Книги по МРТ КТ на английском языке / Functional Neuroimaging in Child Psychiatry Ernst 1 ed 2000

216R. A. Kowatch, P. A. Davanzo and G. J. Emslie

mamillary body rCBF, whereas unsolvable anagrams increased mamillary body and amygdalar CBF and decreased hippocampal rCBF.

To explore the neural bases of externally versus internally generated human emotion, Reiman et al. (1997) measured rCBF using PET in 12 healthy normal females while they watched short Wlm clips with either emotionally laden or neutral content. Tasks alternated between emotion-generating and control Wlm and recall tasks. Both Wlmand recall-generated emotion signiWcantly increased activity in the medial prefrontal cortex and thalamus. Filmgenerated emotion increased rCBF bilaterally in the occipitotemporoparietal cortex, lateral cerebellum, and hypothalamus. Recall-generated sadness was associated with increases in the anterior insular cortex.

Activation studies of adult mood disorders

Using a Tower of London task to study frontal lobe function, Elliott et al. (1997) used PET to measure rCBF in Wve patients with unipolar depression (mean Hamilton score 23.8) and controls matched for age, gender, and educational levels. Unlike controls, depressed subjects failed to show signiWcant activation in the cingulate and striatum and failed to show the normal augmentation of activation in the caudate nucleus, anterior cingulate, and right prefrontal cortex that was associated with increasing task diYculty, suggesting impaired function of these regions in depression.

Blunted activation of the left cingulate in depression has also been demonstrated using a Stroop task with 15O PET. George et al. (1997) studied 11 mood-disordered adults (nine men, two women; six unipolar, three biopolar II, and two bipolar I) and an equal number of ageand sexmatched controls. A control task involved color naming, a standard Stroop task required subjects to name the colors of ink in which incongruent color names appeared (e.g., ªredº printed in blue ink), and a sad Stroop task required the naming of the colors of ink in which emotional words (e.g., grief, misery, sad, bleak) appeared. Depressed subjects were able to activate the left dorsolateral prefrontal cortex, a region commonly hypoactive at rest in depression and hypoactive during the control task in this study. In contrast, activation seen during the interference task (i.e., naming of incongruent colors) was reduced in the left midcingulate, as well as in left insula and right superior temporal gyrus. No signiWcant group diVerences were seen during the sad Stroop test.

Using fMRI, Beauregard et al. (1998) studied seven adults (four women and three men) with major depression (mean age 42 years) and ageand gender-matched controls.

Subjects were imaged while watching a color Wlm clip designed to elicit sadness and while watching a neutral Wlm clip. Transient sadness elicited signiWcant activation in both groups in the medial and inferior prefrontal cortices, the middle temporal cortex, the cerebellum, and the right caudate, suggesting the participation of circuits involving these regions in this emotion. However, relative to controls, depressed subjects showed signiWcantly greater activation while viewing the sad Wlm clip in the left medial prefrontal cortex and right cingulate.

Neuroimaging of pediatric mood disorders

Studies of children and adolescents with mood disorders are just emerging. There have been a few structural studies of children and adolescents with mood disorders, the interpretation of which must be integrated with the changes that are known to occur with brain maturation (Chugani et al., 1987; Chugani and Phelps, 1991; Chiron et al., 1992). This limits direct comparisons with studies of adults. Structural imaging studies of children and adolescents with mood disorders using MRI have begun to implicate the frontal and temporal lobes and basal ganglia.

Hendren et al. (1991) reported clinically abnormal MRI scans in two of three children hospitalized for MDD. The Wrst was a 13-year-old male whose MRI showed abnormally asymmetrical lateral ventricles (right larger than the left), suggesting right-sided ventricular enlargement and decreases in surrounding brain tissue. The second subject was a 12-year-old male whose MRI showed a small area of abnormal signal intensity in the area of the left anterior basal ganglia or medial temporal lobe.

In a volumetric MRI study, Steingard et al. (1996) compared 65 children and adolescents (mean age 13 years) who were hospitalized for either MDD or dysthymia with 18 hospitalized psychiatric controls (mean age 10.7 years) without a depressive disorder: 11 with conduct disorder/ oppositional deWant disorder, two with ADHD, three with post-traumatic stress disorder, and two with an adjustment disorder. Volumetric analyses were used to measure frontal lobe volumes, lateral ventricular volumes, and total cerebral volumes for all subjects. To correct for diVerences in absolute cerebral volume associated with diVerent body and head size, the ratios of frontal lobe and lateral ventricular volumes to total cerebral volume were used to compare diVerences between the two groups; a multivariate analysis was used to control for the eVects of age, gender, and diagnosis. The depressed group had reduced frontal lobe volumes (signiWcantly smaller frontal lobe to total cerebral volume ratio) and increased ventricular volumes (signiWcantly larger ventricular to total cerebral

volume ratio), but normal total cerebral volumes relative to their nondepressed psychiatric controls. The reduction in frontal lobe volume resembles that reported in depressed adults with MDD, suggesting some continuity of deviations in brain anatomy.

In the Wrst anatomic MRI study of pediatric bipolar patients, Botteron et al. (1995) compared T1- and T2- weighted MRI scans from eight manic children and adolescents and Wve age-, but not gender-matched normal subjects. They reported increased rates of subcortical white matter signal hyperintensities, abnormal temporal horn asymmetries, and ventricular abnormalities in four of the bipolar patients, and only one of the normal controls by clinical interpretation. Areas of hyperintensity on MRI usually are caused by increased water content and have been associated with ischemia, inXammation, and demyelination. While the signiWcance of these hyperintensities in children and adolescents with bipolar disorders is uncertain at this time, these Wndings are consistent with those of MRI studies of adults with bipolar I disorders, which frequently Wnd white matter signal hyperintensities in the periventricular space (Altshuler et al., 1995).

Using 1H MRS, Steingard et al. (1998) studied 14 adolescents with MDD (mean age 15.6 years) and 26 normal controls (mean age 14.3 years). Depressed adolescents showed an increase in the ratio of choline to creatine in the orbitofrontal cortex relative to controls, but normal N-acetylas- partate to creatine ratios. These Wndings are similar to Wndings in adult MDD (Charles et al., 1994) and suggest alterations in cholinergic neurotransmission in the orbitofrontal cortex.

In a recent SPECT study with 99mTc-labeled hexamethylpropyleneamine oxime (HMPAO), Kowatch et al. (1999) compared the rCBF in a resting condition of a group of seven adolescents (mean age 15.5 years; range 13±18 years) with symptomatic MDD (DSM-III-R criteria) to those of seven ageand gender-matched normal controls. Previously, the authors have obtained SPECT brain scans on depressed children and adolescents who were inpatients, and visual analysis of these studies suggested abnormalities (relative bilateral hypoperfusion) of the frontal cortex and mesial temporal lobes (Kowatch et al., 1993). This controlled study used a voxel-based T-image analysis to compare the rCBF patterns of a group of adolescents with MDD with those of control adolescents. After normalizing regional to whole brain counts, higher relative rCBF was found in the right mesial temporal cortex, the right superior±anterior temporal lobe, and the left inferolateral temporal lobe in the depressed group relative to controls. Decreased relative rCBF in the depressed group

compared with the control group was localized to the left parietal lobe, the anterior thalamus, and the right caudate. The most spatially extensive area of abnormally low rCBF was in the left superior parietal cortex. Some of these diVerences are shown in Figs. 12.2 and 12.3.

These preliminary Wndings suggest that portions of the right and left temporal lobes, the left parietal lobe, the anterior thalamus, and the right caudate may be involved in adolescent MDD. Parietal lobe rCBF abnormalities in MDD adults have been reported in a number of SPECT studies (Sackeim et al., 1990; Austin et al., 1992; Philpot et al., 1993; Lesser et al., 1994). Mesulam (1985) noted that, in monkeys, the superior parietal lobe receives projections from the primary somatosensory cortex and is designated as the unimodal somatosensory association area. Although lesions of the left parietal cortex area in humans are associated with deWcits in motor planning (de Renzi et al., 1983), the role of the left superior parietal cortex in MDD has yet to be elucidated. The authors also found high levels of relative rCBF in the right mesial temporal cortex, the right superior anterior temporal lobe, and the left inferolateral temporal lobe. The temporal lobes are central to the limbic±thalamic±cortical circuit believed to contribute to the regulation of mood (Ketter et al., 1996; Mayberg 1997). In addition, the majority of adult SPECT studies have reported decreases in temporal lobe rCBF (Soares and Mann, 1997b). Although the above studies implicate the temporal lobes in the pathophysiology of MDD in both adults and adolescents, the direction of the abnormality (low in adult MDD and high in adolescent MDD) is inconsistent. These Wndings raise the possibility of developmental diVerences in the neurobiology of adolescent versus adult MDD. Finally, adolescents with MDD show rCBF abnormalities implicating the limbic±thalamic±cortical circuit and portions of the basal ganglia, consistent with rCBF Wndings in adults with MDD.

Conclusions and future directions

Functional imaging studies have the potential to provide valuable information about the neurobiologic basis of child and adolescent mood disorders and their development into adult mood disorders. SigniWcant progress in this type of research is expected from improvements in functional imaging technologies, the development of normative data bases, and the use of multimodal imaging methods. The goals of brain imaging research will be to delineate the neural circuits underlying mood disorders, the neurobiologic diVerences among speciWc mood disorders and etiological subgroups, and the biology of

transient mood states and ongoing trait vulnerabilities, and, ultimately, to contribute to the development of focused and rational treatments, both pharmacologic and behavioral.

To achieve these aims, speciWc behavioral subtyping (i.e., the study of homogeneous diagnostic groups) is needed. Longitudinal designs of speciWc diagnostic subgroups will be particularly helpful in elucidating stateversus trait-related brain abnormalities, correlates of depressive and manic phases of bipolar illness, and the impact of developmental inXuences on brain physiology. Age and gender, as well as other maturational variables such as sexual maturity (Tanner stage), will need to be considered when designing and interpreting functional neuroimaging studies in children and adolescents with mood disorders. Studies of integrated neural activity will predominantly utilize fMRI because of its lack of ionizing radiation and its excellent temporal resolution. Behavioral paradigms that target speciWc aVective and mood-related cognitive processes and that take into consideration age and gender eVects should prove useful. Such paradigms can be developed to examine the neural correlates of behavioral aspects of mood disorders (e.g. eVects on the perception of facial aVect), as well as to evaluate the responsiveness of certain neural structures, such as the amygdala or other limbic structures. The ability to link abnormalities in integrated neural activity with abnormalities of brain neurochemistry may fuel the development of rational therapies for addressing pathophysiology.

Functional imaging studies should be complemented by controlled, quantitative, and, preferably, longitudinal structural imaging studies. Quantitative image analysis techniques, as well as improved characterization of qualitative abnormalities such as white matter hyperintensities (their extent, number, and localization), are needed for use in well-controlled studies of speciWc subgroups.Where volumetric diVerences are identiWed, appropriate adjustments are required in functional image data analysis to avoid partial volume artifacts introduced by such anatomic diVerences.

Acknowledgements

Support from the National Institute of Mental Health (NIMH), Bethesda, MD (grant K07-MH01057 to R.A.K.) is gratefully acknowledged. We appreciate the administrative support of Kenneth Z. Altshuler M.D., Stanton Sharp Distinguished Chair, Professor and Chairman, Department of Psychiatry.

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