increasingly , it is hypothesized that schizophrenia reflects subtle connectivity dysfunction ( pettersson - yeo et al . , 2011 ) .
converging neurophysiological and neuroimaging data have documented widely distributed abnormalities in brain activity and functional connectivity ( buckholtz and meyer - lindenberg , 2012 ; friston and frith , 1995 ; pettersson - yeo et al . , 2011 ; stephan et al . , 2006 ) ,
validating the overarching disconnection hypothesis of schizophrenia ( andreasen et al . , 1998 ) .
in terms of the structural aspects , a qualitative review ( kubicki et al . , 2005 ) and a quantitative meta - analysis ( ellison - wright and bullmore , 2009 ) have documented widespread reductions in white matter fractional anisotropy in chronic schizophrenia , which have also been observed in first - episode patients ( friedman et al . , 2008 ) .
an abnormal white matter ultrastructure likely underlies abnormal cooperation among brain networks ( calhoun et al . , 2009 ) . after finding abnormal functional connectivity between the frontal and temporal regions , friston and frith ( 1995 ) proposed fronto - temporal disconnection as a key neurobiological feature of schizophrenia
 dysconnectivity  has been introduced to refer to abnormal integration between anatomically distinct brain regions ( stephan et al . , 2006 , 2009 ) .
( 1998 ) suggested that disruption of the cortico - cerebellar  thalamic  cortical ( cctc ) circuits underlies the deterioration in neural synchrony , with improper coordination of the mental processes leading to  cognitive dysmetria .
 abnormal neural synchrony ( ford et al . , 2007 ) is hypothesized to be one of the main causes of cognitive dysfunction in schizophrenia . a recent review ( uhlhaas and singer , 2010 ) concluded that altered neural oscillations and synchrony are crucial elements in the pathophysiology of schizophrenia .
this conclusion was based on aberrant connectivity and synchrony findings in patients with schizophrenia ( friston and frith , 1995 ; garrity et al .
, 2008 ; kim et al . , 2008 ) , as well as differences in effective connectivity in schizophrenia patients compared to controls ( demirci et al . , 2008 ;
the dysconnectivity hypothesis has been extended to explain specific symptoms in schizophrenia , particularly auditory hallucinations ( ah ) ( rish et al . , 2013 ) and visual hallucinations and ah in findings by amad et al .
neuroimaging studies have found abnormal activation in patients with ah , particularly in cortical regions of language processing ( allen et al . , 2008 ) .
several studies have shown abnormal structural and functional connectivity in patients with ah ( benetti et al .
most studies have found reduced functional connectivity between the temporal , limbic and frontal areas ( hoffman et al . , 2011 ; vercammen et al . , 2010
few studies ( e.g. , mechelli et al . , 2007 ) have analyzed synchrony and effective connectivity in a group of patients with schizophrenia and ah .
emotional processing disturbances have been related to the origination of ah ( sanjun et al . , 2006 ; aleman and lari , 2008 ) .
our group has focused on understanding emotional processing in patients with ah . in a previous study
, we obtained evidence of enhanced activation of the limbic and frontal brain areas in a small group of patients with persistent ah engaged in passively listening to emotional words ( sanjun et al . , 2007 ) . these results implicated circuits subserving the processing of emotional stimuli as a neural substrate of ah . in a subsequent work ,
we studied functional connectivity in response to an emotional auditory paradigm in patients with ah by conducting independent component analyses ( ica ) ( escart et al . , 2010 ) .
using this approach , the activated areas could be obtained by selecting the ica components related to the emotional auditory paradigm .
functional connectivity is then characterized by detecting statistical dependencies among the time courses of the areas activated in response to the auditory emotional stimuli ( escart et al . , 2010 ) .
in addition to the temporal , frontal and parietal networks detected in all subjects , in the schizophrenia patients with ah , we observed a specific pattern of functional connectivity involving activation of the limbic structures ( predominantly the amygdala and parahippocampal gyrus ) .
we used an emotional auditory task in this work to analyze the synchrony patterns and granger - causal relationships to study effective connectivity and to determine which brain regions directly influence other brain regions .
we predicted the following results : compared to the controls and schizophrenia patients without ah , the schizophrenia patients with ah would 1 ) have abnormal synchrony between the detected networks and concrete abnormalities in the frontal cortex compared with the other brain regions and 2 ) have different granger - causal interactions between the frontal , parietal , temporal , limbic and cerebellar networks .
a total of 41 male patients with schizophrenia ( 27 with chronic ah and 14 without ah ) were recruited .
the patients with chronic ah fulfilled the following selection criteria for persistent hallucinations ( sanjun et al . , 2007 ) : ( a ) they heard voices that were resistant to treatment for at least 1  year ; ( b ) the voices were present at least once a day during the last year ; and ( c ) at least two antipsychotic drugs had been tried in the last year at doses equivalent to at least 600  mg / day of chlorpromazine .
patients with a history of traumatic brain injury , epilepsy or other neurological or psychiatric history were excluded .
the patients were clinically assessed with the positive and negative syndrome scale ( panss ) ( kay et al . , 1987 ) , the brief psychiatric rating scale ( bprs ) ( ventura et al . , 1993 ) and the psychotic symptom rating scale ( psyrats ) for ah ( haddock et al . , 1999 ) in the 24  h prior to scanning .
the participants were male , right handed ( as assessed with the edinburgh questionnaire , oldfield , 1971 ) and caucasian , and they provided written informed consent to participate in the experiment .
the healthy controls and patients did not differ significantly in terms of sex , laterality , or ethnicity .
the groups differed significantly in educational level , with a greater proportion of individuals with university and high school diplomas ( or equivalence ) in the control group , as expected .
a 1.5  tesla scanner ( philips medical systems ) was used to acquire bold contrasts during a stimulation paradigm ( escart et al .
an emotional auditory paradigm was designed to evoke emotions related to the patients ' hallucinatory experiences ( supplementary material  1 ) .
the activation blocks in one session consisted of 13 spanish words with high emotional content .
the other session had activation blocks containing 13 words with neutral or low emotional content .
four blocks of stimuli ( 20  s each ) were interleaved with four blocks of rest of 20  s each .
the subjects were informed before the test regarding the two types of words they were going to hear and were asked to focus their attention on these words .
pre - processing of the functional data was performed using spm ( http://www.fil.ion.ucl.ac.uk/spm ) ( supplementary material  2 ) .
the ica analysis was performed using the group ica approach fmri toolbox ( gift , http://www.icatb.sourceforge.net ) .
components of interest ( coi ) were selected ( in terms of the individual beta values related to the emotional task ) , and the regressors in each component were entered into a one - sample t - test with a threshold of p  <  0.01 ( escart et al . , 2010 ) .
a correlation test was performed to evaluate the relationship between age and the components of interest loads .
we used the intra - group ica time - course ( tc ) correlation coefficient matrix obtained for all pair - wise combinations of ica - tc to examine functional connectivity across the three groups ( jafri et al . , 2008 ) .
to observe the relationships between every coi pair , we calculated pearson 's correlation coefficients ( friston , 1994 ) ( supplementary material  3 ) .
the data tool granger causal connectivity analysis ( gcca ) was used to analyze causality ( seth , 2010 ) . a key challenge when analyzing such data
is to study the causal connectivity using a driven - data methodology to study multivariate time series .
this kind of methodology combines graph - theoretic and network - theoretic techniques that allow their quantitative characterization ( seth , 2005 ) . within a given causal network , we defined the causal flow of a node , 
i  , as the difference ( weighted or not ) between its inflows and outflows .
a node with positive causal flow exerts strong causal influence on a dynamic system as a whole .
in contrast , a node with negative causal flow is called a causal sink ( seth et al . , 2011 ) .
the causal density of a dynamic system provides an overall measure of causal interactivity ( seth , 2005 ) .
this causal density measure is defined as a causal graph for all pairs of elements in the system .
those interactions that are not significant are assigned zero values , as calculated by the following expression:(1)cd(x)=1n(n1)ijfxixj|x|ij| where x[ij ] is a x subsystem omitting variables xi and xj . this value could be calculated between 0 and 1 and is based on causal density , in which all significant interactions are assigned the value 1 .
causal density measures dynamic complexity because it reflects the complexity of integration and the coexistence of dynamic segregation ( sporns , 2007 ) .
however , the elements are dynamically different ; therefore , diverse elements contribute in a different manner .
i  is a value related to the causal interaction of that node i normalized by the number of nodes .
a system with n - nodes has n elements with n - cdn values , is an unweighted version and is calculated by assigning all significant interactions the value 1 . a node with a high value for cdn
as previously reported ( escart et al . , 2010 ) , the following coi were identified in the control group : temporal ( ce19 ) , fronto - temporo - parietal ( ce18 ) , subcortical 
the following coi were identified in the patient group with ah : temporal ( he17 ) , fronto - parietal ( he14 ) , fronto - temporal ( he11 ) , limbic ( parahippocampal  amygdalar ) ( he06 ) , and occipito - cerebellar ( he02 ) .
the following coi were identified in the patients with schizophrenia but without chronic ah : temporal ( nhe19 ) , fronto - temporal ( nhe18 ) , subcortical 
temporo - parietal  cerebellar ( nhe13 ) and fronto - parietal ( nhe12 ) .
, higher correlations were found for the temporal component ( ce19 ) , particularly in the relationships to the subcortical  fronto - temporal ( ce09 ) and occipito - cerebellar ( ce04 ) components .
the minimal correlation value was found in the relationship between the fronto - temporo - parietal ( ce18 ) and subcortical  fronto - temporal ( ce09 ) components .
1a shows that the temporal ( ce19 ) and subcortical  fronto - temporal ( ce09 ) components were synchronized , whereas the fronto - temporo - parietal ( ce18 ) and occipito - cerebellar ( ce04 ) components were delayed , compared with components ( ce19 , ce09 ) .
1a ( right ) depicts the correlation function calculations for the control group in terms of the phaser graphs .
the lag at which this value is obtained is represented by the means of the angle between the vector and the horizontal axis . as shown in table  3 and fig .  1b , we found high correlations among the temporal ( he17 ) , fronto - parietal ( he14 ) and fronto - temporal ( he11 ) components .
additionally , the limbic ( he06 ) and occipito - cerebellar ( he02 ) components were significantly correlated with one another ; however , they were unrelated to the temporal , fronto - parietal , and fronto - temporal components ( the left side of fig . 
the phasers corresponding to the limbic ( he06 ) and occipito - cerebellar ( he02 ) components ( the right side of fig . 
1c , we found high significant correlations between the temporal ( nhe19 ) , fronto - parietal ( nhe12 ) , subcortico - fronto - temporal  cerebellar ( nh13 ) and fronto - temporal ( nhe18 ) components .
1c depicts the correlation function calculations for the patients without ah in terms of the phaser graphs .
1c shows that the temporal ( nhe19 ) and fronto - temporal ( nhe18 ) components were synchronized , whereas the frontal 
parietal ( nhe12 ) and subcortico - temporo - parietal  cerebellar ( nhe13 ) components were delayed compared with the first two components . based on the granger - causality analysis , the temporal ( ce19 ) and
fronto - temporo - parietal ( ce18 ) components were causal sources , whereas the subcortical  fronto - temporal ( ce09 ) and occipito - cerebellar ( ce04 ) components were causal sinks ( fig . 
the analysis of the causal density units showed that all nodes were highly integrated in the system , with the temporal ( ce19 ) component being the main causal hub .
the temporal ( ce19 ) component exerted the highest granger - causality influence on the remaining system components .
2b , the occipito - cerebellar ( he02 ) component was a strong causal source , whereas the fronto - parietal ( he14 ) and limbic ( he06 ) components were causal sinks .
the graph for the patients with ah shows a large number of interactions among the components .
we observed that the temporal component ( nhe19 ) was a causal source , whereas the fronto - parietal ( nhe12 ) and subcortico - fronto - temporal  cerebellar ( nhe13 ) components were causal sinks ( fig .  2c ) .
the temporal ( nhe19 ) component exerted the highest granger - causality influence on the remaining system components .
in a homogeneous sample of patients with schizophrenia and persistent ah , we found ( 1 ) abnormal synchrony compared to a healthy control group and to patients with schizophrenia without chronic ah , specifically between the cerebellum - limbic and frontal  temporal  parietal networks , as well as ( 2 ) a different pattern of effective connectivity between these functional networks while processing emotional auditory stimuli .
temporal  limbic  cerebellar areas ) in the patients compared to the controls aligns with reports of reduced frontal connectivity ( pettersson - yeo et al . , 2011 ) and disconnections between the frontal and temporal lobes ( calhoun et al .
, 2004 ; garrity et al . , 2007 ; kim et al . , 2008 ) .
we used the task of passively listening to emotional auditory stimuli , which elicited a different pattern of functional response between the controls and patients because we only observed activation in a network comprising subcortical  limbic areas ( amygdala and parahippocampal gyrus ) in the patients with ah ; these results have been previously reported and discussed in depth ( escart et al . , 2010 ) .
this analysis showed that the subcortical  limbic network and an occipito - cerebellum network were more synchronized in the patients with ah ( particularly in the fusiform gyrus , culmen and declive of the vermis ) and desynchronized from the frontal 
parietal  temporal areas . the controls and patients without ah showed more synchronization between the networks ( frontal  parietal  temporal  limbic  cerebellar areas ) than the patients with ah .
our results align with the most common finding in the literature , abnormalities in the frontal lobe ( fornito et al . , 2011 ; salvador et al . , 2010 ; zalesky et al . ,
2011 ; zalesky et al . , 2010 ) and prefrontal regions connections with other brain regions , including the cerebellum and the parietal and occipital cortices .
additionally , altered regional connectivity of the parietal , temporal and occipital cortex , as well as the subcortical nuclei , has been observed ( lynall et al . , 2010 ) . it is hypothesized that language dysfunction located in the frontal and temporal regions and specific dysconnectivity between the two regions play critical roles in the core pathophysiology of schizophrenia studies , particularly in studies of auditory verbal hallucinations ( hubl et al . , 2004 ; seok et al . ,
our second finding was that causal interactions between the functional brain networks differed among the three groups . in the control group and the patient group without ah
, we found that the main causal source was the temporal lobe network component ( ce19 ) , which aligns with previous studies of emotional auditory processing ( phillips et al . , 2003 ) .
in the control group , the temporal ( ce19 ) and fronto - temporo - parietal ( ce18 ) components were causal sources ; however , in the group of patients without ah , only the temporal component ( nhe19 ) was a casual source . in the group of patients with ah
, the main causal source was the occipito - cerebellar network component ( he02 ) , despite the processing of auditory emotional stimuli by the patients .
the study of synchrony could inform our understanding of the functional organization of the brain , particularly in task - evoked processes ( bartels and zeki , 2005 ; mckiernan et al .
our findings support and extend the findings of numerous studies that have identified similar regions ( cerebellar and limbic ) associated with emotional deficits in patients with schizophrenia ( aleman and kahn , 2005 ; andreasen and pierson , 2008 ) .
, the cerebellum could be considered to be crucial for synchrony ( picard et al . , 2008 ; schutter and van honk , 2005 ) .
additionally , the cerebellum is involved in higher cognitive functions ( schmahmann , 2001 ; andreasen and pierson , 2008 ) . the cerebellar circuits process learning ( particularly error - related ) , timing and prediction in relation to motor and cognitive information ( d'angelo and casali , 2012 ) .
the timing hypothesis postulates that the cerebellum is critical for representing temporal relationships among task - relevant events , which is closely related to the concept of synchrony . in this sense ,
the cerebellum function is analogous to a supramodal internal timing unit ( such as a metronome ) ( ivry et al . , 2002 ) .
hypothetically , when the cerebellar timing function is disrupted , the information processing stream becomes desynchronized , providing a nurturing environment for a diverse range of psychopathological conditions ( schutter and van honk , 2005 ) .
regarding schizophrenia , the cerebellum is connected to many regions of the cerebral cortex by the cortico - cerebellar  thalamic  cortical circuits and might play a crucial role in this distributed circuit to coordinate or modulate aspects of cortical activity ( picard et al . , 2008 ) . according to the  cognitive dysmetria  or 
 models of schizophrenia , aberrant cerebellar modulation of information to the cerebral cortex is involved in the pathophysiology of the disorder ( andreasen et al . , 1998 ; schmahmann , 1998a ) .
( 2005 ) study , which preliminarily reported that , compared with controls , patients with schizophrenia demonstrated deficits in cerebellar inhibition .
their data are corroborated by our results demonstrating between - group differences in the causal flow of information between the cerebellar 
occipital component and other regions , with an afferent direction of flow for the controls ( figs . 
2a and 2c ) and an efferent direction for the patients with ah ( fig . 
there is evidence that neuroanatomical damage to the cctc could be the primary pathophysiological alteration in schizophrenia ( konarski et al . , 2005 ) .
it is well known that cerebellar abnormalities exist in schizophrenia patients ( andreasen and pierson , 2008 ) .
our findings suggest that the functional dysconnectivity of the cerebellum with the cerebrum predominantly involves the anterior and vermal areas of the cerebellum , the main areas included in the occipito - cerebellar component in the group of patients with ah .
the vermis has previously been labeled as the  limbic cerebellum  because the anterior vermis is the principal cerebellar target of limbic projections ( schmahmann , 2000 ) .
behavioral studies have supported a relationship between the cerebellar midline structures and the modulation of emotion ( heath and harper , 1974 ; stoodley and schmahmann , 2010 ) , and lesions of the vermis have been shown to produce affective symptoms ranging from emotional blunting and depression to disinhibition and psychotic features ( schmahmann and sherman , 1998b ) .
( 2010 ) , who found less activation of the left cerebellum , right insula and left parahippocampal gyrus in patients with ah
( 2014 ) , which showed decreased connectivity in several brain areas in patients with ah , including between the right cerebellum and left thalamus .
in this study , we relied on ica , a driven - data method that could separate independent spatial 
temporal patterns of neural activity from the fmri data in a manner that has been helpful in studying intrinsic brain networks ( damoiseaux et al . , 2006 ) .
granger - causality was used to explore effective connectivity in fmri data to quantify the strength of interactions between activated brain areas ( goebel et al . , 2003 ; demirci et al . , 2009 ; londei et al . , 2007 ) the ica and granger - causality techniques allowed us to analyze the functional and effective connectivities , respectively .
ica allowed us to select the coi that were candidates for the gcca analysis of their associated time - courses .
the main strength of this methodological framework was the combination of these independent techniques , which allowed us to observe whether different methods would lead to consistent results and more reliable conclusions .
first , all patients were taking antipsychotics at the time of scanning , although we did not find any significant correlations between the chlorpromazine equivalents and our imaging measures .
second , our small sample size limited our power to detect relationships with symptom severity or duration of illness , our findings of impaired synchrony should be confirmed in larger samples , preferably with unmedicated first - episode schizophrenia patients . third , the sample of patients without ah ( n  =  14 ) is relatively small compared with the control group ( n  =  31 ) and patients with ah ( n  =  27 ) groups . including a subgroup of schizophrenia patients treated with the identical medications and differing only in the absence of persistent ah strengthens our confidence in our findings .
fourth , the application of the granger - causality method to the fmri data is somewhat controversial ( friston , 2009 ; roebroeck et al . , 2009 ) .
specifically , granger - causality analysis ignores the influence of other areas when assessing whether coupling between reference regions a and b is driven by region c ( gao et al .
accordingly , we employed gcca ( geweke , 1984 ) , which is based on a direct expansion of the autoregressive model to a multivariate general case , including all measured variables .
patients with schizophrenia and ah exhibit abnormal patterns of neural synchrony , as well as different patterns of granger - causal interaction between functional networks compared with controls and patients with schizophrenia without ah .
the results indicate an anomalous process of neural connectivity in the cortico - cerebellar  thalamic  cortical circuits in patients with ah . a central role for the cerebellum in the pathological processing of emotional stimuli by patients with schizophrenic and persistent ah is suggested , perhaps reflecting deficiencies in predicting the emotional effect of a given stimuli .
 auditory hallucinations ( ah ) are the most frequent positive symptoms in patients with schizophrenia . 
 hallucinations have been related to emotional processing disturbances , altered functional connectivity and effective connectivity deficits . 
 previously , we observed that , compared to healthy controls , the limbic network responses of patients with auditory hallucinations differed when the subjects were listening to emotionally charged words . 
 we aimed to compare the synchrony patterns and effective connectivity of task - related networks between schizophrenia patients with and without ah and healthy controls.schizophrenia patients with ah ( n  =  27 ) and without ah ( n  =  14 ) were compared with healthy participants ( n  =  31 ) . 
 we examined functional connectivity by analyzing correlations and cross - correlations among previously detected independent component analysis time courses . 
 granger causality was used to infer the information flow direction in the brain regions.the results demonstrate that the patterns of cortico - cortical functional synchrony differentiated the patients with ah from the patients without ah and from the healthy participants . 
 additionally , granger - causal relationships between the networks clearly differentiated the groups . in the patients with ah , the principal causal source was an occipital  
 cerebellar component , versus a temporal component in the patients without ah and the healthy controls.these data indicate that an anomalous process of neural connectivity exists when patients with ah process emotional auditory stimuli . additionally , a central role is suggested for the cerebellum in processing emotional stimuli in patients with persistent ah . 
Introduction
Materials and methods
Results
Discussion