Obsessive Compulsive Disorder as a functional interhemispheric imbalance at the thalamic level

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Obsessive Compulsive Disorder (OCD) involves failures in two main inhibitory processes, namely cognitive (obsessions) and behavioral (compulsions). Recent research has supported two cortical–subcortical pathways on OCD pathogenesis: (a) the
  Obsessive Compulsive Disorder as a functional interhemispheric imbalanceat the thalamic level Óscar F. Gonçalves a,1 , Sandra Carvalho a, ⇑ ,1 , Jorge Leite a,1 , Fernando Pocinho b , João Relvas b , Felipe Fregni c a Neuropsychophysiology Laboratory, CIPsi, School of Psychology (EPsi), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal b University Hospital of Coimbra, E.P.E, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal c Neuromodulation Laboratory, Spaulding Rehabilitation Hospital,125 Nashua Street, Boston, MA 02114, Harvard Medical School, United States a r t i c l e i n f o  Article history: Received 10 March 2011Accepted 7 June 2011Available online xxxx a b s t r a c t Obsessive Compulsive Disorder (OCD) involves failures in two main inhibitory processes, namely cogni-tive (obsessions) and behavioral (compulsions). Recent research has supported two cortical–subcorticalpathways on OCD pathogenesis: (a) the frontostriatal loop (dorsolateral-caudate–striatum–thalamus)responsibleforimpairmentsofbehavioralinhibition;(b)theorbitofrontalloop(orbitofrontal,medialpre-frontal and cingulate) responsible for impairments with cognitive inhibitory processes. These failures inboth cognitive and motor inhibitory systems may mediate several neuropsychological deficits in thesepatients, namely memory, attention, planning and decision making. But are those deficits related to spe-cific hemispheric effects, namely functional imbalance between hemispheres? In this article we hypoth-esize that: (1) OCDpatients have aninter-hemispheric functional imbalance, probably due to inadequatefiltering at the thalamic level; (2) the restoration of inter-hemispheric balance, will be correlative tosymptomatic improvement.   2011 Elsevier Ltd. All rights reserved. Introduction Obsessive Compulsive Disorder (OCD) is one of the most debil-itating psychiatric disorders. It has a cross cultural lifetime preva-lence of 2.5% [1,2] being characterized by the presence of obsessions (intrusive, upsetting and unwanted thoughts and/orimages) and/or compulsions (repetitive and stereotyped behavioror mental rituals) [3].Most prevailing evidences indicate that OCD is a biological dis-ease. Functional brain imaging studies have converged in order toproduce a model for pathophysiology of OCD which involveshyperactivityincertaincorticalandsubcorticalregions[4].Paralleland partially antagonistic information-processing pathways seemto be involved in order to appropriately create a balanced controlof thought and movement. The initiation and sustainability of therepetitive behavior is thought to be modulated by the direct path-way. The completion of these behavioral routines will then bemodulated by the indirect pathway. It is suggested that the OCDsymptoms result of an hyperactivity in the direct pathway com-pare to the indirect one leading to a disinhibited thalamus andthe creation of a self-perpetuating circuit between the thalamusand the orbital cortex [5,6]. Also, cortico–striatal projections arepredominantly glutamatergic, thus excessive activity may contrib-ute to the pathophysiology of OCD. Successful treatment is associ-ated with a reduction in the CSTC hyperactivity.Thus, it has been thought that OCD involves failures in twomain inhibitory processes, namely cognitive (responsible for theobsessions) and behavioral (responsible for the compulsions)[7]. Recent research has supported two cortical–subcortical path-ways in OCD pathogenesis: (a) the frontostriatal loop (dorsolat-eral-caudate–striatum–thalamus) responsible for impairments of behavioral inhibition; (b) the orbitofrontal loop (orbitofrontal,medial prefrontal and cingulate) responsible for impairmentswith cognitive inhibitory processes.These two inhibitory processes reflect a broad network of cor-tico–basal ganglia–thalamic loops [8,9]. Default mode network(DMN) studies also support this assumption, as OCD patients,when compared to health controls (HC), showed less functionalconnectivity in anterior cingulate cortex, middle frontal gyrusand putamen [10].Neurophysiological studies in OCD showed decreased intracor-tical inhibition (ICI) on paired-pulse TMS (Transcranial MagneticStimulation) [11,12] and decreased active and resting motorevoked potential threshold [11] that seems to indicate enhancedcortical excitability and lack of inhibition, when compared tohealth controls (HC), thus supporting the assumption of failure ininhibition processes.These failures in both cognitive and motor inhibitory systems[13] may mediate several neuropsychological deficits in these pa-tients, namely memory, attention, planning and decision making 0306-9877/$ - see front matter   2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.mehy.2011.06.004 ⇑ Corresponding author. Address: School of Psychology (EPsi), University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal. Tel.: +351 253604220; fax:+351 253604224. E-mail address:  sandrarc@psi.uminho.pt (S. Carvalho). 1 These authors share equal responsibility for the content of this article. Medical Hypotheses xxx (2011) xxx–xxx Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Pleasecitethisarticleinpressas:GonçalvesÓFetal.ObsessiveCompulsiveDisorderasafunctionalinterhemisphericimbalanceatthethalamiclevel.MedHypotheses (2011), doi:10.1016/j.mehy.2011.06.004  [7,14,15]. But are those deficits related to specific hemispheric ef-fects, namelyafunctionalimbalancebetweenhemispheres?Several studies suggested specific inter-hemisphere effects. AnEEG study [16] demonstrated that OCD patients when comparedtoHCshowless righthemisphericactivation. Additionallythebeta2 frequency was correlated with impairments in visuospatial tasksbut not with verbal performance. Some authors reported relativedecreased variability in the left temporal region [17], ‘‘nonspecifictheta activity’’ [18] and a relative significantly increased power inthe theta-2 band in the left temporal and central regions alongwith a significantly reduced variability in frontal and temporal re-gions [19].The first TMS study with OCD patients [12], showed symptomimprovement when the inhibitory stimulation was on the rightdorsolateral prefrontal cortex (DLPFC) but not on the left one. Thislaterality effect has been also observed in an opposite correlationbetween acute symptomprovocation (as emotional processes playa major role in OCD) and orbitofrontal perfusion in the right andleft hemisphere [20], as well as symptom improvement and dis-ruption of abnormal metabolic activity on the right hemisphereafter cognitive behavioral therapy [21]. Additionally, symptomaticimprovement was found in neurosurgery after right hemisphereanterior capsulotomy but not on left side [22,23]. Neuroimagingstudies also found right hemisphere changes associated with ther-apeutic improvement after medication [24]. Also, abnormalities in the thalamus, a sensory and motor gateway to the cortex, are be-lieved to be involved in the pathophysiological mechanisms impli-cated in the development of OCD symptoms [25,26]. Evidencescome from neurosurgery where partial thalamotomy was associ-ated with a decrease in OCD symptoms in treatment–refractory[25] and neuroimaging studies that demonstrate metabolic abnor-malities within the thalamus that have been correlated with OCDsymptom severity and subsequent treatment response [5,27,28].All of these studies support the idea that there are specifichemispheric effects associated to both OCD symptoms and cogni-tiveprocessing,aswellaswiththepredictionofrecovery.Butnoneof the above studies clearly demonstrates hemispheric asymme-tries and, more important, none of them explore the connectivityin the neural circuitry involved in the pathophysiology.Apossibleinterpretationforinter-hemisphericimbalanceisthatthecognitiveprocessingimpairmentsfoundinOCDmaybeassoci-ated with cortico–basal dysfunction where cortico–subcorticalloops (will act separately, in parallel and with overflow betweenthem) [29] will lead to compensatory processes, performed else-where in the brain.Following this hypothesis Gonçalves et al. [30] proposed thatthe frontal subcortical activation found in OCD would be correla-tive to a deactivation of parietal/occipital areas associated withvisual-perceptual processing, thus supporting the compensatorymechanism hypothesis. This seem to consistent with the hypothe-sis that in OCD there will be a dysfunction of thalamic gating [31]responsible for a defective filtering of cortical input by the basalganglia, therefore leading to compensatory processes.Evidence for the hypothesis of a compensatory activation anddeactivation, that will be ultimately responsible for a functionalhemisphericimbalancehasbeenfoundonseveralclinicaltrialswithrepetitiveTMS(rTMS),demonstratingincreasedsymptomimprove-ment e.g. [32,33] when compared with alternative approaches[34,35]. In a recent study [36], with 21 medication-resistant OCD patients receiving 1-Hz rTMS (inhibitory stimulation), deliveredbilaterally to the Supplementary Motor Area (SMA) it was found asymptomatic improvement along with normalized cortical hyper-excitability(tendencytosymmetrybetweenhemispheres).Nonetheless, due to the unspecific nature of the compensatorymechanisms, the heterogeneity of OCD patients, and the particularcharacteristics of the cortical–basal-ganglia–thalamic loops, thedeficits in these patients seem not to be related to a specific later-alized dysfunction of a particular hemisphere, but probably due toa functional inter-hemisphere imbalance [37]. In other words,there are no data consistently showing that one hemisphere is sig-nificantlyalteredinOCD, but thereis datathatsupportsthenotionthatthereisafunctionalimbalancebetweenthem,probablyduetoinadequate filtering at the thalamic level [31,38].Previous studies in our lab [39] show that it may be possible tomodulate cortically the cortical–basal ganglia–thalamic circuitswith cortical transcranial direct current stimulation (tDCS), asthese circuits seem to be highly engaged. Our studies seem alsoto provideevidencethat despite of site of stimulation, similar neu-romodulation effects could be obtained, as long as the target areasofstimulationareinvolvedinsuchnetworks.Alsothereareseveralstudies that show that it is possible to neuromodulate one hemi-sphere, by stimulating the other e.g. [40,41], bringing additional support to the idea that as long as the areas are engaged in similarnetworks, there will be effects in the entire network.  The hypothesis The main assumption underlying this hypothesis is that OCDsymptoms and deficits are associated with a functional inter-hemispheric imbalance. The restoration of such imbalance willbe correlative of symptomatic improvement. This assumptioncould be a possible explanation as why non-invasive standardizerTMS treatments have only revealed modest clinical effects.In sum, based on previous studies one can hypothesize that:(1) The activation of positive and negative DMN in OCD willreveal a specific functional hemispheric imbalance and theimprovements in symptomatology will be correlative withthe restoration of balance.(2) Quantitative EEG (QEEG), Event-Related-Synchronization(ERS) andEvent-Related-Desynchronization(ERD)will showasymmetric distributions, as well as direct cortical excitabil-itymeasuresbysingleandpairedpulseTMS.Therestorationof functional connectivity will also be correlative of symp-toms improvement.(3) Thecorticalsiteofnon-invasivebrainstimulationwillnotbedeterminantbutthemainfactorwillbethebilaterallydeliv-erance in a cortical area highly engaged in the frontal–stria-tal loops thus targeting changes in the thalamic gating, andultimately restoration of balance. Implications and further studies If future research validates these hypotheses, important impli-cationsmaybederivedforthedevelopmentofnewtherapeuticap-proaches. For instances, psychotherapy and neurofeedbacktechniques could be used, in order to promote functional balancebetween hemispheres. Psychopharmacological treatments couldbe developed in order to surpass this interhemispheric imbalancebythebalanceofglutamateanddopamineatthethalamiclevel.Fi-nally,morerecentmethods,suchastranscranialmagneticstimula-tion or transcranial direct current stimulation, can be used tobilaterally activate and deactivate several cortical areas related tofrontal–subcortical circuits while the patient is confronted withemotional triggers. Conflicts of interest statement Therearenotanyfinancial,relationshipandorganizationalcon-flict of interests that may bias any of the authors in the establish-ment of the hypotheses discussed in this article. 2  Ó.F. 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