SPECIAL ARTICLE Neuroimaging in Child and Adolescent Psychiatry SAMUEL KUPE RM AN, M.D., GAR Y ROBERT GAFFN EY , M.D . , GHADA HAMDAN-ALL EN , M .D ., DAVID F. PRESTON , M .D., AND LAT HE VENKATESH , M .D .

Abstr act. Alth ough less well studied in child and adolesc ent psychiatry than in adult psychiatry , brain imaging has significantly altered psychiatric research and practice . Th is review focuses on the modalities that are used to image the brain. These include structural imaging tech niques of compu ter tom ograph y (CT) and magnetic resonan ce imaging (MRI), as well as functional imagi ng techn iques of co mputed electroe ncephalography (CEEG) , positron e mission tomo graphy (PET) , and single photon em ission computed tomograph y (SPECT) . The technologies are reviewed , strengths and weakne sses of moda lities discu ssed, and research progress reported . J. Am . Acad. Child Adolesc. Psychiatry, 1990, 29,2: 159- 172. Key Words: chi ld psychiatry, brain imaging. One of the most significant areas of grow th beween childand adulthood is the gradual acquisitio n of exten sive mental skills including the ability to think, speak, plan , and express emotion . Th is proce ss of development greatly affects the types and expression of ment al disorders seen durin g an individ ual's lifespan . Compared to adult psychiatric ailments, childhood disorders are more developmental , more influenced by enviro nmental factors, less cyclic, and less degenerative : all factors that lead to increased diffic ulty in diagnosis and treatment. Over the past two decades, adult psychiatry has encouraged and embraced research in the neuro sciences to aid in diagnosis and treatment. Unfort unately, child psych iatry has not kept pace with these deve lopment s. A number of factors may be responsible for this gap , but a major co mponent appears to be the perceived diffic ulty of studying. in an orderly manner, childhood brain pathology or dysfunction. The first step in the scientific study of brain pathology associa ted with a specific disorder is to examine the brai ns of deceased individuals by macroscopic, microscopic , and biochemical means. From these studies, hypotheses are generated that impli cate potential areas of brain involvement, Methods are then deve loped to test these hypotheses in vivo with patie nts who currently have the specified disorder. However, this series of steps is more difficult to complete in child psych iatric disorders; the majority of these are not fatal and therefore limit direct examination of involved brains during childhood. Examining the brains of deceased adults with a pre-existing chi ld psychi atric disorder offer s a part ial

solution to this prob lem, but observed pathology may be confounded by the actual treatment of the disorder or other extri nsic processes (e .g . , aging , other illnesses, etc .) thus decreas ing the strength of any generated hypothesis. However, despite, and maybe because of this lack of direct brain study, child psychiatry needs to adva nce and inco rporate in vivo neuroi maging techn iques. The tremend ous potent ial benefit from improvements in diag nostic and treatment spec ificity more than outweighs curre nt diffi cul ties associated with neuroimaging techniques. Contemporary brain imaging techniques can be divided into two main areas that cover five disciplin es. The first area emphasizes brain structure or anatomy and utilizes co mputerized tomography (CT) and mag netic resonance imaging (MRI). The second area emphasizes different ways of ex amining brain function: blood flow, metabolism , and receptor status utilizing positron emission tomography (PET ) a nd sing le ph ot on e miss io n computerized to mogra phy (SPECT ); and electrophys io logy utiliz ing co mpute rized electrocephalography (CEEG) . All methods exa mine the brain in different ways and hav e inherent stren gths and weakn esses . In the following mate rial, each technology is discussed along with its advantages and disadvantag es, and its current impact on child psyc hiatry. Future imaging techniques are also briefly discusse d .

Computerized Axia l Tomography Basic Considerations Prior to 1973, ce ntral nervou s system (CNS) imagi ng consisted of skull films and ventricular pneu moenceph alography, mod alit ies with poor resolution of brain structures. Introduced that year, computerized axial tomography (CT) allowed clini cians and researchers for the first time to ex amine the entire brai n in vivo . The techn ology involved in computed tomography, devised by Godfre y Houn sfield , utilizes standar d x-rays directed at many angles toward the subject' s brain. Specia l radia tion senso rs within the CT scanner generate a small electrical impulse whic h is proportional to the intensity of the x-ray beam at that detector point: the intensity is dependent on attenuatio n caused by

Accepted July i 7, 1989 . Dr. Kuperman is an Associate Prof essor of Psychiatry and Dr. Hamden-Allen is an Assistant Prof essor ofPsychiatry at the University of i owa Hospi tals and Clinics. iowa City , Iowa . Dr . Gaf fney is an Associate Profess or of Psychiatry. Dr . Yenkatesh is a Fellow in Psy chiatry , and Dr . Preston is a Professor of Radiology . all within the University of Kansas Medical Center. Kansas City , Kansas. Request reprints fr om Dr . Kuperman, Division of Child Psychiatry , Department of Psychiatry , University of Iowa Hospitals and Clinics. Iowa City, Iowa 52242 . 0890·8567/90/2902- 0 159$02.00/0 © 1990 by the American Academ y of Child and Adole scent Psychiatry .

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different tissues , such as white matter , gray matter , bones and fluids, in the space between the x-ray and the electrica l detector s. A computer is used to digitize the electrical impulses generated by the detectors and store their energy values as numbers. The computer then recon struct s the image producing the spectrum of blackening that deline ates white and gray matter, CSF , bone , blood , and pathological areas, but at a higher resolution than obtain able by film recorded modalities. The computer allo ws reconstruction of the image in serial , cross-s ectional views. CT can also utilize contrast material , and intravenous injection of a substance that enhances the del ineation of hyperemic brain areas. Advantages and Disadvanta ges

Experience indicates that CT scanning currently is valuable in child and adolescent psychiatry to investig ate certain macroscopic central nervous system lesions . Although predominantly supplanted by MRI, there are advant ages to CT when certain lesions are suspected, especially those involving calcified tissue (Garber et aI. , 1988). CT would also be the imaging modal ity of choice when the patient has a device or a condition that may be disturbed by the MRI instrument or the MRI magnet ic field: pacemaker, aneurysm clip , ferromagnetic foreign body, pregnancy (Garber et al. , 1988), or claustroph obia. CT has the disadvantages of exposing a child to radiation , of causing possible allergic reaction to the intravenous iodine contrast material , and of bone artifacts obscuring some brain areas, particularly in the posterior fossa. Another disadvantage of CT scanning from a research perspecti ve is the lack of norm al control groups. Most studies use " medical controls" that are children and adolesce nts referred to CT scanning for various neurologic reasons such as headache or dizz iness . These control group s minimize referral bias; howe ver , many of these "controls" have abnormal medical histories or abnormal physical exams. A group of normal children used as controls in a study with CT scans would be expo sed to a dose of radiation which would present an ethic al dilemma. Therefore, it is unlikely that any study will use a normal control group matched for age, sex, handedness, and intelligence. Applications in Child and Adolescent Psychiatry Infantile A utism (IA) . IA is one of the great mysteries of human biology. Why relatively normal appearing children, some with exceptional intelligence , demon strate socia l inappropriateness , language delay, and stereot yped behaviors, remain s puzzling. Thu s, when an imaging modalit y became available to examine the brain , researchers immediat ely utilized the technology to search for neuroanatomical abnormalities. Hier et al. (1979 ) examined the parietal-occipital leftright ratios (an asymm etry-left in normal s) of autistic children and adole scents demon strating increased right-sided measurements . Damasio et al. (1980) studied the ventricles and brain parenchyma of autistic patient s finding abnorma l ventricular asymmetry: the autistic group demon strated a larger left lateral ventricle, rever sed from more typical findings of a larger right lateral ventricle. Caparulo et al . ( 198 I) 160

reported 59% of autistic patients exhibited abnormal CT scans with increased ventricu lar size being the predom inant finding. Campb ell et al. (1982) analyzed 45 CT scans of autistic children noting II had ventricular abnormalities rated from mild to moderate . Gilberg and Svend sen (1983) studied 27 autistic children report ing abnormalities in 26% of the head CT scans includ ing cysts, fourth ventricular widening, and other parenchymal and ventricular abnorm alities. Bauman and Kemper (1986) , after noting neuropathological abnorm alities in limbic areas and cerebellum in a postmortem case study, investigated the posterior fossa anatomy of a group of autistic patients. Using CT sca ns, they found upper and middle enlargement of the fourth ventr icle with concomitant cerebellar atrophy . Recently, Jacob son et al. (1988) reported a significantly larger third ventricle and significantly lower mean caudate radiodensity in their controlled study of nine physically healthy autistic men . They concluded that anatomic aberrances may be occurring at the subcortical basal ganglia level. Not all studie s have demonstrated abnormal CT findings in autistic subjects. Rosenbl oom et al. (1984 ) noted greater variability in the measurem ents of autistic patients' ventricular volumes but indicated that all were essentially normal. Similar findings were noted by Prior et al. (1984). Harcherik et al. ( 1985), using more sophisticated methods of measurement such as ventricular to bra in ratio (YBR) and area densities, reported no differences between several neurop sychiat ric groups includ ing autism, Tourette 's disorder, learnin g disability , and medical control s . Thus , in vivo neuroanatomic imaging using CT scans in autism has produced mixed results; some studies find neuroanatomic aberrances, others failed to report abnorma l findings . It appears that 25% of autistic patients undergoing CT will demon strate neuroanatomic abnormalities, generally consi sting of non- spec ific findings such as ventr iculomegaly . The relationship of neuroanatomic variance to the psychopathology is, as mentioned, thus far a quandary . Tourette's Syndrome (TS) . Two papers from a research group at Yale utilized CT to investigate the neuro anatomy of patients with TS : One found 38% of those patients with abnormal CT scans, but without pathognomonic signs (Caparulo et aI., 1981); the other found no difference in either YBR ratio or brain density among four neuropsychiatric groups including TS and a medical co ntrol group (Harcherik et aI., 1985). A case report by Kjaer et al. (1986) described a large porencephal ic cyst in a female TS patient. The cys t located in the right temporal lobe impinged on the right parietal and occipital lobes, and adjacent basal ganglia and thalamus. There was contr ast enhancement of the left basal ganglia . The authors conclud ed that the radiological abnormalities found were in accord ance with the general concept of dysfunction al basal ganglia in TS . Attenti on Deficit Hyp eractivity Disorder (ADHD). There were no CT scan neuroanatomic abnormalities noted : no differences of YBR or parieto-occipital left/right ratio in a group of 35 children with ADHD compared with a medical control group of 27 children (Shaywitz et al ., 1983). Obsessive-Compulsive Disorder (OCD) . Behar et al. l.Am.Acad .Child Ado/esc. Psychiatry. 29:2, March 1990

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(1984) reported enlarged ventricular to brain ratio s in their controlled CT scan study of adolescents with OCD . Luxenberg et al. (1988 ) observed reduced caudate volume in patients with childhood onset OCD. These studies focused attention onto the relation of caudate function in OCD psychopathology, and have served as a catalyst for other groups seeking to delineate the subtle neuroanatomic alterati ons that appear to be present in the syndrome. Anorexia Nervosa (AN) . Artman et al. ( 1985) investigated the neuroanatomy of patients with AN by CT . The group noted abnormalities such as widened cortical sulci, a widened interhemispheric fissure, ventriculomegaly, and widening of the cerebellar sulci . These abnormalities were reversed when the weight was regained. This verified what the group suspected; severe weight loss affected central nervous system anatomy , neurophysiology, and most likely cognition. Schizophrenia. Although there has been a multitude of studies utilizing CT to inve stigate CNS anatomy in adult schizophrenic patients, there has only been one study of adolescent schizophrenics. Schulz et al . ( 1983) focused their investigation on the CT scans of teenagers with schizophrenia or schizophreniform disorder. Compared to patient s whose condition was diagno sed as borderline personality disorder, the adole scent schizophrenic group demon strated ventriculomegaly. The y concluded that ventricular enlargement is present early in the course of schizophrenia . CT and Neurop sychological Evaluation. In a study of 20 patients ranging in ages from nine to 15 with various psychiatric diagnoses, head CT results were compared with neuropsychological testing on both the Halstead-Reitan Battery and the children ' s version of the Luria-Nebraska Batte ry (Tramontana and Sherrets, 1985). Increased neurop sychological impairment was found among patients with structural variants such as increa sed VBR s or abnormal brain densities, though these CT scan s were not necessarily clinic ally abnormal.

Magnetic Resonance Imaging Basic Considerations Although the noninvasive anatomical CNS imaging revolution began with CT scanning, the clinical implem entation of MRI upgraded in vivo biological imaging by produ cing superior anatomic delineation and resolution . MRI utilize s nuclear magnetic resonance (NMR) technology that has been used in chemistry/ph ysics laboratories for years. First , atoms are aligned by a high strength magnetic field . Next, a high strength radio frequency signal is applied that disturb s this bipolar alignment. Finall y, the MRI detectors measure the intensity of the electrical energy emitted when the radio frequency signal is turned off and the atom s return to their initial bipolar alignment. The best signal/noise ratio is found for hydrog en , hence current MRI image s hydrogen, and subsequently water content of biological tissue. White matter, gray matter , CSF, blood, and diseased tissue all differ in imaging measures allowing excellent anatomic separation of the various normal and pathological components of the CNS (Figure I). J . Am. Acad. Child Ado/esc. Psychiatry, 29:2, March 1990

I. Normal inversion recovery MRI. Note: superb gray -white matter delineati on . Black arrow = caudate. White arrow = put am in . Black arrow with white border = globus pallidus , Blac k outline arrow = thalamus . FI G .

Radiologists speak of TI , T2 , Spin Echo (SE), Inversion Recovery (lR ), Return Tim e (TR), Echo Tim e (TE), Inversion Time (TI), and Spin Density (SD)- technical but clini cally meanin gful terms. The radiologist adj usts the MRI scanner to weigh the scan toward predominantly imagin g Tl or T2 , since a TI-weighted scan optimally delin eates gray-white anatomy , and a T2-wei ghted scan optimally visualizes diseased tissue . In spin echo scans, setting a short TR and a short TE produ ces a T l- weighted scan ; setting a long TR and a long TE produces a T2-weighted sca n. Inversion recovery scans utilize a TI and TR adju stment generating a Tl -weighted scan. Not only are the imaging parameters flexible , but the imaging plane and area vary according to set measures . The radiologist selects from transverse (or axial), coronal , and sagittal and zooms or cones in on questionable anatomic areas.

Advantages and Disad vantages MRI imaging has severa l majo r advantages over CT (Figures 2, 3 , 4 , and 5): (I ) no ionizing radiation (Han et al. , 1985); (2) superior gray-white matter delineation (Steiner, 1985); (3) quality imaging without contrast injections (Zimmerman and Bilanuik , 1986); (4) flexibl e imagin g parameters and imaging planes: and (5) no bone artifact in the posterior fossa (Figures 6 and 7) (Packer et al., 1984). Although the predomin ante use of MRI occurs without contrast material injection , paramagnetic substances, suc h as manganese , gadolinium, and some forms of iron can change tissue contrasts seen in MRI image s by chan ging T I and T2 relaxation times. Similar to radioi sotope scans, these atom s can be incorporated into MRI contrast material which , after intra venou s injection, cross the abnormal blood brain barrier found in pathologi cal bran tissue (Imakita et al., 1988). Unlike the minute amount of radioactive tracer s injected for radioisotope scans , the required amount of par/6/

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FIG. 2. Axial CT scan with contrast of left basal ganglia glioma in a 19 year old infantile-onset autistic patient. White arrow = basal ganglia glioma. Tumor blush is evident medially to the tumor mass.

FIG. 4. Same patient as in previous two figures, only coronal MRI. White arrow = basal ganglia glioma.

amagnetic substances to induce changes in the MRI image is much greater and chemical toxicity of these substances is a concern. Other limitations of MRI, as previously mentioned, include the inability to use MRI when the patient has a pacemaker, aneurysm clip, or ferromagnetic foreign body; the patient is pregnant or claustrophobic; or when the patient's lesion is calcified (Garber et al. 1988).

Applications in Child and Adolescent Psychiatry Infantile Autism. Findings from Bauman and Kemper's (1985) autopsy study and Ornitz et al. 's (1985) physiological study have suggested that autistic patients have abnormalities in the posterior fossa (cerebellum, fourth ventricle, and brainstem). Because the MRI can clearly image the posterior fossa, most studies have focused on this region. Initial stud162

FIG. 3. Axial MRI scan of same patient in Figure 2. Note: superior imaging of involved basal ganglia. White arrow = basal ganglia glioma.

FIG. 5. T,-weighted axial spin echo MRI. Black arrow = basal ganglia glioma. Note how spin echo MRI reveals that this lesion is not cystic.

ies, lacking quantitative measurements, reported a variety of CNS lesions, but no single pathognomonic lesion (Gaffney and Tsai, 1987; Courchesne et aI., 1987). Using quantitative measurements, two groups have recently documented posterior fossa differences in autistic children (Figure 8). Gaffney et al. (1987a) found a larger fourth ventricular area, a smaller coronal cerebellar area (Gaffney et al., 1987b), and a smaller brainstem area (Gaffney et aI., 1988) in autistic children compared to medical controls. Courchesne et al. (1988) divided the cerebellum into eight mid-sagittal lobules and reported that lobules six and seven were decidedly smaller in his autistic children than in an age matched group. This finding, although controversial (Ritvo and Garber, 1988), continues to generate interest in cerebellar developmental aberrances in autism. Still yet other brain areas have been implicated in autism. Gaffney et al. (1989) have found subcortical structure inl.Am.Acad. Child Ado/esc. Psychiatry, 29:2, March 1990

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FIG. 6 . Fourth ventriculomeg aly evident in midsagittal MRI sca n of 9 year old boy with infantile autism. Black arrow = fourth ventricle .

FIG. 8 . MRI coron al sca n of sa me patient as in Figure 7 . White arrows = caudate nucle i. Again note: almos t co mplete atrophy of the ca uda te . the lent iform nuclei, and the co rtex .

Computerized Electroencephalography Basic Considerations

FIG . 7. MRI scan of 9 year old boy with symptoms of dem enti a. agitation , and mood changes and diagnosis of juvenile onset Hunt ington disease. Note: almost co mp lete atrophy of the caudate. the lent iform nuclei. and the cortex. Wh ite arrow points = left and right ca udate nuclei .

volvement of autistic children. Utilizing axial MRI views , they found lateral ventricul ar enl argement. anteri or horn enlargement , and a decrease in the right lent icul ar nucleus. Fragile X. Reiss et at. (19 88) studied four young adult males all of whom had fragile X and multiple symptoms of autism. Compared to age-matched controls, the fragile X group had similar findings as the previously mentioned group of autistic subjects; decreased pons size and increa sed size of the fourth ventricular area . Learning Disabil ities. An earl y MRI investigation (Rumsey et al.. 1986) found no qu alitati ve differences bet ween an adult dyslexic sa mple and norm al controls. Thu s far, however, no quantitative studies have examined learn ing disabled children. l.Am. Acad. Child Ado/esc . Psychiatry, 29:2, March 1990

The electroencephal ogram (EEG) is a non invasive way to examine bioelectric phenomena in the brain . The conventional EEG was first report ed in 1929 by the Germ an psychi atrist Hans Berger who wished to demonstrate specific relationship s of electrophys iology to psychiatric disorders, Unfortunately, researchers (Walter, 1944) soon noted the failure of EEG findings to demonstrate significa nt relationships with even " pro found mental disorders. " Ne vertheles s , man y researchers fe lt this failure was not inherent to the collection of the EEG, but secondary to the massive amount of data generated by the EEG and the inability to effectively deal with it. It was their belief that the technology would have to progress to allow quantitative EEG result s for a more meaningful aid to the diagnosis, prognosis, and treatment of psychiatric patients . The routine EEG procedure consists of placing electrodes on the patient's head usin g the International 10-20 System (Figure 9) and connecting them to an instrument that will produ ce a voltage- versus-t ime-graph on a mov ing sheet of paper. Typicall y, patient s are examined in spec ialized states such as durin g eyes closed , hyperventilation , phot ic stimulation , and asleep. Each EEG record con sists of 150 to 300 page s of voltage trac ings repre senting 30 to 60 minutes of EEG recording . The tracing s of this con venti onal EEG are evaluated throu gh visual inspection. Th e age of the patient must be taken into consideration since the EEG appears related to brain matu ration with the mo st characteristic feature bein g the decre ase in the amount of slower delt a (0 to 4 cps) and theta (4 to 8 cps) activity , normally pre sent in the EEG of infant s, with increasing age (Fenwick, 1985). In health y awake adults, activities slower than 7 cps, particularly slower than 5 cps, are considered abnormal. In children, becau se of the wide range of normal var iant s at each age, classificati on is more difficult. Nevertheless, dif-

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fuse or focal sharp waves, spikes, spike and wave formations, and paroxysm al appea rance of group s with slower and sharper potential s may be observed in patients with CNS patholo gy (Adams and Victor, 1985). Within the last 20 years there has been a steady development of sophistica ted techn ological method s to simplify the data presentation . A co mputer can be used to co llect and analyze data from the electroencephalog ram using two different procedures. In the first procedure, multiple short collection periods of EEG dat a are subjected to a variety of mathematical algorithms to measure the average power of the EEG contained in various frequency bands (spectral analysis). These data can be presented either as a numerical array or plotted as a topogr aphical display of the he ad seen from various angles. In the second procedure, designed to provide clues to the qu alitativ e nature of attentional behaviors and cognitive proc essing , the computer is used to sum and then average multiple short EEG segments that are in synchronism with auditory , visual, or sensory stimuli (evoked response potential-ERP). A typical procedure would be to compare wave forms genera ted to the pre sent ation of a common stimulus (either auditory, visual of som atosensory nature ) with wave forms generated to an infrequent (or oddball stimulus) . Asse ssment occ urs by mea surin g peak height s and latencies of the various wave forms in the ERP: e .g ., in the" oddball " procedure , comparisons are mad e betw een the negative peak that occ urs at 80 to 120 mill iseconds (N I ()() or No) as well as the posit ive peak that occurs at 250 to 400 milliseconds (P300 ) . Th e N i(X) is believed to be associated with the process of selectio n between various classes of stimuli in the environment while the P'm is believed to be associated with comparison of the analyzed stimulus information to cognitive categorie s in memory (Hill yard et al., 1986). Again these data can be presented as a numer ical

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FI G. 10. CEEG of 12 year old boy with attention de ficit-hyperactivity disorder and co nduct disorder. A) Spectral bra in map prior to treatment. Note: midfrontal area of slow wave activity (delta 0 .0-3 .5 Hz and theta 4-7 .5 Hz). B) Following successful treatment with dcsipramine . slow wave activity decreases in this same area.

arra y or as a " cartoon" that depicts a topographical brain map which displays the EEG wave form over time.

Advantages and Disadvantages Compared with other methods for functional neu roim aging (PET or SPECT), computerized electroenceph alography (CEEG) is eas ier to perform, cheaper, does not involve radiation , and is nonin vasive. The data produced are easily quantifiable , and therefore comparable, among different groups of patient s. There are four major disadvantages to CEEG . The first is that the actual brain electrical activity is non specific to the part of the brain that underlies individual electrode s. The electrical sign al recorded is the average of neuronal activity from millions of cells distorted by conduction through scalp and bone and by artifac t fro m muscle movement and other sources of electrica l noise . Th e second disadvantage is that the EEG co llectio n is replete with artifactu al sources of non-cerebral electrica l sig nals present ing filtering problems. The third disadv antage is the lack of kno wledge of how other potentially co nfounding variables besides agei.e. , sex , handedne ss , and perhaps intellectual capacitycontribute to various CEEG findin gs. All the se points lead to the final disadvantage: scie ntific study is still pending to prove the actu al sig nificance of current CEEG findings . While research is proceeding to decrease the se inherent limitations , controversy ex ists as to the current cl inical usefulness of this techn ique (Ca ncro , 1989 ; Nu wer, 1989).

Applications in Child and Adolescent Psychiatry Like most other neuroimaging techniques , CEEG has been much more widely used to investigate adult psychiatric popJ. Am .Acad. Child Ado/esc. Psychiatry. 29:2. March 1990

NE UROIMAGING IN CHILD PSYCHIATRY

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FIG. II. Auditory ERP of same boy as in Figure 10. A) Respon se to frequ ent stimulus indicates large P' potential frontally. B) Response to oddball stimulus reveals asymmetrical , atypical topography. C ) Following treatment with desipramine the P' respon se to the frequent stimulus is small indicating better discrimination . D) P'OQ potential to oddball stimulus reveals marked impro ved topographic and volt age respon se .

ulations. Child psychiatry applications of CEEG can be divided into two types of studies. The first uses a high risk approach in that adults with known psychiatric disturbance are given CEEG to determine CEEG pattern s which are sought in their offspring . The second type of study is more classical in a clinical sense since correlations are sought between CEEG findings and specific psychiatric disorders. Schizophrenia. In 1974 , Itil et al. published a study comparing CEEG findings in families with and without a history positive for schizophrenia. High risk children were characterized by the presence of more high-frequency beta activity , fewer fast alpha waves , and more very slow, lowvoltage delta activity as well as by shorter latencies in auditory ERP. These characteristics are similar to CEEG findings in schizophrenic adults and suggested to these authors that this pattern may be a neurophysiological measure of schizophrenia. Alcohol Abuse . CEEG's of alcoholics and of children of alcoholics tend to have a relative excess of fast EEG activity (beta) and a relative deficit of slower (delta , theta , and alpha) activity that may overcorrect when a dose of ethanol is given l.Am.Acad. Child Ado/esc. Psychiatry, 29 :2, March 1990

(Jones et al . , 1976; Gabrielli et al. , 1982). ERP in these subjects tend s to show decreased amplitude of the P.1(KI and increased latenc y from time of cuing to response (Porjesz and Begleiter, 1985). A CNS maturational lag hypothesis has been used to explain these findings . Infantile Autism . Cantor et al. (1986) used CEEG techniques to compare autistic children, age matched normal children, mentally handicapped children, and a group of normal toddlers. The CEEG data showed that autistic children resemble toddlers in their EEG measures . Like the toddlers, autistic children had more slow wave activity and less alpha (8 to 12) than the age-matched normals . Auti stic subjects also resemble toddlers in the presence of greater coherence (similar EEG frequen cy distribution) and less amplitude asymmetry. The authors hypothesized that autism represented a cerebral function maturational lag in which a lack of cerebral differentiation was the key factor to the autistic syndrome. Simil ar results have been found in a stud y by Gaffney et al. (1989 ) who found an auti stic population to have increa sed amounts of relative delta and theta acti vity in the frontal and left temporal areas with a concomitant 165

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decrea se in the se same areas of beta acti vity. Attention Def icit Hyperact ivity Disorder (ADHD) . A number of studies have dem on strated an increased occ urrence of abnomal routin e EEG in hyperactive children compared to normal controls (Werry et al. , 1972; Satterfield et a!. , 1973; Grunewald-Zuberbeiter et al ., 1975; Sheer , 1976). However, these differences disappeared if children with cerebral palsy or epilepsy were excluded from analysis (Werry et al., 1972). CEEG studies if childre n with hypera ct ivity are difficult to interpret due to different clini cal populations, nonstandard and limited elect rode placement, and different testing conditions (Figures 10 and II ). The most con sistent spec tral finding has been that of less power in the 8 to 10 Hz range (Shetty , 1971; Mont agu , 1975 ; Dykman et a!., 1982; Callaway et al., 1983). ERP findings, contrary to those see n in normal children, tend to indicate little change in peak heights and latencies when comparing common and novel stimuli in ADHD children and suggest these child ren have difficulty in correct selection and eva luation of a given stimulus (Loiselle et al. , 1980 ). Learn ing Disabilities . CEEG examination of dysle xic and normal boys have revealed group difference s in the bifrontal area as well as the left temp oral and left poster ior regions (Duffy et a!. , 1980). The major difference appeared to be an increase of alpha activity, particularly in the anterior brain , that was felt to represent cortical under arrousal. TOUl'ette' s Syndrome . Visual inspection of routin e EEG tracin gs in TS patients has dem on strated a 40 % occ urrence of abnormal EEG s (Wa ldo et a!., 1978; Bergen et a!. , 1981 ; Shapiro and Shapiro, 1982) without a pathognomonic finding . CEEG result s have been publi shed in onl y o ne limited TS study (Domino et al., 1982) with no differences found in alpha activity in the occip ital and central bra in regio ns. Kuperman et a!. (submitted for publication) found decre ased beta activity and increased theta activity in a group of TS patients suggesting a matu ration delay.

Positron Emission Tomography Basic Considerations Positron emission tomography (PET) is composed of three equa lly important subunits: a cyclo tron, a rad ioph armaceutical labor ator y, and the actual imaging camera sys tem. A cyclotron is a device where charged particles , usually proton s or deuteron s, are acce lerated to high energies within a vacuum chamber. When the particles have reached an adequate ener gy state, the stream of energized part icles is extracted from the vac uum chamber and cau sed to collid e with an appropriate target , usually a highl y pur ified nonradioa cti ve isotope . Because of the increased energy of the charged particle, it penetrates the field of surrounding electron s of the target atom, strikes the nucleu s , and is captured , thereby raising the proton number and transmuting the target from one element to another. In PET scanning, the cyclo tron is used to produ ce shortlived radioisotopes of ca rbon ( " C) , nitrogen (UN), oxy gen 15 ( 0 ), and fluorine (I8F). The radioactive atom is qu ickl y extracted from the cycl otron apparatus and taken to the

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radiopharmaceut ical laboratory to be tagged or integ rated into a mole cule appro priate to the function to be studied . Th e tagg ing process must be carried out without del ay as the half-li ves of these isotopes varies from 2 minutes to 2 hour s. The radioi sotope cont aining tracer is usually injected intravenousl y. At this time rapid sequential images may be obtained or imaging may be carried out a short tim e later after the tracer has had adeq uate time to become localized in spec ific areas of the brain. Blood samples may be required for quantitative work . The injected tracer will eventually yie ld a positron , an antimatter electron that is ejected from the nucl ei of the radioisotope . When this positron encounters an electron , usually within a distance of I millimeter, a matter/antimatter reaction occurs that converts the mass of both particles to electromagnetic energy of 2 gamma photons (511 kEv energy) which travel in exac tly opposite directions . It is the energy from this reaction that is used to produce the PET image. Current imag ing devices are composed of many ring s of mult iple small gamma sc intillation detectors. A detector from one side of the ring is connected electronically with detectors from the other side of the ring throu gh a "coincidence circuit. " The logic of the sys tem is that an ionizing event must be dete cted simultaneously in both opposing detectors before the system reco gnizes that an " event," positron emission within the sample volume of brain , has occ urred. Th e meth od of requiring simultaneous events in two opp osed detectors dramaticall y decreases and increases resoluti on of the image . The actual image formation is by the filtered back projection method pioneered by nuclear med icine of the mid 1960 s and now implemented by SPECT, CT and MRI imaging . The patient s are imaged in an area that need s to be co ntrolled for ambi ent sound and light as act ivation of se lect regions of the brain by these external stimuli can be demonstrated by PET and may be used to determine adequac y of regional brain function.

Advantages and Disadvantages The spatial resolution of PET scanning is better than that of current planer and SPECT nuclear medicine techniques but is not as good as CT or MRI. The fun ctional/phy siological information obtained is quite different , and from the psychiatric view point may be much more useful in pat ient management than that obtained by the anatomical/ stru ctural method s. The flexible chemistry invol ved in PET sca nning makes it possible to measure the number of receptors effected by dru g ther apy and thereby permits bett er monitorin g of drug therapy than that currently obtained by observ ing blood levels . The disad vant ages to PET are that it is expensive , logistically difficult, and inherently presents significa nt radi ation exposure. Furth erm ore , to the best of our kno wledge , no one has directl y utilized this technique in child and adolescent psychiatric patients.

Application s in Child and Adolescent Psy chiatry Pervasive Developm ental Disorder (PDD). While there l.Am.A cad . Child Adolesc. Psychiatry, 29:2, March 1990

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is a lack of actual research in child and adolescent patient s with POD or aut ism, two groups have reported result s on young adult pat ient s who se illness began in childhoo d . Rumsey et al. (1985 ) noted hypermetabolic area s in the brains of autistic patients , areas such as frontal cort ex, parietal, temp oral and occipit al lobes, hippocampus , thalamu s, and basal ganglia. These result s were not confirmed by Herold et al. (198 8) who reported the abse nce of hyperm etabolic brain area differences in autistic indiv iduals whe n co mpared with controls. Tourette' s Syndrome . Tw o studies have been co mp leted using PET to study young adults with TS . Si nge r et al. (1985 ), using IIC-Iabeled 3-N- methylspipero ne, found no evidence of hypersensitivity of ca udate dop am ine rgic (02) receptors. Cha se et al. (1986) noted that a TS gro up had significantly reduced glucose metabolism in the frontal lobes, cingul ate gyrus , and in the inferi or corp us striatum: all areas that contain dop am ine neurons . Furthermore , a sig nif icant inverse relationsh ip was noted between the severi ty of both voca l and motor tics and glucose rates in these areas . Anorexia Ne rvosa (AN) . Usi ng IKF-2- fluoro -2-deoxyg lucose, Herholz et al. ( 1987) dem onstrated increased ca udate metaboli sm bilaterally in five late ado lescent/yo ung adult females diagnosed as having AN when co mpared with 15 sim ilarly aged normal males. Repeating the PET sca n in the AN patients after we ight gain de mo nstrated a decrea se in caudate metabolism with no signi ficant differences between the two groups.

Single Photon Emission Computerized Tomography Basic Considerations In 1948 , Ketty and Schmidt used nitrou s oxi de inhalation to measure cerebral blood flow (CBF) . Durin g the 1950s and 1960s , rad ioisotopes of the inert gases xe non and krypton were inje cted into the ca rotid artery and repl aced inhaled nitrou s oxide as tracer s. A decade later , a less invasive technique involving I.13Xenon (IJJXe) inhalation evo lved . Simultaneously , more sophisticated scintillation detectors were developed to provide a 3-d imen sional repr esentation of regional cerebr al blood flow (rCBF) using single photon emissio n co mputerized tomograph y (SPECT). There are several current instruments designed for SPECT , an exa mple of wh ich is described in deta il by Stockley et al. ( 1980) . Thi s instrum ent co nsists of enha nced sodium iodide crys tal detectors , mounted on the wa lls of a hollow square , whi ch co mplete one ro tatio n aro und the subject's head every 10 seco nds . Detected rad iation is processed by a co mputer whi ch, after correctin g for tissu e abso rption, generates the tom ographic imag es of the brain . The subjects are usually ex amined in a dimly lit room with eyes open and ears uncovered . During the first minute of the exa mination, the subjects inhale l.uXe in the air/ oxygen mixtu re (wa sh-in phase ). Thi s is followed by a 3minut e was h-out period during which the patient breath es room air. Radi oacti vity in the lung , which co rre lates with arteria l blood conce ntration of IJJXe in the brain , is moni tored by a sci ntillation probe placed on the patien t' s ches t. Five slices of brain images are ob tained and are located 2, , l .Am .A cad. Child Adolesc. Psychiatry, 29:2 , March 1990

4. 6. 8. and 10 ern above the orbi to-mea tal line . CBF is influ en ced by gender, age, hand edn ess , and other physio logic perimete rs. Wom en have high er cerebra l blood flow than men of similar age, although the difference is not significant. C BF is inversely correlated with age (Gur et al. , 1987a) with the decrease in males occurring 5 to 10 years earlier than in females (Devous et aI., 1986 ). Both right- and left-hand ed indi vidu als have highe r blood flow in the right hemi sph ere , co mpared to the left. with a mor e pro nounced discrepanc y in left-h anded indivi duals (Prohovnik et aI., 1980; Devou s et al. , 1986 ; Gur et al., 1987b ). Mild anxiety . REM sleep and cog nitive activity incre ase ce rebral blood flo w, while ex treme anxiety, slow wave sleep and habitu ation with repe ated testin g are associated with lower CBF values (Devous et al., 1986; Gur et al., 1987b ). Within the brain, CBF will vary according to the region being examined . CBF is highe r in gray matt er (7 1 ± 12 ml /minllOO gms) than it is in myelinated regions (59 ± 12 ml/min/ I00 gms) . CBF studies in norm al ind ividuals indi cate highe r perfusio n to parietal and vis ual co rtices and lower blood flow , by 5 to 15 %. in fro nta l and temporal areas (Devo us et al. , 1986 ). Oth er investigators report highest CBF in the front al regions , es peci ally in younge r populations (Prohov nik et al. , 1980 ; Risberg. 1980 ). Activation procedures ca n also change CBF. Spe ech is re flected by increased per fusion to the left pre-central and mid-temporal area; calculation and arithmetic tasks increase perfusion in the left and right supra -sylvian region s; sensory stimuli are associated with higher blood flow to the contralatera l sensory motor area ; and spatial tasks incre ase flow in the right hem isph ere (Gur et al. , 1987a ).

Adva ntages and Disadvantages CBF measurem ent with SP ECT is a non invasive , painless. and safe proce dure. It is rel atively inexpensi ve since isotopes can be ob tai ned at low cos t. Th e procedure does not take much time and uses a limi ted numb er of per sonnel. It has wide applications in all age groups and ca n be easily used as a foll ow-up procedure with minimal exposure to radiation. Th e rapid acqui sition of data, and speedy washout of the tracer from the bra in. allows repeated measurements within a short period of time which is adva ntageo us in patient acti vation stud ies. There are some drawba cks in using SP ECT suc h as limited spatial resolut ion and extracranial contamination from background radia tion. Err ors of measur ement ca n occ ur in regio ns measuring less than 3 em in d iameter. Lesion s in white matter may not be easily detected because the cle arance rate is much slower in myelinated tis sue , co mpared to the gray matt er. Also, the size of the mach ine and the requirement for a dedicated sca nner prevent thi s procedure from becoming a routine clinical test. Some of the limit ation s of m Xe SPECT arc being addresse d by a new ge neratio n of lipid so lub le radiopharmace utica ls that offe r improved image qual ity (E ll et al., 1987) at a cos t of slightly more radi ation ex pos ure. Cu rre ntly FDA approve d injec table SPECT age nts include N-isapropy l(I-1 23 )-p -i d oam ph etamin e (Il ' IM P. S pect am in e ) a nd technetium -9 9m-he xameth yp rop yl en earnine (Tc- 99 m-

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FIG. 12. Cerebral blood flow TC-HMPAO scan in same boy. unmedicated, as in Figure s 10 and 11. Note that orientation of the head is diffe rent. White areas represent highest perfu sion flow. Perfus ion de fects are appar ent in the left frontal area . Note : correspondi ng CEEG brain mapp ing results.

HMPAO, Ceretec) with several investigators reporting images with resolution comparable to those obtained in PET (Lassen et aI., 1983; Andersen et aI., 1988; Inugami et al. , 1988; Langen et aI., 1987) (Figure 12).

Applications in Child and Adolescent Psychiatry As in other neuroimaging techniques , SPECT utilization has occurred much more often in adults with psych iatric disorders than in children or adole scents. Adult schizophren ics, for instance , seem to have decreased front al lobe blood flow and fail to incre ase flow to this area when given frontal lobe activation tasks such as a continuous performance test or the Wiscon sin Card Scoring Test (Volkow et aI. , 1986). Adult depressed patients have generalized decrease in cerebral blood flow (Uytdenhoef et al. , 1978). Hypofrontal flow distribution is report ed in young alcoholics which may reflect " premature aging " of the brain due to ethanol (Dally et al . , 1988). Howe ver, unlike PET , there are some studie s with children and adolescents. Schizophrenia . In adolescent schizophrenics, prefrontal perfusion is only 0.7 % greater than the blood flow in the

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rest of the hemisphere compared with a 14.6 % incre ase in controls (Chabrol et al., 1985). This is similar to findings in adult schizophrenics and may represent incre ased subcortical activity suggesti ve of an abnormality in the dopamine system. Attention Defi cit Hyperactivity Disorder. Lou et al. ( 1984) reported relati vely decreased blood perfu sion in the ncostriatal and frontal regions and relati vely incre ased per fusion in the primary sensory region in children with attenti on deficit-hypera ctivity disorder. Thi s pattern of flow distribution was reversed with methylph en idate treatment. The authors concluded that dysfunction of the pre front al cortex and neostraitum plays an important role in the pathogen esis of the ADHD . Later work by this same group (Lou et aI., 1989) stressed that decre ased flow and , by inference decreased activity in the striatal area, was a " cardinal" feature in ADHD . In an attem pt to determ ine possible relat ionships of cerebral blood flow to behavioral symptoms associated with ADHD, Hamd an-Allen et al. (submitted for pub lication) compared mean cerebral blood flows to behavioral item s on I.Am .Acad.Child Adolesc .Psychiatry. 29:2 . Mar ch 1990

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FIG. 13. Cerebral blood flow '33XeSPECT scan in a norm al and a hyperact ive six-yea r-old boy. White areas ind icate highe st rate of perfusio n. Note : relat ive hypoperfusion to the frontal lobes (arrow) of the ADHD patient.

the Child Behavior Checklist (Achenbach and Edelbro ck , 1983) and the Iowa Conners Teacher Rating Scale (Loney and Milich, 1982) in a group of ADHD children and a group of matched psychiatric control s. Despite a relative hypoperfusion to the frontal regions (Figure 13), blood flow pattern did not correlate with scores of aggres sion and hyperactivity. Further research in this area is indicated because of the important regulatory role of the prefrontal cortex, especially over impulsivity, aggression, and overactivity and its connections with the catecholamine and serotonin systems. Neuropsychiatry . CBF measurement may have utility in child psychiatric conditions related to brain dysfunction. SPECT has been emplo yed in young children to determine causes of perinatal ischemia (Lou, 1980).

Future Imaging Techniques Two new method s are currently under developm ent and will add to function al brain imaging. The first of these , magnetoencephalography (MEG) is an alternative noninvasive method for studying brain electrical activity. MEG J .Am .Acad . Child Ado/e sc .Psychiatry, 29:2, March 1990

is the study of the magnetic fields of the brain generated by the movement of charged ions across nerve membranes. Though the strength of an individual neuronal magnetic field is not very large certain conditions, i.e., the simult aneous discharge of a large number of neurons orientated in the same axis, will elicit a magnetic field strong enough to be measured ext racranially through the use of a superconductive quantum interference device (SQUID) first developed by Zimmerm an et al. ( 1970) . The advantages of MEG over CEEG is that detection of the magnetic field is not affected by intervening tissues (skin. skull, or SDF) and that by using various computer algorithms the source of the electrica l activity can be localized within the volume of the brain (Beatty et aI. , 1986; Reeve et al. . 1989). Disad vantages include the high expenses of the technology, the need for a lengthy exa mination period and a cooperative patient, the small window of access to brain electrical activity, and the lack of validation studies in clinical populations. While this technique has been used to localize seizure foci, its use in psychiatry has been limited to adult patients. Reite et al. ( 1989) demon strated abnormal interhemispheri c asy mmetry in adult schizophrenic patients when compared to norm al /69

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co ntrols. No publi shed data currently exists on the use of MEG in child psych iatric patients. The second new meth od of functional brain imagin g being developed involves a variation of MRI technology . Using combinations of rad io frequ enc y pul ses and high strength magn etic field s it is po ssible to identify , by comparison of magnetic resonance spec tra, certa in compounds (N-ace ty l aspartate , GABA, lact ate , and phosphocholine and other molecules containing .'1 phosphorous) and to determ ine within a given volume (limited at present to the whol e brain ) the concentration of these co mpounds. The major ad vant age of this technology is that it will allow quantification of ene rgy metabolism due to the impo rtance of pho sph orou s in thi s process (Andreasen , 1989). Disadvantages are those mentioned previously in the MRI section, but may be worse since the required high strength magnetic field is greater than that required for MRI imaging-a minimum 1.5 Tes la (Williams and Cody, 1987). Also. refinements must be made in the available technology to allow the study of subregio ns of the brain. Thi s techn ology has been used to study the effects of perinatal hypoxia . stroke and ischaemi c heart dis ease (Williams and Cody, 1987 ) but a dearth of information has been publi shed about its use in either adult or child psychiatric patient s.

Conclusion Whil e the clini cal interview will remain the basis of the child and adole scent psych iatr y subspec ialty, the emerging technologie s of CT, MRI . CEEG , PET , and SP ECT add to the potential to better understand the neurobiology of norm al development as well as that assoc iated with various psychiatric di sorders. All of the techniques are relati vely new and all have yet to be fully explo ited for research of child and ado lesc ent psych iatric di sorders. Of the two struc tura l procedures, CT and MRI , it is the latter that appears to have the most promise for child and adolescent psychiatry . A recent review of MRI use in pediatrics concluded the superiority of MRI imaging over other anatomic modalities (Cohen. 1986) except for calc ified lesions . The sensitivity of MRI to gray-white delineation encourages studies of developm ent al anomalies, hyd rocephalus . traum a , and neo plasms. As new generation MRI instruments are dev eloped , reso lution will furth er improve and allow visualizat ion with eve n grea ter detail. Th e three modaliti es that asce rta in brain functioning have not been as well studied . PET sca nning has the potent ial for offering the most specific infor mation about brain function ing at the biochem ical level. Recept or sites specific for ind ividual neurotransm itters ca n be visualized allowi ng loca lization of pathology as well as a method to determin e the actions of various psyc hotro pic agent s. How ever , PET requires extensive equipme nt . spec ialized personn el , and invo lves a sig nificant amount of radi ation exposure. Furtherm ore . its use in childre n and adole scent s has been infrequent. Yet, PET' s adva ntages are bein g recogn ized and its use is becomin g increasingly more common in research institut ions . CEEG is the least spec ific of the three functional techniques but it is balan ced by its relative ease of use. inex-

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pensiveness . and lack of ex pos ure to radia tion. T wo major potent ials exis t for this techn ology: it is very sensi tive to the act ions of psychot ropi c medic ation s and therefore may be a way to monit or "brain levels" of medi cation; and , using ERP meth ods , it allows an almost instant aneou s way to monitor cog nitive processing . Yet. further work is needed to incre ase the abi lity of CEEG to localize brain path ology. SPECT's potenti al lies midway betwe en the other two functional meth ods in that it has man y of their individua l benefits and probl em s . Current SPECT appli cat ion s allow measurement of cere bral blood flow an d of so me neu rotransm itter recept or functioning . It also has the ca pability of measur ing , in a slower manner, cognitive acti vation proc essing . Outside of minimal ex posure to radiation, SPECT' s major limitation is that curre nt resolution does not allow clear demarcation of variou s brain areas. However , the technology is progressing such that resolution approach ing that currently obtained by PET scanners should be obtained within the next few years . Thu s. the potenti al curre ntly ex ists for ch ild and ado les ce nt psychi atr ists to beg in the process of understanding the inter face between behavior and brain structure and behav ior and brain funct ion ing . Many more studies than the ones reviewed here are needed . part icul arl y to clarify potent ial co nfoundi ng variables incl udi ng stag e of development (age) . sex, handedness. and inte llectua l capaci ty. In addi tio n, attempts must be made to image the brain using more than one modality , to provide cross valida tion for eac h technique.

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