Obsessive Compulsive Disorder: models of underlying neuronal pathophysiology and the brain mechanisms of thalamocortical dysrythmia and diaschisis
BEKIARIDIS-MOSCHOU D.*, KARLOVASITOU A.**
*Psychologist, Laboratory of Clinical Neurophysiology, Aristotle University, Thessaloniki, Greece, AΗΕΠΑ Hospital
**Professor of Neurology, Laboratory of Clinical Neurophysiology, Aristotle University, Thessaloniki, Greece, AΗΕΠΑ Hospital

Abstract
Neurobiological models of the obsessive-compulsive disorder (OCD) tend to implicate the basal ganglia along with the frontostriatal-thalamic and thalamocortical networks. More specifically the orbitofrontal cortex and the anterior cingulate cortex, with the basal ganglia and related areas seem to be related to the expression of OCD in studies of functional neuroimaging, studies of neuroanatomical imaging and brain lesion studies. These neuronal loops are presented as the main neurological correlates of the observed behaviour. Three neurobiological models of the disorder are presented. One that hypothesizes the existence of a balance between a direct, excitatory and an indirect inhibitory pathway in the neuronal networks responsible for obsessive-compulsive behaviour, one that considers deficits in inhibitory control as a main mechanism of symptom generation and one that gives emphasis to the mechanism of thalamocortical dysrhythmia. One model does not exclude the other, while the third seems to give an account for most of the relevant observations on OCD neurobiology. The phenomenon of diaschisis along with the condition of thalamocortical dysrythmia provide a possible explanation for the development of OCD after focal brain injury. Encephalos 2011, 48(1):29-33.

Key words: Thalamocortical dysrythmia, obsessive compulsive disorder, diaschisis, pathogenesis, neuropathophysiology, thalamocortical loops, brain injury.

1. Introduction

Obsessive-compulsive disorder (OCD) appears in the 2-3% of the general population in most countries for which epidemiological data are available1. It is usually a chronic illness that affects the patient's ability to function in interpersonal relationships and profession compromising their every day life. OCD is typically characterised by the presence of obsessions, which are recurrent, persistent and intrusive ego-dystonic thoughts, impulses or images; and compulsions that consist of repetitive behaviours or mental acts that are executed with the goal of preventing or reducing distress or preventing some dreaded event or situation2.

Most information on the neurobiology of OCD stem from three different research paradigms: functional neuroimaging studies, neuroanatomical imaging and cases where OCD occurs following focal brain lesions (development of OCD after brain injury and as a consequence of infection with group A beta-hemolytic streptococcus) as well as attenuation of symptoms in OCD after focal neurosurgical lesions3. The results reported by each paradigm in isolation are not sufficient to establish a clear direct relation of the neuropathology observed with the disorder. However, the convergence of all the different data in implicating the thalamocortical loops that involve the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC) including the basal ganglia supports an etiological relationship between abnormalities in these neuronal loops and OCD3.

The convergence of the data in these research paradigms suggests that the Cortico-Basal Ganglia-Thalamo-Cortical loops (CBGTC) that involve the OFC and the ACC and their neuronal connections play a role in the creation and expression of OCD. Some important issues that remain unresolved by these studies are which of the implicated brain areas or systems may be the cite of function where the pathophysiology begins, which is the underlying mechanism of the neuronal dysfunction and which of the experimental findings on the neuropathology of the disorder are results of the primary dysfunction.

2. Neurobiological models of the observed abnormalities in the CBGTC loops in OCD

2.1. Imbalance in the "direct" and "indirect" pathways that run through the basal ganglia

An attempt to give an account on the pathophysiology observed in the CBGTC loops in OCD is made by the suggestion that OCD may result from an imbalance between the "direct" and "indirect" pathways through the basal ganglia4. The net effect of the direct pathway, that runs from the cortex to the basal ganglia, then to the thalamus and back to the cortex, is excitatory, while the net effect of the indirect pathway, that forms a similar loop but includes more brain areas including the subthalamic nucleus, is inhibitory. This model has been proven useful in understanding the hyperkinetic and hypokinetic symptoms of Huntington and Parkinson movement disorders respectively5. Excess activity in the direct circuit produces disinhibition and leads to hyperkinetic symptoms, such as those in Huntington's chorea, while excess activity in the indirect pathway produces in total more inhibition leading to the hypokinetic symptoms observed in Parkinson's disorder. The hypothesis is that the kinetic symptoms are produced when the circuits that are involved are responsible for the execution of movement. It has been suggested that when similar abnormalities in neuronal stimulation occur in the CBGTC loops that involve the OFC and the ACC they may lead in the creation of the obsessions and compulsions observed in OCD4. In support of this comes the finding that OCD symptoms are observed with Huntington's patients more often than in the general population6.

2.2. The impaired inhibitory control model

A different explanation of the difficulties encountered in OCD comes from the observation that patients display low performance in inhibitory control tasks7. This finding has led to the hypothesis that OCD symptoms may be the results of dysfunctional inhibitory control with obsessions being recognized as difficulties in inhibiting ideas and compulsive behaviour as difficulties in inhibiting behaviour. Dysfunction in inhibitory control has been, also, detected in other neuropsychiatric disorders such as schizophrenia8, manic depression9 and addiction10. The observation of inhibitory control dysfunction in so many disorders has led most researchers in arguing that inhibitory control may not be one of the underlying causes since the phenotype of the implicated disorders is so different3.

2.3. Thalamocortical dysrythmia as the underlying neuronal mechanism in OCD

A third model for the neurobiology of OCD is based on findings from observations on the neurosurgical treatment of the disorder in cases that have been unresponsive to other forms of treatment. Sarnthein et al., (2003)11 and Jeanmonod et al., (2003)12 suggest the concept of Thalamocortical Dysrythmia (TCD) as the basic neurological mechanism of dysfunction in neuropsychiatric disorders such as OCD along with the disorders of neurogenic pain, epilepsy, tinnitus and movement disorders. TCD as a mode of dysfunction in the brain is suggested by observations in cell physiology and magnetoencephalography of patients that went through neuropsychiatric surgery for the alleviation of severe OCD symptomatology12 and by measurements in thalamic local field potentials and scalp electroencephalographs of patients suffering from neurogenic pain, epilepsy and movement disorders11.

The concept of TCD gives an account for the neurobiology of several neuropsychiatric conditions including OCD. TCD as a model of the neural bases of OCD includes possible neurological mechanisms that have the potential of explaining most findings on the pathophysiology of the disorder such as the functional neuroimaging data4,13,14, the anatomical and spectroscopy studies15-17 as well as the occurrence of OCD as a consequence of brain injury18,19. The implication of the CBGTC loops that involve the OFC and ACC, which is the most consistent finding among studies exploring the neural bases of OCD3, is in agreement with the TCD model of the disorder. Along with obsessive and compulsive symptomatology TCD, is, also, connected to other neuropsychiatric conditions such as psychotic and affective disorders.

2.3.1. The sequence of events that characterize thalamocortical dysrythmia

Sarnthein et al., (2003)11 and Jeanmonod et al., (2003)12 based on neurosurgical, clinical and electroencephalographic data focus on the interactive communication between cortex and thalamus and suggest a specific sequence of neuroanatomical events as the mechanism that characterizes TCD.

In particular, the first step in the sequence is hyperpolarisation of thalamic relay and/or reticular cells through disfacilitation and/or overinhibition of this brain area by the disease source. The condition of thalamic hyperpolarisation leads to deinactivation of calcium T-channels which in turn cause the production of low threshold calcium spikes (LTS). The LTS activate bursts of sodium-dependent action potentials which appear rhythmically in a frequency of 3.8±0.7 HZ. This frequency correlates with the theta low frequency domain. Neurons producing the LTS bursts become locked in the theta low frequency domain by their ionic properties and impose a slow theta rythmicity to the thalamocortical loops that they are part of. Such a burst discharge frequency is diffused through thalamocortical, corticothalamic and reticulothalamic cross modular spread to the cortex, subcortical structures and subsequently back to the thalamus. Sarthein et al (2003)11 were able to collect EEG recordings in the cortex and LFP in the thalamus of TCD patients. Both measurements were found to be mostly in the theta frequency and were correlated with each other. The widespread overproduction of theta frequency brain oscillations produces reduced activation of the thalamocortical modules involved which in turn produces the negative symptoms that are attributed to TCD, such as akinesia, sensory deficits, and depression11,12. The last phase of the proposed set of sequential events in TCD includes the positive symptoms that are attributed to the disorder such as the obsessions or compulsions observed in OCD or the epileptic seizures. These are produced by the activation of cortical areas in high frequencies such as beta and gamma. Cortical areas that are involved in thalamocortical circuitry are, also, connected with other areas of the cortex via cortico-cortical inhibitory interneurons. The overactivation of a brain area in the theta frequency leads to disinhibition of the surrounding areas and thus their overactivation in the beta/gamma frequencies and the production of the positive symptoms. This account of the positive symptoms observed in the disorders that are connected to the TCD condition is supported by Magnetoencephalographic (MEG) recordings that detect in the cortex of TCD patients a) theta overproduction, b) high levels of beta/gamma activity and c) strong temporal correlation between theta and beta/gamma activity11. This activation in high frequencies may be expressed as abnormal EEG spiking activity as demonstrated in psychotic patients20.

Increased low-frequency brain oscillations are, also, encountered in normal functions of the thalamocortical system. Such examples include EEG activity during sleep21, during performance in cognitive tasks22,23 and a few minutes after pain stilulation of healthy volunteers24. What distinguishes the low-frequency thalamocortical neuronal activity of the pathological state of TCD with the occurence of similar brain activity during normal functioning is the long-term and diffused overproduction of low frequency oscillations11.

2.3.2. Diaschisis as the initial brain pathophysiology in the development of OCD after focal brain injury

TCD as a neurobiological model for OCD can include within it's conceptualization the "loss of inhibitory control" model and the "direct-indirect" neuronal pathways imbalance explanation providing a broader and more concise model of the disorder. What is not mentioned, however, is which is the initial brain pathophysiology that leads to the hyperpolarisation of the thalamic neurons and the state of TCD subsequently. In cases where OCD occurs as a consequence of focal brain lesion the initial brain pathophysiology is more apparent.

Brain injuries due to traumatic brain injury or stroke that lead to acquired cognitive disability seem to implicate long-term functional changes that lead to partly reversible impairment of integrative cortical function25. A related finding is that after focal ischemia or traumatic brain injury Positron Emission Tomography (PET) reveals reduction of cortical metabolism in brain areas distant from the cite of injury. This phenomenon is characterized as diaschisis. This downregulation of a brain region in diaschisis is caused by the impairment of the excitatory stimulation of this region that initiates in the area of original injury or focal disturbance. The reduction of stimulation in a neuronal network usually leads to disfacilitation, a form of inhibition of neuronal function during which hyperpolarisation of neuronal membrane potentials occurs. If within the brain areas that are affected by the phenomenon of diaschisis thalamic areas are included, then, along with the reduced excitatory input, the hyperpolarisation of thalamic membrane potentials often leads to different forms of abnormal hypersynchronous activity through the mechanism of TCD described above. The alteration of excitatory activity and inhibition that produces hypersynchrony in relatively restricted neuronal networks contributes to the formation of specific clinical syndromes and impairments of integrative brain function in patients with focal brain injuries. In this way, the presence of hypersynchrony in the OFC and ACC CBGTC loops may account for the forms of OCD that are observed after brain injuries. Several reports describe cases of OCD following lesions of the basal ganglia or the frontal cortex with an emphasis on OFC highlighting the involvement of the CBGTC loops in the pathogenesis of the disorder3.

Among the different forms of diaschisis that have been detected in widespread cortico-cortical and thalamocortical networks injury in the paramedian thalamus appears to have a uniquely marked effect in producing broad functional deficits after focal brain injury25. In general subcortical injuries in restricted areas are able to produce important functional impairment but specifically injury in the paramedian mesodiencephalon can produce disproportionate changes in integrative cortical function26. Injury in the paramedian thalamus accompanies both traumatic brain injury and stroke as a result of a sensitivity of this region to the effects of brain swelling which leads to pressurising these midline structures by the base of the scull27. Volumes of the thalamus have been reported to be larger in treatment-naive adults with OCD than in healthy controls and thalamic volumes were found to correlate positively with symptom severity in both treatment-naive and treatment refractory patients15,28. Also, patients who responded to medication treatment had smaller thalami post-treatment than either treatment-naive or treatment-refractory patients with no differences between the later two groups28.

In this way, it appears possible that through diaschisis and subsequently TCD specific neuronal networks may present impaired function that leads to the development of syndromes according to the network that has been affected. According to this hypothesis, epileptic disorders, OCD, movement disorders and other neuropsychiatric and neurological dysfunctions may occur after focal brain lesions. These dysfunctions appear to be partly or fully reversible since the networks themselves do not present extensive structural damage but with reestablishment or improvement of their neuronal modulation it is possible to reengage them in their previous normal functioning to a certain degree.

3. Conclusion

CBGTC loops and in particular the OFC and ACC related ones are consistently implicated in the pathophysiology of OCD in neuroanatomical, functional imaging and brain lesion studies. Although the convergence of data to this conclusion is remarkable3 an account of the neurological mechanisms involved in the underlying pathogenesis has not been yet available. Three models of the CBGTC loops dysfunction in OCD are presented: the imbalance between the direct and indirect pathways from the cortex to the thalamus via the basal ganglia, the loss of inhibitory control model and the concept of thalamocortical dysrythmia. The third mode of explanation of the neural basis of OCD can also include the previous two and appears to have the potential of explaining most observations related to OCD neurobiology. THC along with the phenomenon of diaschisis provide a sufficient account for the development of OCD after focal brain injury. The usefulness of THC and diaschisis as a neurobiological model of OCD and implications for treatment remain to be seen by further research on the neurological mechanisms that are implicated in these conditions and their connection to behavior and OCD symptomatology.

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