
alcoholism. In the present source localization study using
LORETA, we demonstrated a strong frontal focus in both
alcoholic subjects and subjects with high impulsivity. Vox-
el-by-voxel analyses revealed a great deal of similarity in
the brain areas showing reduced activation between the
alcoholic group and the high-impulsivity group: the voxels
with significant difference (po0.05) in both comparisons
are located within the same Brodmann Areas (BA 6, 8, 24,
32) and 14 of the 35 voxels are identical. In addition, the
LORETA results based on the trait, ‘‘high impulsivity’’
versus ‘‘low impulsivity’’ indicate greater differences than
comparison of groups based on a clinical diagnosis, ‘‘alco-
holic’’ versus ‘‘control.’’ These findings all suggest that
impulsivity may be one of the most important coexisting
conditions that underlie the pathogenesis of alcoholism
and perhaps other disinhibitory disorders. Neuroelectric
measures, such as visual P3, which are sensitive to the
underlying vulnerability to develop certain psychiatric dis-
orders and are hence considered phenotypic markers,
may more closely reflect the presence of these underlying
coexisting conditions. These conditions are part of the
integration of the clinical manifestations in the vast
majority of alcoholic populations, and are likely genetically
influenced. For molecular genetic studies of psychiatric ill-
nesses, rather than studying the clinical endpoints, such as
a dichotomous diagnosis, it is of more value to investigate
the underlying quantitative biological measures of neuro-
biological dysfunction, e.g., visual P3 and BIS scores, in
the genetic predispositions, as they reflect more proximal
effects of such genes (Kendler et al., 2003; Porjesz et al.,
2005).
CONCLUSIONS
This study demonstrates a reduced activ ation of sources
in bilateral frontal lobe in both alcoholic individuals and
individuals with higher impulsivity during processing of
visual targets. Our data also provide evidence of a link
between an index of neuronal disinhibition and a manifes-
tation of impulsivity. The findings suggest that impulsivity
may be an important factor that underlies the pathogene-
sis of alcohol dependence. Studies are underway in our
laboratory to examine the relationship between impulsiv-
ity and ERP characteristics in offspring of alcoholic
subjects, to deter mine whether this relationship antecedes
the development of alcoholism and to identify genes asso-
ciated with the underlying predisposition involved in
disinhibitory disorders.
ACKNOWLEDGMENTS
This article is dedicated to Dr. Henri Begleiter, an ex-
ceptional scientist and mentor. We are truly inspired by his
vision of bringing together the fields of brain oscillations
and genetics of alcoholism.
We thank Aleksey Dumer, Lakshmi Krishnamur thy,
Glenn Murawski, Tracy Crippen, Eric Talbert, Chamion
Thomas, Carlene Haynes, and Joyce Alonzia for their
valuable technical support. We are grateful to Dr. R.D.
Pascual-Marqui for the LORETA software used in this
study. Dr. Andrew C. Chen is a recipient of the American
Psychiatric Association (APA)/American Psychiatric
Institute for Research and Education (APIRE) Janssen
Resident Research Award.
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165REDUCED FRONTAL LOBE ACTIVITY IN HIGH IMPULSIVITY AND ALCOHOLISM
    • "Higher BIS-11 scores in alcoholics confirm previously reported findings of alcoholics having high trait impulsiveness (Chen et al., 2007Chen et al., , 2005). Alcoholics also showed higher omission (Go) errors but did not differ from controls in commission (NoGo) errors as well as on reaction time on the Go trials. "
    [Show abstract] [Hide abstract] ABSTRACT: Higher impulsivity observed in alcoholics is thought to be due to neurocognitive functional deficits involving impaired inhibition in several brain regions and/or neuronal circuits. Event-related Oscillations (EROs) offer time-frequency measure of brain rhythms during perceptual and cognitive processing, which provide a detailed view of neuroelectric oscillatory responses to external/internal events. The present study examines evoked power (temporally locked to events) of oscillatory brain signals in alcoholics during an equal probability Go/NoGo task, assessing their functional relevance in execution and inhibition of a motor response. The current study hypothesized that increases in the power of slow frequency bands and their topographical distribution is associated with tasks that have increased cognitive demands, such as the execution and inhibition of a motor response. Therefore, it is hypothesized that alcoholics would show lower spectral power in their topographical densities compared to controls. The sample consisted of 20 right-handed abstinent alcoholic males and 20 age and gender-matched healthy controls. Evoked delta (1.0-3.5Hz; 200-600ms), theta (4.0-7.5Hz; 200-400ms), slow alpha (8.0-9.5Hz; 200-300ms), and fast alpha (10.0-12.5Hz; 100-200ms) ERO power were compared across group and task conditions. Compared to controls, alcoholics had higher impulsiveness scores on the Barrett Impulsiveness Scale (BIS-11) and made more errors on Go trials. Alcoholics showed significantly lower evoked delta, theta, and slow alpha power compared to controls for both Go and NoGo task conditions, and lower evoked fast alpha power compared to controls for only the NoGo condition. The results confirm previous findings and are suggestive of neurocognitive deficits while executing and suppressing a motor response. Based on findings in the alpha frequency ranges, it is further suggested that the inhibitory processing impairments in alcoholics may arise from inadequate early attentional processing with respect to the stimulus related aspects/semantic memory processes, which may be reflected in lower posterio-temporal evoked fast alpha power. It can thus be concluded that alcoholics show neurocognitive deficits in both execution and suppression of a motor response and inadequate early attentional processing with respect to the semantic memory/stimulus related aspects while suppressing a motor response.
    Full-text · Article · Feb 2016
    • "Frontal lobe structures have also been implicated in several disorders involving impulsivity and externalizing traits (Vollm et al., 2004; Lee et al., 2005; Vollm et al., 2007; Wolf et al., 2011; Costa Dias et al., 2013; Cyders et al., 2014). Taken together, these findings add support to the view that P3 amplitude, impulsivity, and externalizing disorders are etiologically related (Iacono et al., 2003; Iacono and McGue, 2006; Chen et al., 2007; Carlson et al., 2009; Gao and Raine, 2009; Young et al., 2009; Gilmore et al., 2010a; Lejuez et al., 2010). It is important to note that BIS score differences between HR and LR groups varied according to the age group and gender (Fig.7). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. The goal of the present study is to elucidate reward processing deficits, externalizing disorders, and impulsivity as elicited by electrophysiological, clinical and behavioral measures in subjects at high risk for alcoholism from families densely affected by alcoholism in the context of brain maturation across age groups and gender. Methods: Event-related potentials (ERPs) and current source density (CSD) during a monetary gambling task (MGT) were measured in 12-25 year old offspring (N = 1864) of families in the Collaborative Study on the Genetics of Alcoholism (COGA) Prospective study; the high risk (HR, N = 1569) subjects were from families densely affected with alcoholism and the low risk (LR, N = 295) subjects were from community families. Externalizing disorders and impulsivity scores were also compared between LR and HR groups. Results: HR offspring from older (16-25 years) male and younger (12-15 years) female subgroups showed lower P3 amplitude than LR subjects. The amplitude decrement was most prominent in HR males during the loss condition. Overall, P3 amplitude increase at anterior sites and decrease at posterior areas were seen in older compared to younger subjects, suggesting frontalization during brain maturation. The HR subgroups also exhibited hypofrontality manifested as weaker CSD activity during both loss and gain conditions at frontal regions. Further, the HR subjects had higher impulsivity scores and increased prevalence of externalizing disorders. P3 amplitudes during the gain condition were negatively correlated with impulsivity scores. Conclusions: Older male and younger female HR offspring, compared to their LR counterparts, manifested reward processing deficits as indexed by lower P3 amplitude and weaker CSD activity, along with higher prevalence of externalizing disorders and higher impulsivity scores. Significance: Reward related P3 is a valuable measure reflecting neurocognitive dysfunction in subjects at risk for alcoholism, as well as to characterize reward processing and brain maturation across gender and age group.
    Full-text · Article · Sep 2015
    • "Prefrontal structures such as the VMPFC and the DLPFC are frequently associated with reflective processes and deliberate decision making (Ridderinkhof et al. 2004). In contrast, damage to and dysfunction of the prefrontal cortex has been associated with disadvantageous decisions and the inability to suppress impulsive behavior, especially with regard to addiction and pathological behavior (Chen et al. 2007; Dawe et al. 2004; Jentsch and Taylor 1999; Tanabe et al. 2007). Boes et al. (2009) add further evidence in a study demonstrating that the size of the VMPFC varied in boys who differed in rated motor impulsivity and non-planning behavior. "
    [Show abstract] [Hide abstract] ABSTRACT: With the emergence of new technologies, in particular the Internet, the opportunity for impulsive purchases have expanded enormously. In this research-in-progress, we report the current status of an fMRI-project in which we investigated differences between neural processes in the brains of impulsive and non-impulsive shoppers during the trustworthiness evaluation of online offers. Both our behavioral and fMRI data provide evidence that the impulsiveness of individuals can exert significant influence on the evaluation of online offers, and can potentially affect subsequent purchase behavior. We show that impulsive individuals evaluate trustworthy and untrustworthy offers differently than do non-impulsive individuals. With respect to brain activation, both experimental groups (i.e., impulsive, non-impulsive) exhibit similar neural activation tendencies, but differences exist in the Magnitude of activation Patterns in brain regions that are closely related to trust and decision making, such as the DLPFC, the insula cortex, and the caudate nucleus.
    Full-text · Conference Paper · Dec 2014 · International Journal of Psychophysiology
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