The strongest body of evidence favouring the serotoninergic basis of OCD comes from studies indicating the effectiveness of Specific Serotonin Reuptake Inhibitors (SSRIs) in OCD (Fineberg and Montgomery 1990). Available neurobiological and pharmacological data in OCD implicate the serotonin system in its neurochemical dysfunction, and the basal ganglia and frontal cortex as the prime anatomic loci of its neuropathology. Interestingly, these same brain regions have been implicated in
the pathophysiology of GTS. There is growing evidence to suggest the existence of anatomic and functional interactions between 5- Hydroxytryptamine (5HT) and dopaminergic systems (Graybiel 1990). 5HT neurones are believed to maintain a tonic inhibitory influence on dopaminergic function in some regions of the brain, especially the midbrain and brainstem projections to the forebrain (George 1991). The neuroanatomic hypothesis that the basal ganglia and its orbitofrontal connections may form the neuronal circuit which subserves GTS and OCB, and the available evidence about the interaction between 5HT and dopamine, is compatible with the role of the above structures and neurotransmitters in the pathophysiology of GTS spectrum OCB.
3.3. NEUROIMAGING
Functional imaging studies have thrown some light on the brain substrates of GTS and related behaviours. Although no definitive abnormalities have been found, there is a tentative consensus as to the brain areas involved. Particularly implicated are the striatal and frontal areas in both GTS and OCD. OCD has been associated with hyperperfusion; increased metabolic changes in the orbitofrontal cortices and basal ganglia (Baxter et al 1987; 1989; Baxter and Guze 1993; Nordahl et al 1989; Swedo et al 1989). It has also been postulated that the 'frontal hyperperfusion' seen in OCD may be linked to increased arousal and anxiety in these cases (Gath et al 1992). Although limited.
available literature on perfusion patterns in GTS suggest hypoperfusion rather than increased blood flow. For example. Chase et al (1986) found increased relative metabolic activity and rCBF in certain frontal cortical areas in OCD, when compared to GTS. Preliminary studies in GTS as reported by Riddle et al
(1992), Dimitsopulos et al (1993) and Moriarty et al (1995) suggest involvement of caudate, anterior cingulate, medial temporal and dorsolateral prefrontal areas in the form of hypoperfusion. OCD and GTS thus have apparent genetic and biological associations, but conflicting cerebral blood flow findings.
3.4. GENETICS
In addition to the clinical relationship between GTS and OCB, studies have also suggested that OCB may be aetiologically related to the GTS both biochemically and genetically (Eapen & Robertson 1994; Robertson 1994). Pauls et al (1986a) in a family study reported GTS and OCB to be genetically related. The frequency of OCD in the absence of tics among FDRs was significantly elevated in families of both GTS+OCD and GTS-OCD probands. The rate of OCD among FDRs was significantly increased over estimates of the general population and a control sample of adoptive relatives. The rates of GTS, tics and OCD were the same among relatives of GTS probands with OCD (GTS+OCD) when compared with families of probands without OCD (GTS-OCD).
Whilst there is a familial relationship between OCD and GTS, not all cases of OCD are aetiologically related to GTS (Pauls 1990). An implication of this observation is that, there may be a
subtype of OCD that is genetically related to GTS, while others are not.
Segregation analysis of 24 families of OCD, CMT and GTS subjects was performed by Nicolini and colleagues (1991). Hypotheses of single-locus Mendelian inheritance were tested by segregation analysis performed with the computer programme SEGRAN. In SEGRAN, the segregation ratio is calculated from the number of affected and unaffected siblings of the proband, taking into account the size of the sibship. The affected status of the relatives was assigned as OCD, GTS and CMT. These investigators obtained a segregation ratio in the normal by normal parental mating type (both parents unaffected) 0.33+/- 0.16, and in the normal by affected parental mating type 0.39+/- 0.14. Since the ratio in the normal by affected parental mating type was around 0.4; i.e. very close to the expected 0.5, (0.5% = 100%; 0.45 = 90%; 0.4 = 80%), the best likelihood was for the dominant model assuming a penetrance of 80%. These investigators were not able to reject either the autosomal dominant or the recessive model (restricted model) when compared with the unrestricted model by means of a chi-square. Thus, there is increasing evidence to
support the hypothesis that OCD is familial and that genetic factors are important in the expression of the disorder. However, most studies to date have relied on family history data and it is known that in psychiatric disorders such methodology usually underestimates the true prevalence of the disorder in question. This is particularly relevant in the case of OCD, since individuals may be secretive about their symptoms and is therefore subject to reporting bias. Therefore it will only be possible to examine hypothesis about the genetic transmission of OCD by using data where all family members have been directly interviewed.
The results from these investigations do not, however, suggest that all subjects with OCD have a disorder that is aetiologically related to GTS. It may well be that there are at least two sub groups within OCD: those with a family history of GTS and those without such a history (Green and Pitman 198 6). It is debatable whether the OC symptoms observed in members of families with GTS is somewhat a milder form, although the range and character of symptoms may or may not be different from those observed in clinical patients with OCD in the absence of GTS. Yet another question to be addressed therefore is, whether or not the OCD that is unrelated to GTS is also familial, and if so, whether the patterns within families are consistent with genetic transmission.
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