Obsessive-Compulsive Disorder (OCD). A dysfunctional cortico-striato-thalamo-cortical circuitry may play an important role in this disorder (Rauch and Baxter, 1998; Rauch et al., 1998). According to this model, the primary pathology afflicts subcortical structures (striatum/thalamus), which leads to inefficient gating and results in hyperactivity within the orbito-frontal cortex and also within the anterior cingu-late cortex. Compulsions are conceptualized as repetitive behaviors that are ultimately performed in order to recruit the inefficient striatum to achieve thalamic gating and hence to neutralize the unwanted thoughts and anxiety. PET and SPECT studies have consistently indicated that patients with OCD exhibit increased regional brain activity within orbitofrontal and anterior cingulate cortex, in comparison with normal control subjects (Baxter et al., 1988; Machlin et al., 1991; Nordahl et al., 1989; Rubin et al., 1992; Swedo et al., 1992). Observed differences in regional activity within the caudate nucleus have been less consistent (Baxter et al., 1988; Rubin et al., 1992). Pre-and posttreatment studies have reported treatment-associated attenuation of abnormal brain activity within orbito-frontal cortex, anterior cingulate cortex, and caudate nucleus (Baxter et al., 1992; Benkelfat et al., 1990; Schwartz et al., 1996; Swedo et al., 1992). In addition, both pharmacological and behavioral interventions appear to be associated with similar brain activity changes (Baxter et al., 1992; Schwartz et al., 1996). Symptom provocation studies using PET (McGuire et al., 1994) as well as fMRI (Breiter et al., 1996) have also most consistently shown increased brain activity within anterior-lateral orbitofrontal cortex, anterior cingulate cortex, and caudate nucleus during the OCD symptomatic state.
Cognitive activation studies using PET and fMRI have probed the functional integrity of the cortico-striato-thalamo-cortical circuitry in OCD. In these studies patients with OCD perform an implicit learning paradigm that has been shown to reliably recruit stria-tum in healthy individuals (Rauch et al., 1995b, 1997b). In both studies, patients with OCD failed to recruit striatum normally and instead activated medial temporal regions typically associated with conscious information processing. Taken together, these neu-roimaging findings are consistent with dysfunctions of a cortico-striato-thalamo-cortical circuitry and support the view of a primary striatal pathology and striato-thalamic inefficiency, together with orbito-frontal hyperactivity in OCD.
Social and Specific Phobias. Relatively few imaging studies have investigated specific phobias. Most have employed PET imaging. While one study failed to demonstrate changes in rCBF (Mountz et al., 1989), results from others suggested activation of anterior-paralimbic regions (Rauch et al., 1995a) and sensory cortex (Fredrikson et al., 1995; Wik et al., 1993) corresponding to stimulus inflow associated with a symptomatic state. Although such results are consistent with a hypersensitive system for assessment of or response to specific threat-related cues, they do not provide clear anatomic substrates for the pathophysiology of specific phobia. Whereas one SPECT study of patients with social phobia and healthy control subjects found no significant between-group difference during resting conditions (Stein and Leslie, 1996), more recent cognitive activation neuroimaging studies revealed exaggerated respon-sivity of medial temporal lobe structures to human face stimuli (Birbaumer et al., 1998; Schneider et al., 1999). This hyperresponsivity may reflect a neural substrate for social anxiety.
The isotope [15O] was used in one PET study to measure rCBF in 18 patients with social phobia and a nonphobic comparison group while they were speaking in front of an audience and in private (Tillfors et al., 2001). During public versus private speaking, subjective anxiety increased more in the social phobics, and their increased anxiety was accompanied by enhanced rCBF in the amygdala. Cortically, rCBF decreased in the social phobics and increased in the comparison subjects more during public than private speaking in the orbito-frontal and insular cortices, as well as in the temporal pole, and increased less in the social phobics than in the comparison group in the parietal and secondary visual cortices. In summary, rCBF patterns of relatively increased cortical rather than subcortical perfusions were observed in the nonphobic subjects, indicating that cortical evaluative processes were taxed by public performance. In contrast, the social phobia symptom profile was associated with increased subcortical activity. Thus, the authors proposed that the functional neuroanatomy of social phobia involves the activation of a phylogenetically older danger recognition system (Tillfors et al., 2001).
Another interesting PET study identified common changes in rCBF in patients with social phobia treated with citalopram or cognitive-behavioral therapy (Furmark et al., 2002). Within both groups, and in responders regardless of treatment approach, improvement was accompanied by a decreased rCBF response to public speaking bilaterally in the amygdala, hippocampus, and the periamygdaloid, rhinal, and parahip-pocampal cortices. The degree of amygdalar-limbic attenuation was associated with clinical improvement a year later. The authors proposed that common sites of action for citalopram and cognitive-behavioral treatment of social anxiety comprised the amygdala, hippocampus, and neighboring cortical areas, which are brain regions subserving bodily defense reactions to threat (Furmark et al., 2002).
Panic Disorder. Panic disorder (PD) may be characterized by fundamental amygdala hyperresponsivity to subtle environmental cues, triggering full-scale threat-related responses in the absence of conscious awareness. Resting-state neuroimaging studies have suggested abnormal hippocampal activity with abnormally low left/right ratios of parahippocampal blood flow and a rightward shift after treatment with imipramine (Nordahl et al., 1998). One study demonstrated a reduced blood flow in hippocampal area bilaterally (De Cristofaro et al., 1993). In contrast, others have observed elevated metabolism in the left hippocampus and parahippocampal area (Bisaga et al., 1998). Symptom provocation studies have revealed reduced activity in widespread cortical regions, including prefrontal cortex, during symptomatic states (Fischer et al., 1998; Reiman et al., 1989; Stewart et al., 1988; Woods et al., 1988).
In a [15O] PET study, Meyer et al. (2000) found an increased left posterior parietal-temporal cortex activation after a challenge with D-fenfluramine in 17 women with panic disorder. In particular, they found hypoactivity in the precentral gyrus, the inferior frontal gyrus, the right amygdala, and the anterior insula during anticipatory anxiety in PD patients. Hyperactivity in patients compared to control subjects was observed in the parahippocampal gyrus, the superior temporal lobe, the hypothalamus, the anterior cin-gulate gyrus, and the midbrain. After the fenfluramine challenge, the patients showed decreases compared to the control subjects in the precentral gyrus, the inferior frontal gyrus, and the anterior insula. Regions of increased activity in the patients compared to the control subjects were the parahippocampal gyrus, the superior temporal lobe, the anterior cingulate gyrus, and the midbrain. Another [15O] PET study described specific rCBF differences between panic disorder patients and control subjects during anticipatory anxiety and rest (Boshuisen et al., 2002): During anticipatory anxiety there was hypoactivity in the precentral gyrus, the inferior frontal gyrus, the right amygdala, and the anterior insula in the PD patients. Hyperactivity in patients compared to control subjects was observed in the parahippocampal gyrus, the superior temporal lobe, the hypothalamus, the anterior cingulate gyrus, and the midbrain. After a pentagastrin challenge, the patients showed decreases compared to the control subjects in the pre-central gyrus, the inferior frontal gyrus, and the anterior insula. Regions of increased activity in the patients compared to the control subjects were the parahippocampal gyrus, the superior temporal lobe, the anterior cingulate gyrus, and the midbrain. The authors concluded that the pattern of rCBF activations and deactivations observed both before and after the pentagastrin challenge was the same, although different in intensity (Boshuisen et al., 2002).
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