 |
|
Evidence for Impaired Cortical Inhibition in Schizophrenia Using Transcranial Magnetic Stimulation
Zafiris J. Daskalakis, MD, FRCP(C);
Bruce K. Christensen, PhD, CPsych;
Robert Chen, MBB Chir, MSc, FRCP(C);
Paul B. Fitzgerald, MBBS, MPM, FRANZCP;
Robert B. Zipursky, MD, FRCP(C);
Shitij Kapur, MD, PhD, FRCP(C)
Arch Gen Psychiatry. 2002;59:347-354.
ABSTRACT
| |
Background Cortical inhibition (CI) deficits have been proposed as a pathophysiologic
mechanism in schizophrenia. This study employed 3 transcranial magnetic stimulation
(TMS) paradigms to assess CI in patients with schizophrenia. Paired-pulse
TMS involves stimulating with a lower-intensity pulse a few milliseconds before
a higher-intensity pulse, thereby inhibiting the size of the motor evoked
potential produced by the higher-intensity pulse. In the cortical silent period
paradigm, inhibition is reflected by the silent period duration (ie, the duration
of electromyographic activity cessation following a TMS-induced motor evoked
potential). Transcallosal inhibition involves stimulation of the contralateral
motor cortex several milliseconds prior to stimulation of the ipsilateral
motor cortex, inhibiting the size of the motor evoked potential produced by
ipsilateral stimulation.
Methods We measured CI using these 3 paradigms in 15 unmedicated patients with
schizophrenia (14 medication-naive and 1 medication-free for longer than 1
year) (13 were in the transcallosal inhibition paradigm), 15 medicated patients
with schizophrenia (11 taking olanzapine, 1 risperidone, 1 quetiapine, 1 methotrimeprazine
+ perphenazine, 1 quetiapine + loxapine), and 15 healthy controls.
Results Unmedicated patients demonstrated significant CI deficits compared with
healthy controls across all inhibitory paradigms whereas medicated patients
did not (at all inhibitory intervals, paired-pulse TMS: controls = 59.9%,
medicated = 44.3%, unmedicated = 28.7%; cortical silent period: controls =
55.0 milliseconds, medicated = 60.4 milliseconds, unmedicated = 39.7 milliseconds;
transcallosal inhibition: controls = 33.6%, medicated = 23.7%, unmedicated
= 10.4%; P<.05).
Conclusions These results suggest that schizophrenia is associated with deficits
in CI and that antipsychotic medications may increase CI.
INTRODUCTION
SEVERAL LINES of evidence suggest that schizophrenia is a disorder associated
with deficits in cortical inhibition (CI). These deficits have been demonstrated
in cognitive, motor, neurophysiologic, and neuropathologic studies. First,
cognitive studies suggest that patients with schizophrenia have impaired sensorimotor
gating, inferred from their performance in prepulse inhibition tasks. Swerdlow
and Koob1 posit that such impairment is due
to excess activation of subcortical dopamine that leads to decreased activation
of cortical inhibitory projections. Second, Walker et al2
posit that the motor abnormalities in schizophrenia, ranging from generalized
incoordination to agitation and catatonia, are a corollary to disinhibition
of cortical inhibitory neurotransmission. Third, neurophysiologic studies
by Freedman et al3-6
demonstrate that patients with schizophrenia have impaired inhibition of event-related
potential responses to paired auditory stimuli. Fourth, neuropathologic studies
have shown that patients with schizophrenia have morphologic changes in cortical  -aminobutyric
acid (GABA) inhibitory interneurons,7 which
may in turn be linked to findings of reduced gray matter volume in these patients.8 Collectively, these results suggest that CI is dysfunctional
in schizophrenia.
Transcranial magnetic stimulation (TMS)9
represents a noninvasive technique to measure CI. Conventionally, 3 inhibitory
paradigms have been used: paired-pulse TMS (ppTMS), cortical silent period
TMS (CSP), and transcallosal inhibition (TCI).10-12
In ppTMS, if a subthreshold pulse precedes a test pulse by 1 to 5 milliseconds,
inhibitory interneurons are recruited and the motor-evoked potential (MEP)
response is inhibited. In contrast, if a subthreshold pulse precedes the test
pulse by 7 to 20 milliseconds, the MEP response is facilitated.10, 13
Cortical facilitation is mediated, in part, by glutamatergic neurotransmission.14 In CSP, motor cortical stimulation superimposed on
background electromyographic (EMG) activity results in cessation of EMG activity,
producing a silent period. The duration of this silent period represents another
measure of CI.15 In TCI, stimulation of the
contralateral motor cortex a few milliseconds prior to stimulation of the
ipsilateral motor cortex inhibits the size of the MEP produced by ipsilateral
stimulation.12 Evidence that ppTMS, CSP, and
TCI represent cortical inhibitory phenomena and not other mechanisms (ie,
neuronal refractoriness) includes (1) absence of any change in spinal excitability16; (2) failure to suppress the response to double transcranial
electrical stimulation10, 12, 17;
and (3) marked reduction in the corticospinal waves evoked by TMS.18-19
Three previous TMS studies have explored CI in schizophrenia. Puri et
al20 found no differences in CSP duration in
unmedicated patients compared with healthy controls. Davey et al21
found longer CSP duration among medicated patients compared with unmedicated
patients. These studies, however, used TMS intensities that were much lower
than those conventionally used in most CSP studies.11, 15, 22
Boroojerdi et al23 found that TCI was prolonged
in a group of medicated patients with schizophrenia. The authors concluded
that prolonged TCI was indicative of abnormal corpus callosum function, although
it also implies greater CI in these patients.
The objective of the present study was to compare CI, using all 3 TMS
inhibitory paradigms, in medicated and unmedicated patients with schizophrenia
and healthy controls. It was hypothesized that unmedicated patients would
demonstrate deficient CI compared with healthy controls and that medicated
patients would demonstrate greater CI compared with their unmedicated counterparts.
SUBJECTS AND METHODS
SUBJECTS
The study included 30 right-handed patients with a DSM-IV diagnosis of either schizophrenia or schizoaffective disorder
confirmed using the Structured Clinical Interview for DSM-IV (SCID),24 performed by a board-certified research psychiatrist
(Z.J.D). Patients were recruited through the Schizophrenia and Continuing
Care Program at the Centre for Addiction and Mental Health (Toronto, Ontario).
Fifteen patients were unmedicated (14 medication-naive and 1 medication-free
for longer than 1 year) and 15 were medicated with either typical or atypical
antipsychotic medications (16.8 ± 6.7 mg of olanzapine, 11 patients;
7 mg of risperidone, 1 patient; 1200 mg of quetiapine, 1 patient; 100 mg of
quetiapine + 10 mg of loxapine, 1 patient; and 50 mg of methotrimeprazine
+ 16 mg of perphenazine, 1 patient). The control group consisted of 15 healthy,
right-handed volunteers. For all subjects, handedness was confirmed using
the Oldfield Handedness Inventory.25 Controls
were recruited through advertisements in the community and postings within
the hospital. Groups were similar across demographic variables (Table 1). Controls were screened for psychopathology with a modified
SCID. Exclusion criteria included a self-reported comorbid medical illness
or a history of drug or alcohol abuse. The University of Toronto ethics committee
approved the study and written informed consent for each participant was obtained.
|
|
|
|
Table 1. Demographic and Clinical Characteristics of the Sample*
|
|
|
Before the neurophysiologic investigation, we used the Positive and
Negative Syndrome Scale (PANSS) to index the severity of psychopathology.26 Most patients scored in the moderate range of symptom
severity (Table 1). Motor abnormalities
were assessed using the Abnormal Involuntary Movements Scale,27
Simpson-Angus Scale,28 and Barnes Akathisia
Scale.29 None of the subjects demonstrated
evidence of motor abnormalities.
PROCEDURES
Subjects were seated in a comfortable chair. Electromyographic recordings
were made from the right and left first dorsal interosseus muscle (FDI) using
a commercial amplifier (model 2024F; Intronix Technologies Corporation, Bolton,
Ontario) with a bandpass filter of 2 Hz to 5 kHz. The signal was processed
by an IBM-PC/Pentium Pro computer (Dell Computer Corporation, Toronto, Ontario)
and analyzed with Data Manager 1.2 (DataWave Technologies, Longmont, Colo).
Transcranial magnetic stimulation was applied to the hand area of the left
motor cortex using a figure-of-eight magnetic coil and MagStim 200 magnetic
stimulators (MagStim Co, Whitland, Dyfed, Wales). The coil diameter was 70
mm for each loop. In the TCI experiment, a second figure-of-eight coil was
placed over the right motor cortex. The diameter of this coil was 90 mm for
each loop.
For each subject, the optimal coil position, defined as the stimulation
site that produced the largest MEP at moderately suprathreshold stimulation
intensities in the resting right FDI muscle, was determined by moving the
coil in 1-cm steps over the presumed area of the left motor cortex. The site
was marked using a red marker to ensure that the coil was held in the same
position throughout the experiment. The coil was held tangentially on the
head with the handle pointing backward and 45° laterally from midline.
The induced current points forward and perpendicular to the central sulcus
and is optimal for producing transsynaptic activation of corticospinal neurons.30
The motor threshold (MT), expressed as a percentage of the maximum stimulator
output, was measured by approaching from slightly suprathreshold intensities
and reducing in 1% steps.31 Resting MT (RMT)
was defined as the first intensity that produced an MEP of greater than 50
µv in 5 of 10 trials in relaxed FDI.11
Active MT (AMT) was defined as the first intensity that produced an MEP of
greater than 100 µv in 5 of 10 trials in an isometrically moderately
active FDI.32
The CSP was obtained in moderately tonically active FDI by stimulating
the motor cortex with intensities of 10%, 20%, 30%, and 40% above AMT. For
each intensity, 15 trials were performed. The CSP duration was defined as
the time from the MEP onset to the return of any voluntary EMG activity. This
is referred to as the absolute CSP and ends with a deflection in the EMG waveform.33 At each intensity, the mean MEP size and CSP duration
for all 15 trials was calculated separately.
Paired-pulse inhibition and facilitation was also obtained according
to previously published protocols.10 In short,
a subthreshold conditioning stimulus (CS), set at 80% of RMT, preceded a suprathreshold
test stimulus (TS). The TS was adjusted to produce an average MEP of 0.5 to
1.5 mV peak-to-peak amplitude in the contralateral FDI muscle. Conditioning
stimuli were applied to the motor cortex prior to the TS at 1 of 5 random
interstimulus intervals. Four blocks of trials were performed, each consisting
of 6 randomly intermixed conditions presented 3 times each: the TS alone and
5 conditions with the CS preceding the TS at different intervals (2, 4, 10,
15, and 20 milliseconds). The time between trials was 5 seconds. Peak-to-peak
MEP amplitudes were measured for each condition and conditional averages were
obtained from these. Changes in the TS MEP amplitude at each interstimulus
interval were expressed as a percentage of the mean unconditioned MEP amplitude.34 Surface EMG activity was monitored from the FDI at
all times to ensure relaxation, and auditory feedback was given to subjects
through a loudspeaker. This was important since muscle activation has been
shown to result in less inhibition and facilitation in this paradigm.35 Trials contaminated by an increase in background
EMG activity were discarded from further analysis.
Transcallosal inhibition was obtained according to the methods outlined
by Ferbert et al.12 In short, a suprathreshold
CS applied to the right motor cortex several milliseconds prior to a suprathreshold
TS applied to the left motor cortex inhibits the size of the MEP produced
by the TS 50% to 75%. Thus, 2 figure-of-eight coils were held over the left-
and right-hand area of their respective motor cortices. The stimulus in each
coil was set to produce MEPs of 0.5 to 1.5 mV peak-to-peak amplitude in the
contralateral FDI muscle. Six blocks of trials were performed that consisted
of 6 randomly intermixed conditions presented 2 times each: the TS alone and
5 conditions with the CS occurring at different intervals (2, 6, 10, 15, and
20 milliseconds) before the TS. The time between trials was 5 seconds. Peak-to-peak
MEP amplitudes were measured for each condition and from these, conditional
averages were obtained. The order of administration of the 3 paradigms was
counterbalanced between subjects to prevent order effects.
STATISTICAL ANALYSES
Groups were compared using repeated-measures analysis of variance. Group
membership (ie, unmedicated, medicated, and control) was entered as a between-group
independent variable. The inhibitory ISI and the percentage above AMT were
entered as the within-group independent variables in the ppTMS and TCI, and
CSP experiments, respectively. In the ppTMS and TCI experiments, the change
in MEP size—expressed as a ratio of the MEP amplitude of each conditioned
response to the unconditioned response at each inhibitory interstimulus interval—served
as the dependent variable. In the CSP experiment, the CSP duration served
as the dependent variable. Motor threshold differences were analyzed using
a 1-way analysis of variance. Finally, a correlational analysis was used to
examine the association between severity of clinical symptoms and the magnitude
of inhibition in the patient groups. All statistical procedures were 2-tailed
and significance was set at an  level of .05. All analyses were computed
using SPSS 10.0 (Statistical Product and Service Solutions Inc, Chicago Ill).
RESULTS
All subjects except 2 completed the protocol. These 2 unmedicated subjects
withdrew from the TCI experiment because they felt uncomfortable with the
double coil placement on their heads. Therefore, they were dropped from the
unmedicated group in the analysis for this paradigm. A total of 44 of 9036
trials recorded in the entire sample were discarded. In the control group,
11 trials were discarded compared with 22 trials in the medicated and 11 trials
in the unmedicated groups. Therefore, 0.49% of trials were discarded, all
due to movement artifacts. The number of trials discarded was similar across
all experiments (ppTMS, 15; CSP, 10; TCI, 19). The investigator discarded
trials immediately following data collection.
ppTMS
The overall excitability curve was comparable with previously published
reports.10-11,32
Short interstimulus intervals (2 and 4 milliseconds) produced inhibition of
the test response (Table 2) whereas
long interstimulus intervals (10, 15, and 20 milliseconds) produced facilitation.
On measures of inhibition, a significant main effect of group (ie, unmedicated,
medicated, and healthy controls) was obtained (F2,42 = 4.90; P = .01), with no significant group-by-ISI interaction
(F2,42 = 0.24; P = .79). Post hoc tests
(least significant difference [LSD]) revealed significant differences between
the unmedicated and healthy control groups (P = .003)
(effect size: Cohen d = 0.69)36 and trended
toward significantly greater inhibition between the medicated and unmedicated
groups (P = .12) and between the healthy control
and medicated groups (P = .12). Averaged across all
inhibitory ISIs (ie, 2, 4 milliseconds) unmedicated patients demonstrated
31.2% less inhibition compared with healthy controls whereas medicated patients
demonstrated 15.64% less inhibition compared with healthy controls. There
were no group differences on measures of cortical facilitation (ie, measurements
at ISI 10, 15, 20) (F2,42 = 0.39; P =
.67).
|
|
|
|
Table 2. Results From ppTMS Inhibition and Facilitation and CSP and
TCI Measures in Unmedicated and Medicated Patients With Schizophrenia and
Healthy Controls*
|
|
|
CORTICAL SILENT PERIOD
Two raters (1 blind to diagnosis and 1 not) measured CSP durations for
all subjects independently. An intraclass correlation coefficient was calculated
to determine the interrater reliability for this measure. We obtained an average
intraclass correlation coefficient of 0.96 (F89,89 = 56.56; P = .001). A significant main effect of group (ie, unmedicated,
medicated, and healthy controls) (F2,42 = 4.42; P = .02) and a significant group-by-intensity interaction (F2,42 = 4.63; P = .02) was obtained (Table 2). Post hoc tests (LSD) revealed significant differences
between the unmedicated patient and healthy control groups (P = .04) (Cohen d = 0.58) and between the medicated and unmedicated
patient groups (P = .01) (Cohen d = 0.70) but no
difference was found between medicated patient and healthy control groups
(P = .46). One-way analysis of variance showed significant
group differences for 30% above the AMT (F2,42 = 3.90; P = .03) and 40% above the AMT (F2,42 = 4.79; P = .01). Post hoc tests (LSD) demonstrated that unmedicated and medicated
patients were significantly different at 30% and 40% above the AMT (P = .01 in both) whereas unmedicated patients differed
from healthy controls at 40% above the AMT (P = .03).
Averaged across all intensities (ie, 10%-40% above the AMT), the CSP was 15.26
milliseconds shorter in unmedicated patients compared with healthy controls
whereas it was 5.38 milliseconds longer in medicated patients compared with
healthy controls. Examples of EMG recordings from unmedicated and medicated
patients and healthy controls are shown in Figure 1. It has been demonstrated that MEP size influences the
duration of the CSP.15 Therefore, we compared
MEP size and found no significant group differences (F2,42 = 0.38; P = .69), excluding this as a potential confound.
|
|
|
|
Figure 1. Surface electromyographic recordings
from the tonically active first dorsal interosseus muscle following 40% suprathreshold
transcranial magnetic stimulation of A, an unmedicated patient with schizophrenia;
B, a medicated patient with schizophrenia; and C, a healthy control. Each
waveform represents the average of 15 trials. The silent period starts at
the onset of the motor evoked potential and ends with the return of any motor
activity marked by the arrow.
|
|
|
TCI
The overall excitability curve was comparable with that previously published.11-12 Our results suggest that inhibition
begins at an interstimulus interval of 6 milliseconds and continues for as
long as 20 milliseconds. A significant main effect of group (ie, unmedicated
patients and healthy controls) was obtained (F2,40 = 3.16; P = .05) (Cohen d = 0.73), with no significant group x
ISI interaction (F2,40 = 0.92; P = .41).
Post hoc tests (LSD) revealed a significant difference between unmedicated
patient and healthy control groups (P = .02) but
no significant difference between unmedicated and medicated groups (P = .16) or between medicated and healthy control groups
(P = .27). Averaged across all inhibitory ISIs (ie,
2-20 milliseconds), unmedicated patients demonstrated 23.25 % less inhibition
compared with healthy controls whereas medicated patients demonstrated 9.92%
less inhibition compared with healthy controls.
CI AND CLINICAL SYMPTOM SEVERITY
Paired-pulse TMS inhibition correlated with psychotic symptom severity
in patients with schizophrenia across PANSS total (inhibition x PANSS
total: r = 0.50, P = .01;
95% confidence interval, 0.17-0.73), Positive (inhibition x PANSS Positive: r = 0.46, P = .01; 95% confidence
interval, 0.12-0.70), and Global dimensions (inhibition x PANSS Global: r = 0.53, P = .001; 95% confidence
interval, 0.21-0.75), and trended toward significance for the PANSS Negative
dimension (inhibition x PANSS Negative: r =
0.35, P = .06) (Figure 2). For this calculation, ppTMS inhibition was averaged over
the results obtained at the 2 inhibitory ISIs (ie, 2 and 4 milliseconds).
Because the PANSS may not represent a true linear scale, we also correlated
these measures using a Spearman rank correlation and found similar results
(inhibition x PANSS Total:  = 0.53, P
= .003; inhibition x PANSS Positive: = 0.53, P = .003; inhibition x PANSS Negative: = 0.35, P = .06; inhibition x PANSS Global: = 0.56, P = .001). There was no significant correlation between other measures
of inhibition (ie, TCI and CSP) and severity of psychotic symptoms. All subjects
demonstrated minimal motor abnormalities (Table 1) that may have precluded our ability to correlate CI with
the severity of these symptoms.
|
|
|
|
Figure 2. Relationship between the Positive
and Negative Syndrome Scale (PANSS) total score and cortical inhibition in
30 patients with schizophrenia. HEP indicates motor evoked potential.
|
|
|
MT
The RMT over the left cortex was significantly lower in unmedicated
patients with schizophrenia (mean [SD], 34.40 [6.51]) compared with medicated
patients (mean [SD], 40.13 [6.47]) and healthy controls (mean [SD], 40.47
[7.13]) (F2,42 = 3.87; P = .03) (Figure 3). Post hoc tests (LSD) revealed
significant differences between unmedicated patient and healthy control groups
(P = .02) and unmedicated and medicated groups (P = .02) but not between medicated patient and healthy
control groups (P = .90). In the analysis of CI (ie,
ppTMS, TCI), baseline MT differences are included as a part of the calculation
for CS and TS and therefore, controlled for in all subjects.
|
|
|
|
Figure 3. Resting motor threshold in controls
(n = 15), medicated (n = 15), and unmedicated patients (n = 15) with schizophrenia.
Resting motor threshold was defined as the first intensity that produced a
motor evoked potential of more than 50 µV in 5 of 10 trials with the
first dorsal interosseus muscle relaxed.
|
|
|
COMMENT
Our results demonstrate that unmedicated patients with schizophrenia
have significant deficits in CI compared with healthy controls across all
3 TMS paradigms. Medicated patients had significantly greater CI compared
with unmedicated patients in the CSP paradigm and a trend toward greater inhibition
in the ppTMS and TCI paradigms. The similarity between the results obtained
from these 3 separate inhibitory paradigms is of note (Table 2). That is, unmedicated patients consistently demonstrated
deficient CI compared with healthy controls while medicated patients trended
toward greater CI compared with unmedicated patients. Thus, these results
provide TMS evidence for deficient CI in schizophrenia.
Several neurophysiologic studies have provided evidence for inhibitory
deficits in schizophrenia. For example, Adler et al,3
in an auditory conditioning-test paradigm, showed that healthy controls suppress
the amplitude of the P50 wave response to the second or TS, whereas patients
with schizophrenia had loss of suppression of this response. Several studies
have confirmed such findings.4-5,37-43
Although the relationship between evoked potential inhibition and TMS inhibition
has yet to be elucidated, several comparisons exist. First, both forms of
inhibition seem to be enhanced with the addition of atypical antipsychotic
medications.44 Second, the magnitude of inhibitory
deficits in schizophrenia is similar. Thus, our findings are consistent with
those of Adler et al and bolster the evidence for deficient CI as a pathophysiologic
feature of this illness.
Several lines of evidence suggest that inhibitory deficits exist in
multiple cortical and subcortical regions. First, Walker et al2
posit that the motor abnormalities in schizophrenia are a corollary to the
increased activity of subcortical dopaminergic neurons that results in disinhibition
of cortical inhibitory neurotransmission. Second, Benes et al45-46
reported that patients with schizophrenia have inhibitory deficits due to
fewer GABAergic interneurons in the prefrontal, anterior cingulate, and hippocampal
formation. Third, Freedman et al6 demonstrated
that P50 inhibitory dysfunction in patients with schizophrenia may arise out
of hippocampal interneuron abnormalities. Fourth, Swerdlow and Koob1 posit that inhibition deficits in sensorimotor gating
are the result of excess activation of subcortical dopamine that results in
decreased activation of cortical inhibitory projections. It remains unclear,
however, if these different inhibitory measures represent a unified inhibitory
process across different contexts or separate inhibitory phenomena. Future
research efforts directed at measuring inhibition in multiple cortical areas,
using TMS and EEG, will be helpful in this regard.47
Our results demonstrate that CI deficits, as indexed with ppTMS, were
correlated with the severity of psychosis. In contrast, no other measure of
CI was correlated with the degree of psychosis. Some evidence suggests that
these CI measures may reflect different inhibitory neural pathways. For example,
ppTMS inhibition may be mediated by GABAA interneurons48 as opposed to CSP inhibition, which may be mediated
by GABAB interneurons.49-52
This evidence, albeit preliminary, suggests that GABAA inhibitory
abnormalities may, in part, underlie psychotic symptomatology in this illness.
On close inspection of Figure 2,
it seems that the 3 subjects with the lowest PANSS scores drive the estimated
correlation. By removing these subjects, however, our PANSS ratings become
restricted to moderate and severe scores, thus limiting our ability to find
a correlation. Future research efforts aimed at replicating this finding and
exploring this relationship are necessary.
Our results also demonstrate that patients with schizophrenia have deficits
in TCI. There is considerable evidence that TCI is mediated by neuronal pathways
that travel through the corpus callosum. First, in our experiments as well
as others,11-12 inhibition begins
at an interstimulus interval of 6 milliseconds. This is consistent with estimates
of callosal conduction time (approximately 10 milliseconds) in humans.53-55 Second, in patients
with bona fide corpus callosum abnormalities (eg, patients with agenesis of
the corpus callosum as well as multiple sclerosis), TCI was profoundly impaired.56-58 Therefore, deficits
in TCI may be related to disrupted corpus callosum pathways that mediate inhibition.
In schizophrenia, there is considerable evidence of corpus callosum abnormalities
(for review see Woodruff et al59), which imply
that TCI deficits are likely due to disruption of these crossed pathways.
Animal evidence suggests that these pathways are excitatory and terminate
on local inhibitory GABAergic interneurons to mediate inhibition.60 Therefore, our finding of TCI deficits in patients
with schizophrenia may reflect either a disruption in crossed pathways mediating
inhibition or deficient local inhibitory neurons. Given the consistency of
our findings in all 3 inhibitory paradigms, our results support the latter.
Medicated patients demonstrated a trend toward enhanced CI compared
with unmedicated patients, making it unclear what effects antipsychotic medications
have on CI, particularly in patients with schizophrenia. In healthy volunteers,
Ziemann et al61 demonstrated that the antipsychotic
haloperidol resulted in significantly less CI in the ppTMS paradigm compared
with baseline. In contrast, Boroojerdi et al23
demonstrated that patients with schizophrenia, treated primarily with olanzapine
and clozapine, possessed increased TCI and hence, enhanced CI compared with
healthy controls. It is possible, given that baseline dopaminergic tone may
be different in patients with schizophrenia compared with healthy controls,62-63 that haloperidol-induced changes
to CI may act to correct these baseline abnormalities. In addition, olanzapine
has been shown to cause a down-regulation of GABAA receptors in
animal studies,64 suggesting enhanced inhibitory
GABAergic neurotransmission. However, the effect of antipsychotic medications
on CI in schizophrenia needs further substantiation with these and other inhibitory
experiments.
Unmedicated patients with schizophrenia had lower RMT compared with
medicated patients and healthy controls. The MT is conventionally regarded
as a measure of the membrane excitability of corticospinal neurons and interneurons
in the motor cortex.65 It is increased by drugs
that block voltage-gated sodium channels66-67
but is not affected by drugs that alter GABA,66
glutamate,68-69 or dopamine transmission.61 Two previously published reports20, 23
suggest that patients with schizophrenia have no differences in MT compared
with healthy controls. Puri et al20 reported
this finding in unmedicated patients with schizophrenia. Abarbanel et al,70 however, demonstrated a lower MT in patients with
schizophrenia treated with a variety of antipsychotic medications compared
with controls and patients with depression. Our findings suggest that membrane
excitability is lower in unmedicated patients with schizophrenia compared
with medicated patients and healthy controls.
There are several limitations to these initial experiments. First, CI
differences between unmedicated and medicated patients with schizophrenia
were not significant across all measures, likely due to small effects, limited
sample size, and large variance in these measures. Second, we are uncertain
if the differences observed between unmedicated and medicated patients were
truly the result of medication effects or related to other confounding variables
(eg, duration of illness). Third, it is unclear if differences in CI in the
medicated group were related to the effects of medications on GABA, dopamine,
or through some other neurotransmitter system.
In summary, unmedicated patients with schizophrenia demonstrated deficits
in CI compared with healthy controls. Moreover, medications seemed to reduce
CI deficits in these patients. We contend that disrupted CI may represent
an important neurophysiologic mechanism responsible for the symptoms seen
in patients with schizophrenia.
AUTHOR INFORMATION
Submitted for publication January 2, 2001; final revision received June
26, 2001; accepted August 13, 2001.
This study was supported through a research training fellowship from
the Ontario Mental Health Foundation, Toronto (Dr Daskalakis).
We give special thanks to Ms Annette Wolf for her endowment to the TMS
Lab at the Centre for Addiction and Mental Health. We also wish to thank Jeff
Logan, Corey Jones, HBSc, and Ted Harris-Brandts, BASc, PEng, for their assistance
with these experiments.
Corresponding author and reprints: Zafiris J. Daskalakis, MD, Schizophrenia
and Continuing Care Program, Centre for Addiction and Mental Health, Clarke
Division 250 College St, 7th Floor, Toronto, Ontario, Canada (e-mail: Jeff__Daskalakis{at}camh.net).
From the Schizophrenia and Continuing Care Program, Centre for Addiction
and Mental Health, Department of Psychiatry (Drs Daskalakis, Christensen,
Zipursky, and Kapur), and Division of Neurology, Toronto Western Hospital
(Dr Chen), University of Toronto, Toronto, Ontario; and Dandenong Psychiatry
Research Centre, Monash University and Dandenong Area Mental Health Service,
Victoria, Australia (Dr Fitzgerald).
REFERENCES
| |
1. Swerdlow NR, Koob GF. Dopamine, schizophrenia, mania, depression: toward a unified hypothesis
of cortico-striatal-pallido-thalamic function. Behav Brain Sci. 1987;10:197-245.
2. Walker EF. Developmentally moderated expressions of the neuropathology underlying
schizophrenia. Schizophr Bull. 1994;20:453-480.
3. Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R. Neurophysiological evidence for a defect in neuronal mechanisms involved
in sensory gating in schizophrenia. Biol Psychiatry. 1982;17:639-654.
ISI
| PUBMED
4. Waldo M, Myles-Worsley M, Madison A, Byerley W, Freedman R. Sensory gating deficits in parents of schizophrenics. Am J Med Genet. 1995;60:506-511.
FULL TEXT
|
ISI
| PUBMED
5. Griffith J, Hoffer LD, Adler LE, Zerbe GO, Freedman R. Effects of sound intensity on a midlatency evoked response to repeated
auditory stimuli in schizophrenic and normal subjects. Psychophysiology. 1995;32:460-466.
ISI
| PUBMED
6. Freedman R, Adler LE, Myles-Worsley M, Nagamoto HT, Miller C, Kisley M, McRae K, Cawthra E, Waldo M. Inhibitory gating of an evoked response to repeated auditory stimuli
in schizophrenic and normal subjects: human recordings, computer simulation,
and an animal model. Arch Gen Psychiatry. 1996;53:1114-1121.
FREE FULL TEXT
7. Benes FM. Model generation and testing to probe neural circuitry in the cingulate
cortex of postmortem schizophrenic brain. Schizophr Bull. 1998;24:219-230.
8. Benes FM. Cortical pathology: a new generation of quantitative microscopic studies. In: Harrison PJ, Roberts GW, eds. The Neuropathology
of Schizophrenia: Progress and Interpretation. New York, NY: Oxford
University Press; 2000:81-104.
9. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex [letter]. Lancet. 1985;1:1106-1107.
ISI
| PUBMED
10. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD. Corticocortical inhibition in human motor cortex. J Physiol (Lond). 1993;471:501-519.
FREE FULL TEXT
11. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W. The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res. 1996;109:127-135.
ISI
| PUBMED
12. Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD. Interhemispheric inhibition of the human motor cortex. J Physiol. 1992;453:525-546.
FREE FULL TEXT
13. Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol (Lond). 1996;496 (Pt 3):873-881.
14. Clark KA, Randall AD, Collingridge GL. A comparison of paired-pulsed facilitation of AMPA and NMDA receptor-mediated
excitatory postsynaptic currents in the hippocampus. Exp Brain Res. 1994;101:272-278.
ISI
| PUBMED
15. Cantello R, Gianelli M, Civardi C, Mutani R. Magnetic brain stimulation: the silent period after the motor evoked
potential. Neurology. 1992;42:1951-1959.
FREE FULL TEXT
16. Fuhr P, Agostino R, Hallett M. Spinal motor neuron excitability during the silent period after cortical
stimulation. Electroencephalogr Clin Neurophysiol. 1991;81:257-262.
FULL TEXT
|
ISI
| PUBMED
17. Inghilleri M, Berardelli A, Cruccu G, Manfredi M. Silent period evoked by transcranial stimulation of the human cortex
and cervicomedullary junction. J Physiol. 1993;466:521-534.
FREE FULL TEXT
18. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation and inhibition after transcranial magnetic
stimulation in conscious humans. J Physiol. 1997;498:817-823.
FREE FULL TEXT
19. Chen R, Lozano AM, Ashby P. Mechanism of the silent period following transcranial magnetic stimulation:
evidence from epidural recordings. Exp Brain Res. 1999;128:539-552.
FULL TEXT
|
ISI
| PUBMED
20. Puri BK, Davey NJ, Ellaway PH, Lewis SW. An investigation of motor function in schizophrenia using transcranial
magnetic stimulation of the motor cortex [see comments]. Br J Psychiatry. 1996;169:690-695.
FREE FULL TEXT
21. Davey NJ, Puri BK, Lewis HS, Lewis SW, Ellaway PH. Effects of antipsychotic medication on electromyographic responses
to transcranial magnetic stimulation of the motor cortex in schizophrenia. J Neurol Neurosurg Psychiatry. 1997;63:468-473.
FREE FULL TEXT
22. Ziemann U, Paulus W, Rothenberger A. Decreased motor inhibition in Tourette's disorder: evidence from transcranial
magnetic stimulation. Am J Psychiatry. 1997;154:1277-1284.
ABSTRACT
23. Boroojerdi B, Topper R, Foltys H, Meincke U. Transcallosal inhibition and motor conduction studies in patients with
schizophrenia using transcranial magnetic stimulation. Br J Psychiatry. 1999;175:375-379.
FREE FULL TEXT
24. Spitzer RL, Williams JBW, Gibbon M. Structured Clinical Interview for DSM-IV (SCID). New York, NY: Biometrics Research; 1995.
25. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971;9:97-113.
FULL TEXT
|
ISI
| PUBMED
26. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13:261-276.
27. Fann WE, Stafford JR, Malone RL, Frost JD Jr, Richman BW. Clinical research techniques in tardive dyskinesia. Am J Psychiatry. 1977;134:759-762.
FREE FULL TEXT
28. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11-19.
PUBMED
29. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676.
FREE FULL TEXT
30. Kaneko K, Kawai S, Fuchigami Y, Morita H, Ofuji A. The effect of current direction induced by transcranial magnetic stimulation
on the corticospinal excitability in human brain. Electroencephalogr Clin Neurophysiol. 1996;101:478-482.
FULL TEXT
| PUBMED
31. Ziemann U, Bruns D, Paulus W. Enhancement of human motor cortex inhibition by the dopamine receptor
agonist pergolide: evidence from transcranial magnetic stimulation. Neurosci Lett. 1996;208:187-190.
FULL TEXT
|
ISI
| PUBMED
32. Chen R, Tam A, Butefisch C, Corwell B, Ziemann U, Rothwell JC, Cohen LG. Intracortical inhibition and facilitation in different representations
of the human motor cortex. J Neurophysiol. 1998;80:2870-2881.
FREE FULL TEXT
33. Tergau F, Wanschura V, Canelo M, Wischer S, Wassermann EM, Ziemann U, Paulus W. Complete suppression of voluntary motor drive during the silent period
after transcranial magnetic stimulation. Exp Brain Res. 1999;124:447-454.
FULL TEXT
|
ISI
| PUBMED
34. Ziemann U, Lonnecker S, Paulus W. Inhibition of human motor cortex by ethanol: a transcranial magnetic
stimulation study. Brain. 1995;118:1437-1446.
FREE FULL TEXT
35. Ridding MC, Inzelberg R, Rothwell JC. Changes in excitability of motor cortical circuitry in patients with
Parkinson's disease. Ann Neurol. 1995;37:181-188.
FULL TEXT
|
ISI
| PUBMED
36. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, New Jersey: Lawrence Erlbaum Associates; 1988.
37. Boutros NN, Zouridakis G, Overall J. Replication and extension of P50 findings in schizophrenia. Clin Electroencephalogr. 1991;22:40-45.
ISI
| PUBMED
38. Erwin RJ, Mawhinney-Hee M, Gur RC, Gur RE. Midlatency auditory evoked responses in schizophrenia. Biol Psychiatry. 1991;30:430-442.
FULL TEXT
|
ISI
| PUBMED
39. Judd LL, McAdams L, Budnick B, Braff DL. Sensory gating deficits in schizophrenia: new results. Am J Psychiatry. 1992;149:488-493.
FREE FULL TEXT
40. Ward PB, Hoffer LD, Liebert BJ, Catts SV, O'Donnell M, Adler LE. Replication of a P50 auditory gating deficit in Australian patients
with schizophrenia. Psychiatry Res. 1996;64:121-135.
FULL TEXT
|
ISI
| PUBMED
41. Jin Y, Potkin SG, Patterson JV, Sandman CA, Hetrick WP, Bunney WE Jr. Effects of P50 temporal variability on sensory gating in schizophrenia. Psychiatry Res. 1997;70:71-81.
FULL TEXT
|
ISI
| PUBMED
42. Clementz BA, Geyer MA, Braff DL. Multiple site evaluation of P50 suppression among schizophrenia and
normal comparison subjects. Schizophr Res. 1998;30:71-80.
FULL TEXT
|
ISI
| PUBMED
43. Yee CM, Nuechterlein KH, Morris SE, White PM. P50 suppression in recent-onset schizophrenia: clinical correlates
and risperidone effects. J Abnorm Psychol. 1998;107:691-698.
FULL TEXT
|
ISI
| PUBMED
44. Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL. Normal P50 suppression in schizophrenia patients treated with atypical
antipsychotic medications. Am J Psychiatry. 2000;157:767-771.
FREE FULL TEXT
45. Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL. Deficits in small interneurons in prefrontal and cingulate cortices
of schizophrenic and schizoaffective patients. Arch Gen Psychiatry. 1991;48:996-1001.
FREE FULL TEXT
46. Benes FM. Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol Psychiatry. 1999;46:589-599.
FULL TEXT
|
ISI
| PUBMED
47. Ilmoniemi RJ, Virtanen J, Ruohonen J, Karhu J, Aronen HJ, Naatanen R, Katila T. Neuronal responses to magnetic stimulation reveal cortical reactivity
and connectivity. Neuroreport. 1997;8:3537-3540.
ISI
| PUBMED
48. Hanajima R, Ugawa Y, Terao Y, Sakai K, Furubayashi T, Machii K, Kanazawa I. Paired-pulse magnetic stimulation of the human motor cortex: differences
among I waves. J Physiol. 1998;509:607-618.
FREE FULL TEXT
49. Roick H, von Giesen HJ, Benecke R. On the origin of the postexcitatory inhibition seen after transcranial
magnetic brain stimulation in awake human subjects. Exp Brain Res. 1993;94:489-498.
ISI
| PUBMED
50. Siebner HR, Dressnandt J, Auer C, Conrad B. Continuous intrathecal baclofen infusions induced a marked increase
of the transcranially evoked silent period in a patient with generalized dystonia. Muscle Nerve. 1998;21:1209-1212.
FULL TEXT
|
ISI
| PUBMED
51. Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J. Differential effects on motorcortical inhibition induced by blockade
of GABA uptake in humans. J Physiol (Lond). 1999;517:591-597.
FREE FULL TEXT
52. Sanger TD, Garg RR, Chen R. Interactions between two different inhibitory systems in the human
motor cortex. J Physiol. 2001;530:307-317.
FREE FULL TEXT
53. Shibasaki H, Yamashita Y, Kuroiwa Y. Electroencephalographic studies myoclonus. Brain. 1978;101:447-460.
FREE FULL TEXT
54. Wilkins DE, Hallett M, Berardelli A, Walshe T, Alvarez N. Physiologic analysis of the myoclonus of Alzheimer's disease. Neurology. 1984;34:898-903.
FREE FULL TEXT
55. Amassian VE, Cracco RQ. Human cerebral cortical responses to contralateral transcranial stimulation. Neurosurgery. 1987;20:148-155.
ISI
| PUBMED
56. Rothwell J, Colebatch J, Britton T, Priori A. Physiological studies in a patient with mirror movements and agenesis
of the corpus callosum. J Physiol. 1991;438:34P.
57. Meyer BU, Roricht S, Grafin von Einsiedel H, Kruggel F, Weindl A. Inhibitory and excitatory interhemispheric transfers between motor
cortical areas in normal humans and patients with abnormalities of the corpus
callosum. Brain. 1995;118:429-440.
FREE FULL TEXT
58. Meyer BU, Roricht S, Woiciechowsky C. Topography of fibers in the human corpus callosum mediating interhemispheric
inhibition between the motor cortices. Ann Neurol. 1998;43:360-369.
FULL TEXT
|
ISI
| PUBMED
59. Woodruff PW, McManus IC, David AS. Meta-analysis of corpus callosum size in schizophrenia. J Neurol Neurosurg Psychiatry. 1995;58:457-461.
FREE FULL TEXT
60. Berlucci G. Commisurotomy studies in animals. In: Boller F, Grafman J, eds. Handbook of Neuropsychology. Vol 4. Amsterdam, the Netherlands: Elsevier; 1990:9-47.
61. Ziemann U, Tergau F, Bruns D, Baudewig J, Paulus W. Changes in human motor cortex excitability induced by dopaminergic
and anti-dopaminergic drugs. Electroencephalogr Clin Neurophysiol. 1997;105:430-437.
FULL TEXT
| PUBMED
62. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB. Single photon emission computerized tomography imaging of amphetamine-induced
dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A. 1996;93:9235-9240.
FREE FULL TEXT
63. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. From the cover: increased baseline occupancy of D2 receptors by dopamine
in schizophrenia [see comments]. Proc Natl Acad Sci U S A. 2000;97:8104-8109.
FREE FULL TEXT
64. Farnbach-Pralong D, Bradbury R, Copolov D, Dean B. Clozapine and olanzapine treatment decreases rat cortical and limbic
GABA(A) receptors. Eur J Pharmacol. 1998;349:R7-8.
65. Moll GH, Heinrich H, Wischer S, Tergau F, Paulus W, Rothenberger A. Motor system excitability in healthy children: developmental aspects
from transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol Suppl. 1999;51(suppl):243-249.
66. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W. Effects of antiepileptic drugs on motor cortex excitability in humans:
a transcranial magnetic stimulation study [see comments]. Ann Neurol. 1996;40:367-378.
FULL TEXT
|
ISI
| PUBMED
67. Chen R, Samii A, Canos M, Wassermann EM, Hallett M. Effects of phenytoin on cortical excitability in humans. Neurology. 1997;49:881-883.
FREE FULL TEXT
68. Liepert J, Schwenkreis P, Tegenthoff M, Malin JP. The glutamate antagonist riluzole suppresses intracortical facilitation. J Neural Transm. 1997;104:1207-1214.
FULL TEXT
|
ISI
| PUBMED
69. Ziemann U, Chen R, Cohen LG, Hallett M. Dextromethorphan decreases the excitability of the human motor cortex. Neurology. 1998;51:1320-1324.
FREE FULL TEXT
70. Abarbanel JM, Lemberg T, Yaroslavski U, Grisaru N, Belmaker RH. Electrophysiological responses to transcranial magnetic stimulation
in depression and schizophrenia. Biol Psychiatry. 1996;40:148-150.
FULL TEXT
|
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Is subjective duration a signature of coding efficiency?
Eagleman and Pariyadath
Phil Trans R Soc B 2009;364:1841-1851.
ABSTRACT
| FULL TEXT
Evidence for Impaired Long-Term Potentiation in Schizophrenia and Its Relationship to Motor Skill Leaning
Frantseva et al.
Cereb Cortex 2008;18:990-996.
ABSTRACT
| FULL TEXT
Dysfunctional Neural Plasticity in Patients With Schizophrenia
Daskalakis et al.
Arch Gen Psychiatry 2008;65:378-385.
ABSTRACT
| FULL TEXT
Increased cortical inhibition in persons with schizophrenia treated with clozapine
Daskalakis et al.
J Psychopharmacol 2008;22:203-209.
ABSTRACT
Alternating and Postictal Psychoses: Review and a Unifying Hypothesis
Sachdev
Schizophr Bull 2007;33:1029-1037.
ABSTRACT
| FULL TEXT
The effects of inhibitory and facilitatory intracortical circuits on interhemispheric inhibition in the human motor cortex
Lee et al.
J. Physiol. 2007;580:1021-1032.
ABSTRACT
| FULL TEXT
Dopamine transporter genotype influences the physiological response to medication in ADHD
Gilbert et al.
Brain 2006;129:2038-2046.
ABSTRACT
| FULL TEXT
High Level Bilateral Talks. Focus on "Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation on Interhemispheric Inhibition"
Harris-Love and Cohen
J. Neurophysiol. 2005;94:1664-1665.
FULL TEXT
Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation on Interhemispheric Inhibition
Pal et al.
J. Neurophysiol. 2005;94:1668-1675.
ABSTRACT
| FULL TEXT
Reduced Cerebellar Inhibition in Schizophrenia: A Preliminary Study
Daskalakis et al.
Am. J. Psychiatry 2005;162:1203-1205.
ABSTRACT
| FULL TEXT
Interactions between long latency afferent inhibition and interhemispheric inhibitions in the human motor cortex
Kukaswadia et al.
J. Physiol. 2005;563:915-924.
ABSTRACT
| FULL TEXT
Bilateral motor cortex disinhibition in complex regional pain syndrome (CRPS) type I of the hand
Schwenkreis et al.
Neurology 2003;61:515-519.
ABSTRACT
| FULL TEXT
Organization of Ipsilateral Excitatory and Inhibitory Pathways in the Human Motor Cortex
Chen et al.
J. Neurophysiol. 2003;89:1256-1264.
ABSTRACT
| FULL TEXT
Transcranial Magnetic Stimulation: A New Investigational and Treatment Tool in Psychiatry
Daskalakis et al.
J. Neuropsychiatry Clin. Neurosi. 2002;14:406-415.
ABSTRACT
| FULL TEXT
|
