James Warwick

Single photon emission computed tomography in posttraumatic stress disorder before and after treatment with a selective serotonin reuptake inhibitor

BACKGROUND Posttraumatic stress disorder (PTSD) is recognized as a disorder mediated by specific neurobiological circuits. Functional imaging studies using script-driven trauma imagery and pharmacological challenges have documented altered cerebral function (activation and deactivation) in several brain regions, including the amygdala, hippocampus, prefrontal cortex and anterior cingulate. However, the neural substrates of PTSD remain poorly understood and the effect of selective serotonin reuptake inhibition on regional cerebral activity is deserving of further investigation. METHODS Eleven adult patients (seven men, four women) (mean age+S.D.=33.6+/-9.2 years) with a DSM-IV diagnosis of PTSD, as determined by the Structured Clinical Interview for DSM-IV (SCID-I) and the Clinician-Administered PTSD Scale (CAPS), underwent single photon emission computed tomography (SPECT) with Tc-99m HMPAO pre- and post-8 weeks of treatment with the selective serotonin reuptake inhibitor, citalopram. Symptoms were assessed at baseline and at 2-week intervals with the Clinician-Administered PTSD Scale (CAPS), Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impression Scale (CGI). Image analysis of baseline and post-treatment scans was performed using Statistical Parametric Mapping (SPM). RESULTS Treatment with citalopram resulted in significant deactivation in the left medial temporal cortex irrespective of clinical response. On covariate analysis, a significant correlation between CAPS score reduction and activation in the left paracingulate region (medial prefrontal cortex) was observed post-treatment. No significant pre-treatment differences were observed between responders and non-responders in anterior cingulate perfusion. CONCLUSIONS These preliminary findings are consistent with clinical data indicating temporal and prefrontal cortical dysfunction in PTSD and preclinical data demonstrating serotonergic innervation of these regions. However, further studies, in particular in vivo receptor imaging studies, are needed to confirm whether these regional abnormalities correlate with clinical features and treatment response.

Single photon emission computed tomography (SPECT) of anxiety disorders before and after treatment with citalopram.

BackgroundSeveral studies have now examined the effects of selective serotonin reuptake inhibitor (SSRI) treatment on brain function in a variety of anxiety disorders including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (social phobia) (SAD). Regional changes in cerebral perfusion following SSRI treatment have been shown for all three disorders. The orbitofrontal cortex (OFC) (OCD), caudate (OCD), medial pre-frontal/cingulate (OCD, SAD, PTSD), temporal (OCD, SAD, PTSD) and, thalamic regions (OCD, SAD) are some of those implicated. Some data also suggests that higher perfusion pre-treatment in the anterior cingulate (PTSD), OFC, caudate (OCD) and antero-lateral temporal region (SAD) predicts subsequent treatment response. This paper further examines the notion of overlap in the neurocircuitry of treatment and indeed treatment response across anxiety disorders with SSRI treatment.MethodsSingle photon emission computed tomography (SPECT) using Tc-99 m HMPAO to assess brain perfusion was performed on subjects with OCD, PTSD, and SAD before and after 8 weeks (SAD) and 12 weeks (OCD and PTSD) treatment with the SSRI citalopram. Statistical parametric mapping (SPM) was used to compare scans (pre- vs post-medication, and responders vs non-responders) in the combined group of subjects.ResultsCitalopram treatment resulted in significant deactivation (p = 0.001) for the entire group in the superior (t = 4.78) and anterior (t = 4.04) cingulate, right thalamus (t = 4.66) and left hippocampus (t = 3.96). Deactivation (p = 0.001) within the left precentral (t = 4.26), right mid-frontal (t = 4.03), right inferior frontal (t = 3.99), left prefrontal (3.81) and right precuneus (t= 3.85) was more marked in treatment responders. No pattern of baseline activation distinguished responders from non-responders to subsequent pharmacotherapy.ConclusionsAlthough each of the anxiety disorders may be mediated by different neurocircuits, there is some overlap in the functional neuro-anatomy of their response to SSRI treatment. The current data are consistent with previous work demonstrating the importance of limbic circuits in this spectrum of disorders. These play a crucial role in cognitive-affective processing, are innervated by serotonergic neurons, and changes in their activity during serotonergic pharmacotherapy seem crucial.

Single photon emission computed tomography op the brain with Tc-99m HMPAO during sumatriptan challenge in obsessive-compulsive disorder: Investigating the functional role of the serotonin auto-receptor

1. Symptoms of obsessive-compulsive disorder (OCD) may be acutely exacerbated by administration of certain serotonin agonists Exacerbation of OCD symptoms by sumatriptan, a 5HT1D agonist (Zohar, 1993), is consistent with pre-clinical data suggesting that the serotonin auto-receptor plays an important role in this disorder (El Mansari et al, 1995). 2. In order to investigate the functional role of the serotonin auto-receptor in OCD, the authors undertook single photon emission computed tomography in OCD patients after administration of sumatriptan and placebo. The authors hypothesized that, as in the case of m-chlorophenylpiperazine (mCPP) challenge (Hollander et al, 1995), exacerbation of OCD symptoms would be accompanied by increased cortical metabolism and thus blood flow, and more specifically by increased activity in the orbitofrontal-striatal circuit. They also expected, that as in the case of mCPP challenge (Hollander et al, 1993), exacerbation of OCD symptoms would be associated with a relatively poor response to subsequent treatment with serotonin specific reuptake inhibitors. 3. Sumatriptan (100 mg orally) and placebo were administered on separate days to 14 patients who met DSM-IV diagnostic criteria for OCD, using a randomized double-blind design. After 90 minutes, patients were injected with Tc-99m HMPAO and underwent single photon emission computed tomography (SPECT) of the brain. Activity in regions of interest was calculated, and compared using repeated measures analysis of variance. Patients were subsequently treated with a serotonin specific reuptake inhibitor (SSRI). 4. Behavioral response to sumatriptan was heterogenous, with 4 patients showing acute exacerbation, and 4 patients demonstrating a decrease in symptoms. On sumatriptan challenge, there was a significant association between symptom exacerbation and decreased activity in frontal areas. There was an association between decreased activity in an inferior frontal area with worse response to treatment, and also patients with symptom exacerbation after sumatriptan had poorer response to SSRI treatment. 5. Heterogeneity of behavioral response to sumatriptan in OCD is consistent with previous studies demonstrating conflicting and heterogenous behavioral responses to serotonergic challenges (Hollander et al, 1992), and with underlying heterogeneity in the neurobiology of this disorder. 6. It may be hypothesized that increased frontal activity in some patients with OCD is itself a compensatory mechanism. In patients with such compensatory hyperactivity, administration of a serotonin auto-receptor agonist results in decreased frontal activity and exacerbation of OCD symptoms. These patients may also be less likely to respond to treatment with a SSRI. 7. Further work combining pharmacological challenge paradigms and functional imaging techniques in OCD may be helpful in elucidating the neurobiology of this complex disorder.

Disrupted functional connectivity in social anxiety disorder: a resting-state fMRI study

Dysfunction of the corticolimbic circuitry has been highlighted in social anxiety disorder (SAD) during social stimuli. However, few studies have investigated functional connectivity in SAD during the resting state, which may improve our understanding of SAD pathophysiology. The aim of this study was to investigate whether whole-brain functional connectivity might be aberrant in SAD patients, and if so, whether these changes are related to the measured clinical severity. Seventeen SAD patients and 19 healthy controls participated in resting-state functional magnetic resonance imaging. The brain was first divided into 90 paired brain regions and functional connectivity was then estimated by temporal correlation between each of these regions. Furthermore, connections that were significantly disrupted in SAD patients were correlated with clinical severity measured using the Liebowitz Social Anxiety Scale. Compared with healthy controls, SAD patients showed decreased positive connections within the frontal lobe and decreased negative connections between the frontal and occipital lobes. In particular, the weaker negative connections between the frontal lobe, which mainly involved the right median prefrontal cortex, and the occipital lobe had a significant positive correlation with the severity of SAD symptoms. The results support the hypothesis that some abnormalities of functional connectivity exist in SAD patients, which relate to the frontal cortex and occipital cortex. In addition, decreased functional connectivity between the frontal and occipital lobes and within the frontal lobe might be related to abnormal information processing and reflect disturbed neural organization resulting in defective social cognition, which could represent an early imaging biomarker for SAD.

Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure

The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET–CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET–CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.The absence of a gold standard to determine when antibiotics have induced sterilizing cure confounds the development of new approaches to treat pulmonary tuberculosis (PTB). We detected PET-CT imaging response patterns consistent with active disease along with the presence of Mycobacterium tuberculosis mRNA in sputum and bronchoalveolar lavage samples in a substantial proportion of adult, HIV-negative PTB patients after standard 6-month treatment plus one year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of non-resolving and intensifying lesions on PET-CT might indicate ongoing transcription, suggesting that even apparently curative PTB treatment may not eradicate all organisms in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies and better treatment response markers are likely needed for the successful development of improved and shortened PTB treatment strategies.

Resting brain perfusion in social anxiety disorder : A voxel-wise whole brain comparison with healthy control subjects

INTRODUCTION Social anxiety disorder (SAD) is a condition characterised by fears of social interaction and performance situations. SAD may be related to a dysregulation or hyperactivity of cortico-limbic circuitry. This is the first voxel-based whole brain study comparing resting function in SAD to a normal control group. METHODS Resting perfusion in adult subjects with generalised SAD was compared with healthy adult volunteers using Statistical Parametric Mapping (SPM). In subjects with SAD, correlations were also sought between resting perfusion and clinical severity measured using the total Liebowitz Social Anxiety Scale (LSAS). RESULTS Twenty-eight subjects with SAD were compared with 19 healthy volunteers. SAD subjects had increased resting perfusion in the frontal cortex and right cerebellum, and decreased perfusion in the pons, left cerebellum, and right precuneus. Total LSAS correlated positively with left frontal cortex resting perfusion, and negatively with right fusiform and right lingual perfusion. CONCLUSION This study demonstrated increased resting frontal function in social anxiety disorder that is consistent with its hypothesised role in the modulation of excessive limbic activity in anxiety disorders. The correlation of posterior cortical resting function with the severity of SAD symptoms may point to defective perception of self and others.

Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[ 18 F]fluoro- D -glucose positron emission and computed tomography

Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.

Imaging of Brain function using SPECT

Single photon emission computed tomography (SPECT) is a technique widely used in nuclear medicine for the imaging of the many organs including the skeleton and heart, as well as for whole body imaging for the detection of tumors. The use of tracers of cerebral perfusion and more recently brain neurotransmitter systems has resulted in the development of a number of applications for brain SPECT in neurology and psychiatry. Indications have been established in cases of dementia, epilepsy, neurovascular disorders, Parkinsonism, and following minor head trauma. It also has the potential to be a valuable research tool for the study of in vivo brain function. In this paper an overview will be given of the principles underlying Brain SPECT, the performance of the procedure, and its applications as a diagnostic modality and research tool.

Should SPECT-CT replace SPECT for the evaluation of equivocal bone scan lesions in patients with underlying malignancies?

IntroductionBone scintigraphy is used extensively in evaluating metastatic disease. There are currently no clear recommendations for the use of single photon emission computed tomography (SPECT)/CT in metastatic bone disease. Given its limited availability there is a need to identify the clinical indications for which SPECT/CT is clearly beneficial in influencing patient care and outcome. MethodsForty-two patients with equivocal lesions on planar scintigraphy were recruited and underwent SPECT/CT imaging. On reading of SPECT alone and then SPECT/CT, lesions were classified as malignant, benign or equivocal. Follow-up clinical information, radiological studies and/or bone scans were used as a gold standard. SPECT and SPECT/CT were compared in terms of the number of equivocal findings and accuracy on a patient-wise and lesion-wise basis. ResultsForty-two patients with 189 skeletal lesions were examined. There was a diverse variety of primary tumours, with the majority being breast (n=22) and prostate cancer (n=8). SPECT/CT resulted in a significant reduction in the proportion of patients (48–14%, P=0.0015) and lesions (31–9%, P<0.0001) with equivocal findings. The overall accuracy of SPECT/CT was significantly higher on both a patient-wise (52–79%, P=0.0026) and lesion-wise basis (67–92%, P<0.0001). ConclusionSPECT/CT significantly outperforms SPECT alone for the interpretation of skeletal lesions in patients undergoing bone scanning for metastases. When available SPECT/CT is indicated in patients in whom correct classification of equivocal lesions is expected to alter the patients management.

A comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder

AbstractIntroduction: The serotonin specific reuptake inhibitor (SSRI) citalopram and the reversible mono-amine oxidase-A inhibitor (RIMA) moclobemide have both been used successfully for the treatment of social anxiety disorder (SAD). In this study we investigate the effects of these compounds on resting brain function using single photon emission computed tomography (SPECT). Methods: Subjects meeting DSM-IV criteria for SAD underwent regional cerebral blood flow (rCBF) SPECT using Tc-HMPAO at baseline and after 8 weeks of treatment with either citalopram or moclobemide. Using statistical parametric mapping brain SPECT studies were analysed to determine the effects of treatment on rCBF, to compare the effects of citalopram and moclobemide, and to detect correlations between changes in rCBF and clinical response. Results: Subjects received citalopram (n=17) or moclobemide (n=14) as therapy. Subjects in both treatment groups demonstrated a significant improvement of SAD symptoms as measured by the Liebowitz Social Anxiety Scale total score. All subjects demonstrated a decrease in rCBF in the insulae post therapy. Subjects receiving citalopram had decreased superior cingulate rCBF after therapy compared to those receiving moclobemide. Conclusion: Both SSRIs and RIMAs decreased rCBF in the insulae during treatment of SAD; an effect that may be consistent with the role of these regions in processing internal somatic cues evoked by emotional stimuli. Citalopram had a greater effect on superior cingulate perfusion, an effect that is consistent with evidence of high levels of 5-HT transporters in this region.