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The Basal Ganglia:  Their Role in the Pathophysiology of Obsessive-Compulsive Disorder and Tourette’s Syndrome

by Kortney Hillier (MD class of 2007)


Introduction
How many of you have certain habits, rituals or superstitions?  Who sits in the same chair every day during lecture?  How many of you have the same routine each morning; get up, shower, get dressed, eat breakfast, brush teeth etc.  What about your friend who has to use her lucky pencil and wears the same shirt every time she/he writes an exam.  These routines are considered a normal part of life.  They increase efficiency when performing certain tasks and decrease anxiety in times of stress.  What if these rituals got out of control?  What if someone felt that is was absolutely essential to perform his or her morning routine perfectly?  They might feel that it is necessary to brush each tooth exactly ten times and if they accidentally brushed one tooth eleven times they would have to start all over again.  These rituals are no longer adaptive and become pathological. These behaviours are a part of obsessive-compulsive disorder (OCD) and include different forms of tic disorders.  Dysfunction of the basal ganglia have been implicated in multiple diseases including, obsessive-compulsive disorder (OCD), Tourette’s syndrome (TS), Parkinson’s disease and attention deficit disorder (ADHD) [17].  Although the exact pathophysiology of these disorders has yet to be established, we will discuss proposed mechanisms, including the role of the basal ganglia.

The Basal Ganglia
The basal ganglia are the largest subcortical structures of the forebrain [17] (see Figure 1 & 2) and are involved in many different functions including motor control (planning for movement), cognition, learning and emotions [17].  They are composed of distinct nuclei, including the striatum (caudate nucleus and putamen) which receive most of the cortical input.  Huntington’s disease and other hyperkinetic disorders are related to the degeneration of the striatum [17]. The striatum is also part of the learning and memory mechanism in the brain, including the development of certain habits. The globus pallidus, subthalamic nuclei as well as the substantia nigra, are also included.  The substantia nigra is divided into the pars compacta, which is the dopamine containing region and the pars reticularis [14,17].  In this paper I will consider mainly the dopaminergic pars compacta.

The basal ganglia connect with the cerebral cortex, the thalamus and the brainstem and are involved in motor control by way of the “frontal cortico-basal-thalamic circuit [17].” (see Figure 3).  The basal ganglia receive most of their input from the neo-cortex and project through to the thalamic nuclei and back to the frontal cortex via output nuclei [17,19]. 


Figure 1: Coronal Section of the Basal Ganglia and the Limbic System

Figure 2: 3D View of the Basal Ganglia

Figure 3: Model of the Frontal Cortico-basal-thalamic Circuit [23]

 

 

 

 

 

 

 

 

 

Obsessive-Compulsive Disorder
OCD is a disease involving obsessions, compulsions or both [22, 23].  Obsessions are recurrent intrusive thoughts, which cause the patient much anxiety [22, 23].  The most common obsessions involve fear of contamination; feelings of anxiety, worry or fear that germs, body secretions, environmental pollutants (radiation, dust) or simply that contact with sticky or “disgusting” substances will be harmful to them or to someone in their family [23].  Aggressive thoughts and/or images (fear of harming themselves or others) is also common and children may stop eating for the fear of getting too close to a knife [23]. Other common obsessions include; fear of unintentionally saying something or swearing, and fear of being held responsible for something terrible like a fire or flood [23]. Compulsions are repetitive behaviours or mental acts aimed at preventing or reducing distress and/or anxiety raised by the obsessions [22,23].  Common examples include; cleaning or washing  (which can present as bleeding hands), checking; (checking door locks or the stove), ordering (certain objects must be in certain places, objects have to be “just right”), mental rituals (counting and praying), hoarding (collecting newspapers, magazines, candy wrappers), and tic-like compulsions (rubbing, patting, eye blinking, or staring) which aim to reduce anxiety, fear or worry caused by the obsessions [22,23].

Etiology of OCD
The etiology of OCD has many components.  The genetics involved in OCD is evidenced by twin studies as well as family studies [19,22,23].  Family studies have shown that approximately 35% of patients with OCD will also have first degree relatives with OCD and this number increases with an earlier age of onset [22].  The transmission model is still not fully understood and does not appear to fit into a simple Mendelian pattern [23].  The neurotransmitters most likely involved include serotonin and norepinephrine, based on the fact that selective serotonin reuptake inhibitors (which increase serotonin) and oral clonidine (which lowers norepinephrine) have been noted to reduce symptoms of OCD [19,22,23].

Brain imaging studies have also come up with interesting data.  Functional imaging has shown increased activity in the orbitofrontal cortex, the caudate nucleus as well as the cortico-striatal pathway [17,19].  Structural imaging has shown the caudate to be bilaterally smaller in patients with OCD [17,19].  There have been many models developed to try and explain how these brain-imaging studies might lead to obsessive-compulsive behaviours.  One group hypothesized that if the basal ganglia did not filter cortical impulses properly as may occur in OCD, there will be an increase in thalamic activity [23].  These excitatory impulses originating in the thalamus will reach the orbitofrontal cortex, producing a “barrier’ to these patients from removing certain (usually irrelevant) worries from their focus of attention [23].  This concept might be better understood if we consider the frontal cortico-basal-thalamic circuit as a closed system.  The basal ganglia should work as a circuit breaker and break the circuit each time an “overload” occurs.  However, if the circuit breaker fails to work, as is the case in OCD, behaviours will continue to repeat themselves over and over again [23].  A similar theory by Graybiel suggests that these cortico-basal-thalamic circuits form the neural systems critical for habit learning and for routine performance in normal people. She proposes that the dysfunction of three key structures might account for the principal features of OCD.  These structures, which are all linked by the cortico-basal-thalamic circuit include the orbitofrontal cortex, the anterior cingulate cortex and the caudate nucleus [19].  All three of these structures are important for evaluation of stimuli as positive or negative (rewarding or punishing).  Furthermore, all three have been linked to aspects of executive functioning.

Lesions of the orbitofrontal cortex may lead to ineffective behavioural planning or decision-making based on poor predictions of positive or negative consequences of certain actions.   For example, it has been shown that exposure to a particular stimuli can activate a certain state that through experience, has become associated with that stimuli [8].  In OCD, this reactivation of specific markers in response to expected outcomes have become excessive, causing the repetitive behaviours.  Another example of this is shown in people with ventromedial frontal cortex lesions.  These participants were given the odds in certain gambling tasks and yet they still lost because they were unable to weigh the risks and benefits (rewards and punishments) of their decisions [8]. The anterior cingulate cortex is adjoined to the medial prefrontal cortex and interconnected with the orbitofrontal cortex and the limbic system [6,19].  It is directly connected to the rostral cingulate motor area, which projects to the motor cortex [6,19].  Monkeys with lesions to the rostral cingulate motor area were found to be incapable of selecting an action based on the rewards associated with it [19].  As for the basal ganglia, different sets of cortico-basal-thalamic loops are thought to have specialized functions depending on the cortical areas participating in each loop [19,23].  In OCD, which typically involves obsessions as well as compulsions, the circuits connecting the orbitofrontal, anterior cingulate cortex and the basal ganglia are most likely involved.  However, in Tourette’s syndrome (TS), where repetitive actions are the predominant symptoms, circuits through the putamen (motor loop) are most affected.

Relationship Between OCD and Tourette’s Syndrome
As you may have already guessed from some of the information above, there is a lot of overlap between OCD and TS.   It may be simplest to think of these disorders as if they were on a continuum, shifting from motor to cognitive symptoms and to hypothesize that different regions of the brain are affected by the behaviours (see Figure 4). Using this model it is easier to understand how overlap between these two diseases can occur and why approximately 70-80% of patients with OCD also present with tic-like compulsions [23].


Figure 4: Model of Obsessive-Compulsive Disorder and Tourette’s Syndrome on a Continuum [23]

 

 

 

 

 

 

 

Tourette’s Syndrome
Tourette’s syndrome (TS) or “Gilles de la Tourette’s syndrome” is characterized by persistent motor and vocal tics.  It appears to be four times more common in boys than girls, and most likely has an autosomal dominant inheritance pattern with incomplete penetrance [23].  The onset of most patients is late childhood and symptoms appear to wax and wane getting worse in times of stress, anxiety or fatigue and spontaneously improving in adolescence [22,23]. Tics are sudden, rapid and repetitive, non-rhythmic vocalizations or stereotypical movements that occur for no apparent reason [14,22,23].   Simple motor tics usually occur at seven years of age and progress to complex vocal tics within 1 to 2 years [23].  An example of a simple motor tic is eye blinking, while a complex motor tic might be something such has hopping.  Simple vocal tics include sniffling, and throat clearing, while complex vocal tics include whistling and repeating sentences.  Children for the most part have no control over these tics and attempt to hide them by making seemingly normal movements like running their hands through their hair or adjusting their glasses [23].  Some patient’s report a “weird sensation” such as an itch or an “inner energy, which can be relieved by the tic [23].

The etiology of TS is similar to OCD since they can be considered to be a spectrum of disease.  Like OCD, family and twin studies, have proven that TS has a genetic component.   It is believed to be bilinear, meaning it is an autosomal pattern intermediate between dominant and recessive [23].  Also similar to OCD, neuroimaging of TS patients has shown abnormal activity in the striatum, especially in the putamen, which receives input from the sensory-motor cortex.  Further evidence has shown compulsive behaviours occurring in patients with lesions of their striatum [14].  Most structural imaging studies have found there to be a decreased volume in all striatal areas, however there appears to be a lack of consensus as to which areas show consistent decreases.  Functional MRI studies have also shown correlations between tic severity and tic suppression.  For example, the intensity of an urge to tic was correlated with increased activity in the caudate.  Furthermore, a PET study found the cerebral flow to the cingulate cortex to be increased in TS [27].  In another PET study, the metabolism of the caudate and thalamus was inversely correlated with clinical severity [21].  It has also been shown that there is increased activity in the primary sensori-motor cortex, which could also just be a non-specific reflection of excessive movement.  Other investigators found increased activity in the orbital-frontal cortex, which they suggest may be related to impulsivity, self-injurious behaviour, echo phenomena, and other obsessive-compulsive symptoms, due to its possible role in behavioural inhibition [19].

One theory suggests that tics may occur if the inhibitory activity of GABAnergic projections from the striatum to the globus pallidus are lower in TS [23].  Therefore, the corpus striatum does not inhibit the action of the GLUTaminergic neurons found in the thalamus, and excitatory projections are sent from the thalamus to the cortex.  Since TS patients are incapable of inhibiting stimuli secondary to certain sensory phenomena, there will be activation of the “cortico-basal-thalamic circuit” and development of motor and phonic tics [23].  Animal studies have also furthered our knowledge of how the two types of cells within the corpus striatum (striosomes and matrisomes) are involved in the development of tics [19,23].  Both are controlled by a tonically active neuron.  When the striosomes become more stimulated than the matrisomes, stereotyped movement occurs [14,23].  Another interesting theory involves the parahippocampal region.  Through the integration of sensory and limbic information, it is thought to play a key role in monitoring motor responses to external stimuli.  Because the insula seems to function as an alternate route for connecting the motor and sensory speech areas it may also be linked to vocal tics.  It is possible that the ventral striatum couples the motor and limbic mechanisms, and therefore the mesolimbic dopamine system could regulate the ventral striatum, and control the information flow from the limbic structures to the pallidum, thus governing the initiation of responses [26].

As already mentioned, the so-called obsessive-compulsive spectrum has emphasized the functional and structural alteration in the frontal cortex, basal ganglia and cortico-basal-thalamic circuits linking these brain regions.  However, in TS, neurotransmitters such as dopamine and norepinephrine have also been implicated in TS.  For example, it has been shown that patients with TS, improve on clonidine (an adrenergic agonist).  Abnormalities of dopamine transmission have also been suggested, and dopamine antagonist therapies are administered to Tourette’s patients [22,23].  Both typical and atypical antipsychotics, which decrease dopamine, have been used to suppress tics, while methylphenidate, amphetamines, and cocaine, which increase dopamine, also increase tic severity [22,23].  In some patients, tics have been shown to worsen by neuroleptic withdrawal.  Unfortunately, this is not so clear cut as dopamine receptor agonists have also successfully treated tics [2].  It is clear that dopaminergic function is abnormal in TS, but unclear as to the exact mechanism.

Future Research
The cerebellum projects to the hypothalamus, hippocampus, amygdala and basal ganglia, as well as the substantia nigra and locus ceruleus, therefore stimulating the release of dopamine and norepinephrine.  Early research also suggests that the cerebellar vermis, together with the fastigial nucleus and floccularnodular lobe are an extension of the limbic system and could therefore be involved in human emotion.  Further research exploring these concepts will possibly shed some light on how the cerebellum may play a role in OCD and TS.

References
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Appendix
Table I:  DSM-IV Criteria; Obsessive-Compulsive Disorder
  1. Either obsessions or compulsions

Obsessions as defined by (1), (2), (3), and (4):

    1. recurrent and persistent thoughts, impulses, or images that are experienced at some time during the disturbance, as intrusive and inappropriate and that cause marked anxiety or distress
    2. the thoughts, impulses, or images are not simply excessive worries about real-life problems
    3. the person attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize them with some other thought or action.
    4. the person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind (not imposed from without as in thought insertion)

Compulsions as defined by (1) and (2):

    1. repetitive behaviours (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly
    2. the behaviours or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation; however, these behaviours or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive
  1. At some point during the course of the disorder, the person has recognized that the obsessions or compulsions are excessive or unreasonable. Note: This does not apply to children.
  2. The obsessions or compulsions cause marked distress, are time consuming (take more than 1 hour a day), or significantly interfere with the person’s normal routine, occupational (or academic) functioning, or usual social activities or relationships.
  3. If another Axis I disorder is present, the content of the obsessions or compulsions is not restricted to it (e.g., preoccupation with food in the presence of an Eating Disorder; hair pulling in the presence of Trichotillomania; concern with appearance in the presence of Body Dysmorphic Disorder; preoccupation with drugs in the presence of a Substance Use Disorder; preoccupation with having a serious illness in the presence of Hypochondriasis; preoccupation with sexual urges or fantasies in the presence of a Paraphilia; or guilty ruminations in the presence of Major Depressive Disorder).
  4. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
Table II:  DSM-IV Criteria; Tourette's Disorder
  1. both multiple motor tics and one or more vocal tics must be present at the same time, although not necessarily concurrently
  2. the tics must occur many times a day (usually in bouts) nearly every day or intermittently over more than 1 year, during which time there must not have been a tic-free period of more than 3 consecutive months
  3. the age at onset must be less than 18 years
  4. the disturbance must not be due to the direct physiological effects of a substance (e.g. stimulants) or a general medical condition (e.g. Huntington's disease or post-viral encephalitis).
Table III:  ICD-10 Criteria;  Combined vocal and multiple motor tic disorder [de la Tourette's syndrome]
  1. A form of tic disorder in which there are, or have been, multiple motor tics and one or more vocal tics, although these need not have occurred concurrently. Onset is almost always in childhood or adolescence. A history of motor tics before development of vocal tics is common; the symptoms frequently worsen during adolescence, and it is common for the disorder to persist into adult life.
  2. The vocal tics are often multiple with explosive repetitive vocalizations, throat-clearing, and grunting, and there may be the use of obscene words or phrases. Sometimes there is associated gestural echopraxia, which also may be of an obscene nature (copropraxia). As with motor tics, the vocal tics may be voluntarily suppressed for short periods, be exacerbated by stress, and disappear during sleep.