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

production in the activation state in individuals with panic disorder remains unclear.

Conclusion

The brain regions implicated in panic disorder by the above studies are consistent with the brain networks subserving fear and anxiety. Structural asymmetries, such as those reported in the hippocampal/parahippocampal regions, may be chance Wndings as a result of the high variability and small diVerences of left±right measures or may reXect developmental processes that contribute to brain lateralization. The functional signiWcance of these Wndings needs to be further explored.

SpeciWc (simple) phobias

As deWned by DSM-IV (American Psychiatric Association, 1994), speciWc phobia, previously referred to as simple phobia, consists of fear and anxiety associated with speciWc objects (e.g., snakes) or situations (thunder and lightning), which result in signiWcant impairment. Adults with speciWc phobias recognize their symptoms to be excessive and unreasonable, while children may be unable to do so (Bernstein et al., 1996). When exposed to the phobic stimulus, children with speciWc phobia experience feelings of dread, intense anxiety, physiologic symptoms, and marked fear (Silverman and Rabian, 1993). Anderson et al. (1987) studied a sample of 792 nonreferred 11-year- old children and found that speciWc phobias occurred in 2.4% of this sample. Assessment of 300 children aged 7 to 11 years in a pediatric primary care setting demonstrated speciWc phobia to be the most prevalent anxiety disorder in this population, with a prevalence rate of 9.2% (Benjamin et al., 1990). To date, there have been no published brain imaging studies in pediatric patients with speciWc phobia.

The only imaging study of speciWc phobia is that of Rauch et al. (1995), who used PET with H215O in a withinsubject symptom provocation design. Seven adults (one male, six females) with simple phobia were assessed during both neutral and individually tailored procedures designed to provoke their particular phobias. Comparison of phobic versus neutral conditions demonstrated signiWcantly increased rCBF in the anterior cingulate, insular, anterior temporal, somatosensory, and posterior medial orbitofrontal cortices and the thalamus. The authors speculated that the somatosensory activation induced by symptom provocation might be caused by tactile imagery (such as the imagery of touching a box containing the feared animal).

Social phobia social anxiety disorder

Social phobia is characterized by intense and excessive fear of social and/or performance situations such as public speaking, eating in front of others, or using public restrooms (American Psychiatric Association, 1994). Patients with social phobia recognize their symptoms to be excessive and unreasonable, and the symptoms go beyond appropriate nervousness. Social phobia most often emerges during early to middle adolescence (Schneir et al., 1992; Strauss and Last, 1993). Equal numbers of males and females are aVected (Bernstein et al., 1996). Patients with social phobia and those with DSM-III-R avoidant disorder share many of the same characteristics (Last et al., 1992; Bernstein et al., 1996). The critical distinguishing factor is that avoidant disorder has an earlier age of onset than does social phobia (Francis et al., 1992), which suggests that avoidant disorder and social phobia may lie on the same neurodevelopmental continuum (Bernstein et al., 1996). Therefore, avoidant disorder has been subsumed under social phobia in DSM-IV. Black and Uhde (1995) recently described selective mutism as a social phobic condition as well. Patients with selective mutism do not talk in speciWc social settings (e.g., in a class) but do speak in other situations (e.g., at home) (American Psychiatric Association, 1994). In fact, Black and Uhde's (1995) comprehensive analysis of 30 patients with selective mutism demonstrated that 90% of patients with selective mutism met criteria for social phobia on the basis of their inability to speak in certain situations. Only three published studies of neuroimaging in social phobia exist, none of which includes children.

Using morphometric MRI, Potts et al. (1994) studied 22 patients (36" 8 years of age; 13 males, nine females) with social phobia and 22 ageand sex-matched controls and found no signiWcant diVerences between case±control pairs in total cerebral, striatal, or thalamic volumes. However, patients with social phobia exhibited a signiWcantly greater age-related decrease in putamen volumes than did controls, but the change in volume did not correlate with severity of illness.

Using 1H MRS, Davidson et al., (1993) studied 20 patients (aged 35.7"6.7 years; 11 males, nine females) with social phobia and 20 ageand sex-matched healthy comparison subjects. Compared with controls, at baseline, social phobics had signiWcantly lower MRS signals of various markers of neuronal viability in the thalamus and caudate nucleus (Cho and Cr SNR values) and also diVusely in cortical and subcortical areas (NAA). Severity of social phobic symptoms correlated inversely with MRS signals (Cho, Cr, and NAA SNR values) in subcortical regions. After treat-

ment with clonazepam, the SNR values for Cho and Cr increased in some, but not all, social phobic patients compared with their pretreatment states. These exploratory Wndings suggest the presence of diVuse neuronal abnormality. However, the exact nature of this neuronal abnormality cannot be speciWed given the uncertain functional signiWcance of the MRS signals.

A subsequent repeat 1H MRS study in 19 social phobic patients (aged 42.0"11.6 years; Wve males, 14 females) and 10 controls (aged 37.8"10.5 years; six males, four females) showed signiWcantly lower MRS signals of neuronal viability (NAA/Cr) associated with greater MRS signal related to serotonin function (myo-I/NAA) in the cerebral gray matter (Tupler et al., 1997). The eVect of an 8-week treatment with the benzodiazepine clonazepam did not alter any of the MRS measures.

Here again, while data are too scant to implicate speciWc neuronal networks in social phobia, they suggest the presence of detectable abnormalities.

Post-traumatic stress disorder

PTSD follows exposure to a traumatic event or situation that would be stressful to anyone. However, the diVerence between a normal response and that in PTSD is that the stressor is re-experienced repeatedly despite constant eVorts to avoid stimuli that remind or re-expose the individual to the trauma. To meet DSM-IV criteria (American Psychiatric Association, 1994), symptoms must persist for at least 1 month and the disorder must result in signiWcant impairment and emotional distress. Although the classic image of a person suVering from PTSD is ªshell shockº from battle or war, this syndrome is not uncommonly seen in children and adolescents exposed to severe trauma, e.g., kidnapping, rape, physical/sexual abuse, or natural disasters (Terr, 1996).

Structural imaging studies

Anatomic MRI studies of adult patients with PTSD have demonstrated subtle structural brain abnormalities including an increased incidence of a small cleft in the cal- losal-septal interface and a cavum of the septum pellucidum (Krishnan et al., 1988; Myslobodsky et al., 1995; Canive et al., 1997). Five of ten male patients with PTSD aged 33"7.3 years had this latter abnormality compared with only 3 of 21 healthy male comparison subjects aged 31"6.7 years (Myslobodsky et al., 1995). A cavum of the septum pellucidum is likely to be a neurodevelopmental deviance that may reXect an abnormality of cell migration,

myelinization stages, pruning, or a combination of all three. Such a neurodevelopmental anomaly may be a potential marker of susceptibility to the development of PTSD. It may represent an epiphenomenon of the actual mechanisms that confer vulnerability to PTSD.

One model of PTSD involves the hypothesis that stressrelated rises in cortisol levels have adverse eVects on hippocampal function. When nonhuman primates are exposed to stressful situations, cortisol levels increase and produce neurotoxic eVects on the hippocampus (Sapolsky et al., 1990), a structure known to subserve the consolidation of memory. Its role in memory may be particularly relevant in PTSD, a disorder characterized by unwanted and often distorted memories of the traumatic event.

Bremner et al. (1995) used volumetric MRI to compare hippocampal volumes in 26 Vietnam veterans with PTSD with 22 comparison subjects without PTSD but matched for age, sex, race, educational and socioeconomic status, and history of alcohol use. Patients with PTSD had signiWcantly smaller right hippocampal volumes than comparison subjects, without volumetric diVerences in the basal ganglia or the temporal lobe as a whole. A similar MRI study (Gurvits et al., 1996) compared seven Vietnam veterans with chronic combat-induced PTSD with seven without PTSD and eight healthy comparison subjects. Here again, patients with PTSD had signiWcantly smaller left and right hippocampal volumes than both the veterans without PTSD and the normal controls (Fig. 13.9). No signiWcant diVerences were detected for total brain volume, ventricular volume, ven- tricular-to-brain ratio, or amygdalar volumes. Scores on the Combat Exposure Scale correlated with hippocampal volume, suggesting that stress associated with the traumatic event may have had neurotoxic eVects on the hippocampus (Gurvits et al., 1996). Alternatively, decreased hippocampal volume may be a neurodevelopmental abnormality that confers vulnerability to PTSD.

Recently, Bremner et al. (1997) used volumetric MRI in adult patients with PTSD secondary to childhood physical and sexual abuse. Seventeen adult patients with PTSD who had been sexually and physically abused were compared with 17 controls matched for age, sex, race, handedness, education, height, weight and alcohol abuse. The patients with PTSD had signiWcantly reduced left hippocampal volumes compared with controls, but no volumetric abnormalities of the amygdala, temporal lobe, or the basal ganglia.

Functional neuroimaging study

Using PET and H215O, Rauch et al. (1996) conducted a study of eight adult patients with PTSD (aged 41.1"3.7 years;

two males, six females) during exposure to an ªactiveº script (intended to evoke PTSD symptoms) and to a neutral control script. Compared with the neutral condition, the active condition showed increased rCBF in right limbic, paralimbic, and visual cortex, and decreased rCBF in left inferior frontal and middle temporal cortices. These results provide additional evidence that limbic and paralimbic systems contribute to the expression of PTSD symptoms.

The authors hypothesized that increased rCBF in the visual cortex may reXect the patient's visual re-experience of the traumatic event.

Summary

The structural imaging Wndings suggest that functional dysfunction in the hippocampus is associated with PTSD.

Future functional brain imaging studies will need to examine this hypothesis carefully and to correct functional data for potential diVerences in size (correcting for partial volume eVect, see Chapters 1 and 2).

Neuroimaging and diagnostic speciWcity

In reviewing studies exploring the neural substrates of anxiety disorders, it is tempting to ponder the scientiWc grounds for grouping various maladaptive behaviors under the common umbrella of anxiety disorders. While too few data exist with which to address this issue, the possibility that a modiWed taxonomy of psychiatric disorders might emerge is intriguing, as well as provocative. Relevant to this issue are two studies that have constrasted diVerent anxiety disorders to identify both common and distinct functional neuroanatomic substrates.

Rauch et al. (1997) combined data from 23 adults with OCD (eight), simple phobia (seven), and PTSD (eight) who participated in H215O PET studies using a symptom provocation paradigm. Symptom provocation activated the right inferior frontal and posterior medial orbitofrontal cortices and bilaterally the insular cortex, lenticulate nuclei, and brainstem in all three disorders. A signiWcant correlation was observed between severity of anxiety and rCBF in the brainstem. These Wndings suggested that paralimbic dysfunction might be common to the pathogenesis of these three anxiety disorders. However, it is unclear whether this shared activation pattern merely reXects the normal pathway of anxiety or a speciWc pathway involved in maladaptive behaviors that characterize these anxiety disorders. The study of anxiety in healthy controls will be critical for answering this question.

Lucey and colleagues (1997) compared rCBF across three diVerent anxiety disorders: OCD (15), panic disorder with agoraphobia (15), and PTSD (16) using SPECT with 99mTclabeled hexamethyl-propyleneamine oxime ([99mTC]- HMPAO). They observed signiWcant diVerences between patients with OCD, PTSD, and panic disorder, and healthy comparison subjects. SpeciWcally, patients with OCD and PTSD exhibited abnormally low rCBF in bilateral superior frontal cortices and in the right caudate nucleus. In addition, global CBF was correlated with the severity of anxiety, and left and right caudate rCBF were correlated inversely with PTSD symptom severity. The authors hypothesized that some of the common Wndings in OCD and PTSD may reXect similarities in symptoms, with both disorders involving repetitive, ritualistic behaviors and intrusive thoughts.

Based on the above Wndings of common regional brain activation during symptom provocation across anxiety dis-

orders, it is possible that the dysfunction is rather temporal (not detected using the temporal resolution of the order of 8min, which is the minimal scan interval time in PET blood Xow studies) than at the spatial level (same regions activated). Anxiety disorders may result from an inability of functional systems that mediate ªnormalº anxiety to habituate. This hypothesis can best be tested in fMRI studies, which aVord better temporal resolution (scans can be repeated at a faster pace than in PET studies).

Conclusion and future directions

In summary, the literature on neuroimaging studies of childhood-onset anxiety disorders is remarkable by its paucity in children, but also in adults. Neuroimaging tools are just beginning to be utilized for unraveling the neural mechanisms underlying neuropsychiatric disorders; yet they promise to provide unprecedented information.

Developmental neurobiologic models for pediatric anxiety disorders are of importance because they will guide future research. Current neurobiologic models have been generated for adult anxiety disorders, and there is a need to include in these models the contribution of brain development and maturation to allow better understanding of the origin of these disorders. As brieXy mentioned in this chapter, the taxonomy of anxiety disorders is likely to be modiWed as we understand their pathogenesis better. Currently, there is some emphasis in identifying homogeneous phenotypes of psychiatric disorders to help in the search for vulnerability or even causal genes. Synergistic advances in clinical (behavioral and psychopharmacologic), genetic, and neuroimaging research are expected to provide the basis for a new generation of focused, rational, and eVective preventive and therapeutic interventions.

The rapid advances in noninvasive brain imaging oVer an unprecedented opportunity to test model-generated hypotheses in pediatric anxiety disorders. Precise, quantitative, high-resolution MRI studies are crucial to detect any underlying anatomic abnormalities. Moreover, since volumetric abnormalities have already been observed in certain anxiety disorders, such measures can help to guide fMRI and MRS studies. If volumetric diVerences exist between patients with anxiety disorders and controls, precise mesurement is mandatory for the interpretation of any putative functional, metabolic, or neurochemical abnormalities. This is especially critical when studying pediatric populations where developmental maturation is ongoing. Keshavan (1997) has discussed neural network dysplasias with diVerential brain

maturational abnormalitites in neurodevelopmental disorders such as OCD. Longitudinal studies, as well as studies of unaVected, Wrst-degree relatives at increased risk for developing anxiety disorders, are needed to clarify whether the regions already implicated by structural and functional imaging studies of aVected adults, such as ventral prefrontal±striatal regions in OCD or hippocampal/parahippocampal regions in panic disorders and PTSD, are degenerative, developmental, or some combination of both.

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Introduction

This chapter will discuss and integrate the numerous conXicting Wndings produced by a wide variety of functional imaging studies in Tourette's syndrome (TS) performed by diVerent investigators under diVerent experimental protocols over a large number of years. We hope in our analysis to identify the neural systems that seem to be most strongly implicated in the pathophysiology of this disorder. We also hope in our analysis to enliven the typically static interpretation of brain images by emphasizing the dynamic interplay of pathophysiology and adaptation, not only in the people who have this particular illness but also in the many others who have diYculty controlling a wide array of unwanted impulses. This dynamic interplay of pathophysiology and adaptation presents important diYculties for the interpretation of existing TS functional imaging studies that will aVect the design of the next generation of studies in TS and other developmental neuropsychiatric disorders.

Phenomenology

Simple and complex tics

The tics of TS are rapid, purposeless jerks of brief duration that most commonly aVect musculature of the face, head, neck, shoulders, and vocal apparatus. They less commonly aVect the torso and extremities. These rapid and brief movements are referred to as ªsimpleº motor or phonic tics, and they are the kind of tics most frequently seen in patients with TS.With increasing age, individuals who have TS become particularly adept at the temporary inhibition of their tics, although tics cannot be inhibited indeWnitely. Less commonly seen in TS are slower, semi-purposeful

movements of longer duration, which are referred to as ªcomplexº tics. These include movements such as tapping, touching, rubbing, uttering of words or phrases, and coprolalia.

Highly complex tics can be exceptionally diYcult to distinguish from compulsive behaviors and stereotypies. Tics are commonly preceded by a persistent, intrusive awareness of an urge to tic or to move the body part in which the tic will occur, and this urge is relieved, if only momentarily, immediately upon performing the tic behavior (Leckman et al., 1993). This premonitory urge and the patient's preoccupation with it can be diYcult to distinguish from the obsessional urges that typically precede compulsive behaviors.

Genetic basis

Family genetic and twin studies have provided compelling evidence that TS has strong genetic determinants (Price et al., 1985; Pauls et al., 1986, 1991). These genetic determinants, once they are identiWed and characterized, will oVer the opportunity of studying the neuroanatomic and functional basis of involuntary urges and their behavioral counterparts in a relatively homogeneous disorder. The study of similar urges and behaviors can then inform the study of disorders that are more heterogeneous, though etiologically related to TS.

Although the vertical transmission of the putative TS vulnerability genes does not seem to involve the X-chro- mosome, males are between 4 and 10 times more likely than females to be aVected with TS (Burd et al., 1986; Comings et al., 1990; Nomoto and Machiyama, 1990; Apter et al., 1993). These sex-speciWc prevalence diVerences must have a neural correlate, and functional imaging studies must ultimately account for them. In addition, because the male preponderance of TS easily can lead to

diVerences in sex composition of the patient and control groups, studies must be carefully designed to avoid sex diVerences in the composition of the groups and to avoid confounding the Wndings of the study.

Comorbid illnesses

Patients with TS are often plagued by recurrent, intrusive thoughts, mental images, and urges to action of classically deWned obsessive-compulsive disorder (OCD). Family studies have shown that at least one form of OCD is a manifestation of the putative genes that confer vulnerability to and transmission of TS (Pauls et al., 1986). Similarly, attention-deWcit hyperactivity disorder (ADHD) is diagnosed in approximately 50% of all clinically identiWed patients with TS. Evidence from a recent family genetic study suggests that at least some of the ADHD in TS families may be caused by the TS genes (Pauls et al., 1993).

A spectrum of semi-involuntary behaviors

SuperWcially, the behavioral phenotypes of TS, OCD, and ADHD diVer dramatically: one consists of motor and vocal tics, another consists of obsessions and compulsions, and yet another consists of inattention, hyperactivity, and impulsivity. It is astounding that a single genetic vulnerability can produce these vastly diVerent phenotypes. The genetic relatedness of certain subtypes of these disorders raises the question of whether their phenotypes might be more intimately related than their surface appearance would suggest. The resemblance between OCD symptoms and complex tics suggests, for example, that the symptoms of TS and OCD lie on a spectrum of ªcompulsoryº behaviors. Those symptoms that have a prominent ideational component belong to OCD on the one end and those with little or no ideational component belong to the simple tics of TS on the other; complex tics belong somewhere between these two extremes. Similarly, the symptoms of ADHD share some of the features of tics. Tics, for example, can be thought of as ªhyperkinesiaº, and motoric hyperactivity is a prominent feature of ADHD. Patients with TS can inhibit their tics for only brief periods of time, and the impaired inhibition of impulses is a hallmark of ADHD. In this way, both children with ADHD and those with TS have excessive motor activity and diYculty inhibiting speciWc behaviors.

It may be that a given genetic vulnerability to TS can produce not three behaviorally unrelated disorders but instead an entire spectrum of related semi-involuntary behaviors. Genes, however, do not code for a behavior or even a spectrum of behaviors. They code for proteins, and

those proteins are expressed in speciWc cells in a regionally speciWc fashion. The brain regions whose function the proteins aVect then produce the predisposition to the speciWed behaviors. This suggests that the region or regions of the CNS in which disordered functioning produces the symptoms of TS, OCD, and ADHD could be related because of the expression of the TS gene product in those regions. Therefore, the phenomenologic similarities and the genetic relatedness of these conditions may provide important clues in the search for their shared neurobiologic substrate. The substrates of TS, OCD, and ADHD cannot be identical, however, because the disorders are still phenomenologically distinct, and those distinctions ultimately must be brain based.

Frequent confounds in studies of Tourette s syndrome

The phenomenology of TS introduces numerous potential confounds that can seriously impair our ability to interpret adequately the Wndings from functional imaging studies. These confounds include the eVects of chronic illness when studying adolescents and adults, diVerences in age between patient and control groups, underlying structural diVerences between groups, and selection of inappropriate methods of regional normalization.

EVects of chronic illness

Perhaps the most serious limitation of radiotracer studies is the ethical concern of exposing younger children to radioactivity. Because the modal onset of tic symptoms is 6 years of age, imaging investigations of adolescents and adults will necessarily be studying in large part the eVects of chronic illness. The brain is a tremendously plastic organ and its primary function can be viewed as one of adaptation to maintain homeostasis. Tics and comorbid illnesses are a tremendous burden for children to carry, and adaptation to them will probably alter broadly distributed neural systems throughout the brain. We will see, for instance, that the voluntary suppression of tics, an activity that for many children with TS occupies an inordinate amount of time in their waking life, activates broad expanses of cerebral cortex and basal ganglia. Repeated and chronic activation of these brain regions is likely to induce plastic changes in the underlying neuronal structural and functional architecture. If we are to understand TS pathophysiology better, it is, therefore, imperative that we Wnd ways to study its neural substrate in the absence of chronic compensatory change. This involves somehow