Impaired inter-hemispheric facilitatory connectivity in schizophrenia.

Abstract

To investigate the inter-hemispheric connections between the dorsal premotor cortex (dPM) and contralateral primary motor cortex (M1) in schizophrenia.
Sixteen medicated, nine unmedicated schizophrenia patients and 20 healthy age-matched subjects were studied by twin-coil Transcranial Magnetic Stimulation. To activate distinct facilitatory and inhibitory transcallosal pathways between dPM and the contralateral M1, the intensity of dPM stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold). Interstimulus intervals between conditioning stimulus and test stimulus were 6, 8 and 15 ms.
Schizophrenia patients had comparable efficacy of the inhibitory pathway. On the other hand, medicated patients showed less facilitation of contralateral M1 following dPM stimulation at 80% of active motor threshold, at interstimulus interval=8 ms. The individual amount of facilitation induced by dPM conditioning at 80% of active motor threshold at interstimulus interval=8 ms correlated negatively with negative symptoms.
Inter-hemispheric facilitatory dPM-M1 connectivity is selectively altered in schizophrenia.
This study produced evidence that dPM-M1 connectivity is dysfunctional and that correlates with negative symptoms. These results converge with previous studies which strongly hypothesize that inter- and intra-hemispheric connectivity disturbances may play a major role in schizophrenia.

Full text

Page 1

Impaired inter-hemispheric facilitatory connectivity in schizophrenia
Michele Ribolsic,⇑, Francesco Moria, Valentina Magnic, Claudia Codecàa, Hajime Kusayanagia,
Fabrizia Monteleonea, Ivo Alex Rubinoc, Alberto Siracusanoc, Giorgio Bernardia,b,
Diego Centonzea,b,1, Giacomo Kocha,b,1
aClinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy
bCentro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia IRCCS, Rome, Italy
cClinica Psichiatrica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy
a r t i c l ei n f o
Article history:
Accepted 26 August 2010
Available online xxxx
Keywords:
Connectivity
Schizophrenia
Inter-hemispheric
Facilitation
TMS
Corpus callosum
a b s t r a c t
Objectives: To investigate the inter-hemispheric connections between the dorsal premotor cortex (dPM)
and contralateral primary motor cortex (M1) in schizophrenia.
Methods: Sixteen medicated, nine unmedicated schizophrenia patients and 20 healthy age-matched sub-
jects were studied by twin-coil Transcranial Magnetic Stimulation. To activate distinct facilitatory and
inhibitory transcallosal pathways between dPM and the contralateral M1, the intensity of dPM stimula-
tion was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of
active motor threshold). Interstimulus intervals between conditioning stimulus and test stimulus were 6,
8 and 15 ms.
Results: Schizophrenia patients had comparable efficacy of the inhibitory pathway. On the other hand,
medicated patients showed less facilitation of contralateral M1 following dPM stimulation at 80% of
active motor threshold, at interstimulus interval = 8 ms. The individual amount of facilitation induced
by dPM conditioning at 80% of active motor threshold at interstimulus interval = 8 ms correlated nega-
tively with negative symptoms.
Conclusions: Inter-hemispheric facilitatory dPM–M1 connectivity is selectively altered in schizophrenia.
Significance: This study produced evidence that dPM–M1 connectivity is dysfunctional and that corre-
lates with negative symptoms. These results converge with previous studies which strongly hypothesize
that inter- and intra-hemispheric connectivity disturbances may play a major role in schizophrenia.
? 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights
reserved.
1. Introduction
Schizophrenia is a serious mental disorder with lifetime preva-
lence estimates of about 0.4–0.5% (Goldner et al., 2002). Recent
data point towards network alterations leading to abnormal con-
nectivity as important determinants of schizophrenia pathophysi-
ology, i.e. schizophrenia may be caused not by focal brain
abnormalities but by a pathological interaction between brain re-
gions (Stephan et al., 2009; Ribolsi et al., 2009).
Recent advances in neuroimaging techniques have reported
abnormalities in functional and structural connectivity in schizo-
phrenia (Karlsgodt et al., 2008). In particular, many morphological
and functional imaging studies have shown altered connectivity
between prefrontal and parietal cortex (Woodward et al., 2009),
frontal and temporal areas (Spoletini et al., 2009), occipital and
frontal areas (Kunimatsu et al., 2008), thalamus and cortical areas
(Welsh et al., 2008), thalamus and cerebellum (Magnotta et al.,
2008), hippocampus and other cerebral regions (Zhou et al.,
2008). More importantly, recent findings confirm that reduced
frontotemporal functional connectivity in schizophrenia is associ-
ated with auditory hallucinations. (Lawrie et al., 2002). Event
RelatedPotential(ERP)studies,
EEG-coherence and P300 studies, support the hypothesis of
dysconnectivity between brain regions (Winterer et al., 2003; Buc-
ci et al., 2007; Pachou et al., 2008).
Interestingly, there is also evidence of dysconnectivity in the
early stages of the disease (Begré and Koenig, 2008). In particular,
recent DTI findings confirm the presence of white matter abnor-
malities even in the early course of the illness, in particular in fron-
totemporal, frontoparietal and temporooccipital connections with
projection fibres and cerebellar white matter being among the
affected tracts (Kyriakopoulos and Frangou, 2009).
inparticularevent-related
1388-2457/$36.00 ? 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2010.08.013
⇑Corresponding author. Address: Clinica Psichiatrica, Dipartimento di Neuro-
scienze, Università Tor Vergata, Viale Oxford 00133, Rome, Italy. Tel.: +34
90887413; fax: +39 0641400343.
E-mail addresses: michele.81@live.it, mic19812000@yahoo.it (M. Ribolsi).
1These authors contributed equally to this work.
Clinical Neurophysiology xxx (2010) xxx–xxx
Contents lists available at ScienceDirect
Clinical Neurophysiology
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A new method based on twin-coil Transcranial Magnetic Stim-
ulation (tcTMS) directly investigates the neurophysiological inter-
actions and the ongoing functional connections between different
cortical areas (Daskalakis et al., 2005; Fitzgerald et al., 2008; Koch
et al., 2007).
Using this novel approach, we have shown that an altered pat-
tern of connectivity between posterior parietal cortex (PPC) and
ipsilateral primary motor cortex (M1) characterizes patients with
schizophrenia. Interestingly, the degree of failure in parieto-motor
interaction correlated with negative symptoms in the group of pa-
tients suggesting that alterations in cortico-cortical connectivity
might play an important role in the onset of psychotic symptom-
atology (Koch et al., 2008).
Another growing body of research is investigating transcallosal
connectivity. Corpus callosum plays an important role in the
pathophysiology of schizophrenia (Walterfang et al., 2008a;
Woodruff et al., 1997). Nasrallah (1985) argued that Schneiderian
first-rank symptoms, such as delusions, may result from the
abnormalintegrationofinter-hemispherically
information. Recently, a reduction in the thickness of the genu
of the corpus callosum was found in those subjects who later
developed a first-episode psychosis (Walterfang et al., 2008b).
Interestingly, DTI studies have found a specific role of anterior
transcallosal dysconnectivity in underlying positive symptoms
(Brambilla et al., 2005). In this context, converging data in
schizophrenia showing a disruption of white matter communica-
tion strongly hypothesize that inter- and intra-hemispheric
connectivity disturbances may play a major role in schizophrenia
(Brambilla and Tansella, 2007).
The aim of the current study was to investigate the function-
ing of inter-hemispheric connections originating from the left
premotor dorsal area (dPM) in patients with schizophrenia.
dPM play an important role in schizophrenia; it is involved in
making decisions concerning the right moment for action
(Rushworth et al., 1998). Impairment in motor abilities such as
sequence learning has been related to the dysfunction of this area
in schizophrenia (Marvel et al., 2007). Studies conducted with
TMS on premotor cortices show a reduced motor facilitation dur-
ing action observation in schizophrenia thus supporting the
hypothesis of a mirror neuron deficit (Enticott et al., 2008). Re-
cent studies in healthy subjects reveal that it is also possible to
probe the functional connectivity of these areas in human cortex
using twin-coil TMS. Mochizuki et al. (2004) found that a condi-
tioning TMS pulse over the dPM at 90% or 110% of the resting
motor threshold (RMT) activated an inhibitory pathway, reducing
the amplitude of motor evoked potentials (MEPs) in hand mus-
cles elicited by a second TMS pulse to the contralateral M1.
The effect was best seen if the interstimulus interval (ISI) was
8–10 ms. The opposite effect, facilitation of contralateral MEPs,
was found when left dPM conditioning stimuli of lower intensity
(80% active motor threshold (AMT) at ISI = 8 ms (Bäumer et al.,
2006) were applied.
Inter-hemispheric facilitation and inhibition can be induced dif-
ferentially by conditioning M1 and dPM using different condition-
ing pulses as they activate separate anatomical pathways that
project to different populations of interneurons in the receiving
M1. However, little is known about the neurophysiological mech-
anisms that are responsible for dPM–M1 connectivity (Bäumer et
al., 2006).
These connections are thought to play a relevant role during
movement selection (Koch et al., 2006). The purpose of our study
therefore was to explore the connections between left dPM and
right M1 in a group of patients with schizophrenia and to compare
these with a group of healthy control subjects, thereby testing the
hypothesis that transcallosal communication originating from dPM
may be defiant in schizophrenia.
transmitted
2. Methods and materials
2.1. Subjects
Included were: a group of schizophrenia patients under anti-
psychotic treatment (age 41.6 ± 9.4), a group of schizophrenia pa-
tients unmedicated for at least 1 month (age 40.5 ± 9.4) and a
group of healthy volunteers (age 38.4 ± 8.45). We recruited 25
right-hand schizophrenia patients (16 medicated and 9 unmedi-
cated); diagnoses (see Table 1) were made with the Structured
Clinical Interview for DSM-IV (SCID-P) by two expert independent
psychiatrists (I.A.R.; A.S.). The inter-judgement agreement for the
diagnosis of schizophrenia was perfect (ICC = 1). Before TMS eval-
uation, we used the Brief Psychiatric Rating Scale (BPRS-18 item),
the Positive and Negative Syndrome Scale (PANSS) and the Global
Assessment Functioning (GAF) to index the severity of psychopa-
thology. None of the patients had a past history of drug or alcohol
abuse. Medicated patients were taking typical and atypical anti-
psychotic drugs (23.33 ± 11.54 mg of aripiprazole, 3 patients;
7.3 ± 3.86 mg of haloperidol, 5 patients; 350 ± 168.32 mg of cloza-
pine, 4 patients; 500 ± 258.19 mg of amisulpride, 4 patients;
150 mg of chlorpromazine, 1 patient; 3.33 ± 0.57 mg of risperi-
done, 3 patients; 750 ± 0 mg of quetiapine, 2 patients). To compare
the amount of different antipsychotic drugs, the doses of antipsy-
chotic have been converted in chlorpromazine equivalents. The
formulas were then solved for chlorpromazine 100 mg to deter-
mine each drug’s chlorpromazine equivalent in milligrams, using
100 mg of chlorpromazine as the comparator (Woods, 2003).
These patients were also being treated with benzodiazepine
drugs, antidepressive and mood stabilizers. None of the patients
had extrapyramidal symptoms.
A control group of 20 healthy male subjects (HS) took part in the
study; no significant difference between the age of the two groups
was found (t = ?1.25; df = 24; p = 0.22). Control subjects were
screened for psychopathology with a modified SCID. Exclusion cri-
teria were a comorbid medical illness or a past history of drug or
alcohol abuse. All subjects were right-handed on the basis of Edin-
burgh Handedness Inventory, and they all gave informed written
consent for the study. The experimental procedures used were ap-
proved by the Local Ethics Committee and were carried out in
accordance with the Declaration of Helsinki.
2.2. TMS
Electromyographic (EMG) traces were recorded from the first
dorsal interosseous (FDI) bilaterally with 9-mm diameter, silver–
silver chloride (Ag–AgCl) surface cup electrodes. The active elec-
trode was placed over the muscle belly and the reference electrode
over the metacarpophalangeal joint of the index finger. Responses
were amplified with a Digitimer D360 amplifier (Digitimer, Wel-
wyn Garden City, Hertfordshire, United Kingdom) through filters
set at 20 Hz and 2 kHz with a sampling rate of 5 kHz, then recorded
by a computer with SIGNAL software (Cambridge Electronic De-
vices, Cambridge, United Kingdom). A twin-coil stimulation tech-
nique with two high-power Magstim 200 machines (Magstim
Co., Whitland, Dyfed, UK) was used. The magnetic stimulus had a
nearly monophasic pulse configuration with a rise time of about
100 ls, decaying back to zero over about 0.8 ms. The conditioning
stimulator was connected to a small custom-made figure-of-eight-
shaped coil (external diameter 55 mm) in order to reduce the effec-
tive area of stimulation, and the test stimulator was connected to a
standard, larger, figure-of-eight-shaped coil (external diameter
70 mm). The hand motor area of M1 was defined as the point
where stimulation evoked the largest MEP from the contralateral
FDI muscle. In order to stimulate M1, the coil was always placed
2
M. Ribolsi et al./Clinical Neurophysiology xxx (2010) xxx–xxx
Please cite this article in press as: Ribolsi M et al. Impaired inter-hemispheric facilitatory connectivity in schizophrenia. Clin Neurophysiol (2010),
doi:10.1016/j.clinph.2010.08.013

Page 3

tangentially to the scalp at a 45? angle to the midline in order to
induce a posterior–anterior (PA) current flow across the central
sulcus. The intensity of test stimulus (TS), applied over right M1,
was adjusted to evoke a motor evoked potential (MEP) of approx-
imately 1 mV peak-to-peak in the relaxed left FDI. A conditioning
stimulus (CS) was applied over left dPM (Fig. 1A). As in previous
studies, 8% of the distance between nasion and inion (typically
about 3 cm) was calculated for each subject and the dPM area de-
fined as the distance anterior to M1 in order to minimize M1 acti-
vation when applying TMS pulses to dPM (Koch et al., 2006, 2008;
Mochizuki et al., 2004; Bäumer et al., 2006). To activate both facil-
itatory and inhibitory transcallosal pathways, the intensity of CS
was adjusted to be either suprathreshold (110% of resting motor
threshold-RMT) or subthreshold (80% of active motor threshold-
Table 1
Demographic and clinical characteristics of the sample.
No.AgeSexIllness durationBPRSPANSS GAF Eq CpzAntidepressive drugsBenzodiazepines Diazepam EqMood stabilizers
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Mean
SD
46
48
41
26
23
30
37
36
50
40
54
56
48
46
41
44
41.6
9.4
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
F
–
–
20
23
20
9
1
11
15
16
28
24
38
23
23
27
5
25
19.2
9.3
45
74
35
61
53
40
39
57
68
44
44
38
82
77
75
64
56
15.8
79
117
101
79
83
59
107
98
78
81
96
69
82
103
103
116
90.7
16.8
51
10
30
60
50
51
40
20
51
28
50
30
35
41
39
38
39
13.2
283.3
600
566.6
775
250
400
800
500
700
1000
997.5
150
250
997.5
250
150
541.8
308.3
–
–
–
Citalopram 10 mg
–
–
Citalopram 20 mg
–
–
–
–
Paroxetine 20 mg
–
–
–
–
–
–
Lorazepam 2.5 mg
Zolpidem 10 mg
Alprazolam 1 mg
Zolpidem 20 mg
Alprazolam 1 mg
Lorazepam 1.5 mg
Alprazolam 0.5 mg
Lorazepam 2.5 mg
Clonazepam 4 mg
Alprazolam 3 mg
Clonazepam 4 mg
Lorazepam 1 mg
Clonazepam 1 mg
–
–
Zolpidem 10 mg
–
–
25
5
20
10
20
15
10
25
80
60
80
10
20
0
0
5
20.6
24.5
–
–
–
–
–
–
–
–
–
Carbolithium 300 mg
–
–
–
–
–
–
–
–
1
2
3
4
5
6
7
8
9
Mean
SD
52
43
36
33
59
33
31
37
41
40.5
9.4
M
M
M
M
F
M
M
M
M
–
–
2
3
19
14
26
2
3
14
16
11
8.8
28
50
39
29
38
50
43
38
36
39
7.8
52
48
66
94
50
59
66
75
67
64.1
14.4
40
30
50
51
51
55
48
42
46
45.8
7.5
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Age and illness duration are given in years. PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment Functioning; Eq Cpz, chlorpromazine equivalents.
Fig. 1. Cortico-cortical connectivity between the dorsal premotor cortex (dPM) and the primary motor cortex (M1) was tested with a twin-coil procedure. A conditioning
stimulus (CS) was applied at different intensities over the left dPM before MEPs were obtained by right M1 stimulation with subjects at rest. CS preceded TS applied over M1
by different ISIs ranging from 15 to 6 ms (A). Inhibitory dPM–M1 connectivity induced with CS set at 110% RMT did not differ among patients and healthy controls (B).
Facilitatory connections activated by CS set at 80% AMT were reduced in medicated patients with schizophrenia in comparison with a group of healthy subjects, in which a
stronger facilitation of MEPs following dPM conditioning was evident at ISI = 8 ms (C).
M. Ribolsi et al./Clinical Neurophysiology xxx (2010) xxx–xxx
3
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Page 4

AMT) (Koch et al., 2006, 2007; Mochizuki et al., 2004). We chose to
stimulate left dPM because both pathways were reliably activated
following stimulation of this area (Koch et al., 2006). We defined
RMT and AMT according to international standards (Rothwell,
1997). Interstimulus intervals (ISIs) between CS and TS were 6, 8
and 15 ms. We performed two blocks with different CS intensities
set at 80% AMT and 110% RMT. The order of presentation of blocks
varied pseudo-randomly among subjects. Each block consisted of
50 trials. Four conditions were randomly intermingled: TS alone
(MEP), and CS + TS (conditioned MEP for each three different ISIs).
Twenty responses were collected for the test stimulus alone and 10
responses for conditioned MEPs at each ISI. Measurements were
made on each individual trial and the mean peak-to-peak ampli-
tude of the conditioned MEP was expressed as a percentage of
the mean peak-to-peak amplitude of the unconditioned test pulse.
2.3. Data analysis
The effects of paired TMS over left dPM on the size of motor
evoked potentials recorded from the left hand in response to right
M1 TMS were analyzed as the percentage of the mean peak-to-
peak amplitude of the unconditioned test M1 pulse. Mean percent-
age values were analyzed in a mixed-design ANOVA, with ‘group’
as a between-subjects factor (medicated, unmedicated, healthy
controls), plus ‘conditioning intensity’ (110% RMT or 80% AMT)
and the ‘ISI’ between left dPM and right M1 pulses (6, 8 and
15 ms) as within-subjects factors.
We employed Pearson r correlation coefficient in univariate cor-
relations to explore any influence of the clinical parameters on the
individual amount of facilitation induced by dPM conditioning at
80% AMT and at ISI = 8 ms. Then we performed multiple regression
analysis to determine predictors of impaired connectivity among
the following clinical measures: negative and positive sub-scale
of the PANSS, GAF, disease duration, chlorpromazine equivalents,
diazepam equivalents. Variables were entered in the model in this
order following a hierarchical order based on our previous observa-
tion showing a significant correlation between dysconnectivity and
negative symptoms (Koch et al., 2008). Normality was tested by
Kolmogorov–Smirnov test.
3. Results
The procedure was well tolerated by all subjects. There were no
significant differences between medicated and unmedicated pa-
tients with schizophrenia and HS when comparing RMT. RMT of
the left M1 (used to calibrate the intensity of CS over dPM) was
respectively 42.7 ± 4.8% of maximal stimulator output (MSO) in
the medicated group, 38.9 ± 5.7% in the unmedicated group and
39.6 ± 6.8% in the HS group. AMT of the left M1 was respectively
31.8 ± 5.1% of maximal stimulator output (MSO) in the medicated
group, 34.1 ± 4.2% in the unmedicated group and 32.8 ± 5.9% in
the HS group. The MEPs amplitude recorded for TS did not differ
between the three groups. We found that inter-hemispheric dorsal
premotor–motor connectivity differed between patients with
schizophrenia and the HS groups (see Fig. 1B and C), with medi-
cated patients with schizophrenia showing reduced inter-hemi-
spheric facilitation, but normal inhibition. This was borne out in
the ANOVA showing the significant main effects of the mean with-
in-subjects factor ISI (F = 9,15; p < 0.001) and of the triple interac-
tion GROUP ? INTENSITY ? ISI which was also significant (F = 3.89;
p < 0.05).
Subsequent post hoc analysis showed that when compared to
healthy subjects only the medicated patients with schizophrenia
had less facilitation for CS intensity = 80% AMT at ISI = 8 ms
(p < 0.05) (Fig 1C).
The individual amount of facilitation induced by dPM condi-
tioning at 80% AMT at ISI = 8 ms correlated negatively with the
negative sub-scale of the PANSS (r = ?0.46; p < 0.05), showing that
patients with lower negative symptoms had less impaired connec-
tivity (see Fig. 2A). No other correlations were found with positive
sub-scale of PANNS (r = 0.12; p = n.s. Fig. 2B), GAF (r = ?0.01;
p = n.s.) and with disease duration (r = 0.22; p = n.s.). In the medi-
cated group the facilitation induced by dPM conditioning at 80%
AMT did not correlate with the chlorpromazine equivalents
(r = 0.18; p = n.s.), hence antipsychotic drugs did not influence
the strength of dPM–M1 connectivity. Finally, no correlation was
found with benzodiazepines (Diazepam equivalents) (r = 0.11;
p = n.s.).
A subsequent multiple regression analysis confirmed that the
individual amount of facilitation induced by dPM conditioning at
80% AMT at ISI = 8 ms was predicted only by the negative sub-scale
of the PANSS (standardized b = ?.61; p = 0.03). No other significant
predictor beta values were found.
4. Discussion
This study provides evidence that facilitatory connections be-
tween left dPM and contralateral primary motor cortex are selec-
tively dysfunctional in patients with schizophrenia. Accordingly,
a comparison of patients with schizophrenia with a sample of
healthy age-matched subjects did not show typical facilitatory
interactions between these two cortical areas seen by using a
twin-coil TMS approach. Conversely, the inhibitory pathways were
not impaired. Most of the patients were under antipsychotic treat-
ment such as antidopaminergic agents which may have interfered
with cortico-cortical transmission. However, in the medicated
group no correlation was found between the chlorpromazine
equivalents and the degree of altered inter-hemispheric facilitatory
connectivity in these patients. Therefore, we may argue that anti-
dopaminergic drugs are not likely to directly influence these mea-
sures. It should be noted that when compared to the healthy
controls, the non-medicated patients showed a similar profile of
activation of dPM–M1 facilitatory pathways. It may well be that
the activation of dPM–M1 facilitatory pathways did not differ from
healthy controls since these patients presented less severe symp-
toms than the medicated patients. In fact, we found a significant
correlation among individual dPM–M1 facilitation and PANNS neg-
ative scores when data from both medicated and non-medicated
patients with schizophrenia were analyzed together, suggesting
that patients with less severe symptoms had less impaired connec-
tivity. However, it should be pointed out that pooling both groups
and reporting a correlation of symptom severity does not allow us
to exclude potential confounders. If medication does cause the ef-
fect, and patients with more symptoms are more likely to be med-
icated, then the same pattern would emerge as if the symptoms
had caused the effect.
Several studies have reported the role of premotor cortices, in
particular dPM, in schizophrenia. It is generally agreed that, while
M1 plays a major role in the generation of segmented distal move-
ments, dPM is involved in different complex functions such as
selecting motor programmes based on sensory information, or in
decisional processes that depend on previously learned arbitrary
associations (Wise et al., 1997; Schluter et al., 1998). Impaired mo-
tor abilities have been commonly reported in schizophrenia. Vari-
ous studies observed that these patients are slow in initiating
movements, have prolonged reaction times and present difficulties
in executing repetitive movements such as finger tapping (Vrtun-
ski et al., 1989; Boks et al., 2000). Functional imaging studies have
reported abnormalities in the activation of the motor system,
showing a decreased activity in the primary motor cortex and in
4
M. Ribolsi et al./Clinical Neurophysiology xxx (2010) xxx–xxx
Please cite this article in press as: Ribolsi M et al. Impaired inter-hemispheric facilitatory connectivity in schizophrenia. Clin Neurophysiol (2010),
doi:10.1016/j.clinph.2010.08.013

Page 5

the premotor areas (Wenz et al., 1994; Schröder et al., 1999;
Müller et al., 2002; Rogowska et al., 2004). Furthermore, previous
rTMS studies have reported abnormal premotor–motor cortex
modulation in schizophrenia, in particular reduced premotor rTMS
suppression of motor cortical excitability in patients with schizo-
phrenia than in control subjects (Oxley et al., 2004).
Moreover, reduced activation of the premotor areas was more
pronounced during right hand movements, consistent with the
hypothesis of hemispheric asymmetry in schizophrenia (Rogowska
et al., 2004). Recent TMS studies in patients with schizophrenia
have also shown a reduced activity of the mirror neuron system,
interpreted possibly as a dysfunction of premotor areas (Enticott
et al., 2008). It is likely that the altered patterns of connectivity ob-
served here may reflect a dysfunctional activity of connections
originating from dPM that could be involved in the previously de-
scribed impaired motor abilities. Abnormalities of corpus callosum
(CC) have been shown in schizophrenia patients by magnetic reso-
nance imaging (MRI) studies (Goghari et al., 2005; Bachmann et al.,
2003). DTI studies have supported the existence of widespread
microstructure disruption of CC in schizophrenia, which may ulti-
mately lead to inter-hemispheric misconnection (Brambilla and
Tansella, 2007). However, although reported in previous studies
investigating the connections between the two primary motor cor-
tices with TMS, we did not find any difference in the latency of in-
ter-hemispheric interactions (Fitzgerald et al., 2002; Daskalakis
et al., 2002; Hoy et al., 2008), which would suggest that our find-
ings may not be strictly related to microstructural disruption of
CC. Conversely, the excitatory connectivity between dPM and mo-
tor cortex may be impaired at the level of synaptic transmission. It
should be noted that most of the long-range fibres that cross the
corpus callosum are facilitatory (Kukaswadia et al., 2005). It is
known that facilitatory transcallosal cortico-cortical fibres reach
a population of different classes of GABAergic inhibitory neurons
in the motor cortex with distinct pharmacological properties that
have different connectivity and interact differentially with pyrami-
dal neurons (Reis et al., 2008; Xiang et al., 1998). Hence, it is pos-
sible that the reduced activation of dPM facilitatory pathways may
involve either a decreased activation of the output of dPM neurons
or an altered processing of such input within intracortical circuits
of the contralateral M1.
Our work has produced evidence of a correlation between the
degree of impairment of dPM–M1 connectivity and negative symp-
toms. This is in line with our previous study where we observed
that patients with greater negative symptomatology had more im-
paired parieto-motor connectivity (Koch et al., 2008). Negative
symptoms, e.g., blunted affect and social withdrawal, have been
correlated with the hypothesis of dysconnectivity in schizophrenia
as they could also be explained by abnormal modulation of synap-
tic plasticity. It has recently been postulated that a central patho-
logical mechanism in schizophrenia might be an aberrant N-
methyl-D-aspartate receptor (NMDAR)-mediated synaptic plastic-
ity due to abnormal regulation of NMDARs by neuromodulatory
transmitters like dopamine (DA), acetylcholine (ACh), or serotonin
(5-HT) (Stephan et al., 2009; Daskalakis et al., 2008). Preliminary
studies have investigated a possible therapeutic role for NMDA
agonists glycine and D-serine in producing reductions in persistent
negative and cognitive symptoms (Tuominen et al., 2006). The
hypothesis of an aberrant glutamatergic transmission may con-
verge with our findings of impaired excitatory connectivity be-
tween dPM and motor cortex.
5. Limitations
Several limitations have to be considered in this study. First, we
have hypothesized a disruption of the connectivity between the
dorsal premotor cortex and the contralateral primary motor cortex
in schizophrenia. However, it may be that cortico-cortical connec-
tivity may be disrupted between any two regions of the cortex (i.e.
not simply premotor to motor).
Second, another limitation is that, given that they may be gen-
der differences in laterality in normality and disease states, in our
sample there are only two females in the patient group and none in
the control group.
Furthermore, in this study we have recruited patients treated
with benzodiazepines and antipsychotics, which should be ex-
cluded due to the potential confound on inhibition and facilitation
in the cortex. This could potentially account for the lack of differ-
ences in inhibition between medicated and unmedicated patients
that is primarily GABAergically mediated. In our study we have
showed that there is no correlation between drug doses and the ef-
fect, but this is not enough to exclude any confounding effects due
to medications. However, further investigations are needed to clar-
ify this aspect.
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Please cite this article in press as: Ribolsi M et al. Impaired inter-hemispheric facilitatory connectivity in schizophrenia. Clin Neurophysiol (2010),
doi:10.1016/j.clinph.2010.08.013