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Blood flow response to auditory stimulations in normal, mentally retarded, and autistic children: A preliminary transcranial Doppler ultrasonographic study of the middle cerebral arteries
Abstract
Using the noninvasive transcranial ultrasonic Doppler method, flow dynamics of the middle cerebral arteries were investigated in relation to auditory stimulations in 12 children with autistic behavior compared with 12 normal controls and 10 mentally retarded children. In normal children, auditory stimulation evoked lateralized modifications: blood flow increased and resistance index decreased on the left side; such modifications were not recorded on the right side. This pattern should indicate vasodilatation mechanisms induced by changes in the metabolism of the brain areas supplied by the left middle cerebral arteries (MCA). Although less asymmetrical, this pattern was also found in the mentally retarded children. Autistic children significantly differed from these two groups. They displayed a symmetric pattern of responses with a blood flow decrease and resistance-index increase on both sides; this could suggest abnormal metabolic mechanisms induced by auditory stimulation in autistic children and could be related to the previous hypothesis of impairment in the development of cerebral lateralization in autism. These preliminary results show that transcranial Doppler ultrasonography may be a valuable and practicable tool for the noninvasive study of evoked blood flow responses in psychopathology.
... En las estructuras anatómicas relacionadas con el procesamiento auditivo se han encontrado alteraciones morfológicas, como menor tamaño en el tronco del encéfalo y en el cerebelo, a través de Resonancia Magnética Nuclear (MRI, Magnetic Resonance Imaging), en niños y adultos con autismo (Hashimoto et al., 1995). Mediante Doppler Transcraneal (TCD, Transcranial Doppler), se han encontrado trastornos en la distribución del flujo sanguíneo cuando los sujetos con autismo escuchaban un estímulo auditivo (Bruneau, Dourneau, Garreau, Pourcelot, & Lelord, 1992). A través de Tomografía por Emisión de Positrones (PET, Positron Emission Tomography), se estudió como se estructura el cerebro de las personas con autismo en el procesamiento de los estímulos auditivos verbales, y se encontró una dominancia atípica para el lenguaje (Müller et al., 1999). ...
... Mediante la técnica Doppler se ha comprobado que en personas sin alteraciones aumentaba el flujo sanguíneo en el hemisferio izquierdo cuando escuchaban estímulos auditivos. Sin embargo, en las personas con autismo, este incremento se producía en ambos hemisferios (Bruneau et al., 1992). ...
... Mediante Doppler transcraneal (TCD, por sus siglas en inglés de Transcranial Doppler), una técnica no invasiva que ofrece la posibilidad de estudiar el cerebro funcionando, se han encontrado trastornos en la distribución del flujo sanguíneo cuando los sujetos con autismo escuchaban un estímulo auditivo (Bruneau et al., 1992). En el grupo de control se observó un patrón relativamente estable de cambios en el flujo sanguíneo en respuesta al tono: la circulación se incrementó y los índices de resistencia disminuyeron en el hemisferio izquierdo. ...
A broad description of autism disorders is performed, as well as changes in visual and auditory perception and its difficulties in social perception and executive functions. Conducting five experiments with a group of low IQ adults with autism, compared with a group of low IQ adults without autism is described. The experiments investigating the perception of emotions in a complex scenographical context; identifying emotional responses consistent with a given context; making appropriate decisions in emotional contexts; causal attribution of expressed emotions; and perception of emotions through video clips. From the results psychopathological correlates of the perception of emotions are determined and predictions about performance in emotion recognition based on psychopathological variables are performed. The results show clear difficulties in social adaptation, perception, understanding of causality, and cognitive and executive functions in low IQ adults with autism. All these difficulties determine their ability to understand emotions.
... Bruneau et al. [27] Children with autistic behaviour (AB), mentally retarded children without autistic symptoms (MR) and healthy control children n = 34 (AB n = 12, MR n = 10, control n = 12)/mean age AB 7 years (SD = <1), MR 6 years (SD < 1), control 7 years (SD < 1)/ AB 67%, MR 70%, control 33% male fTCD using auditory stimuli (passive task); SV, DV, MV and RI Nineteen (of the 25) papers assessed TCD measures during rest, and six employed fTCD (i.e. changes in velocity relative to a cognitive operation). ...
... changes in velocity relative to a cognitive operation). The vast majority investigated clinical samples (20 of 25): including preterm infants [11][12][13][14], infants from high risk pregnancy [15], Sickle cell disease [16][17][18][19][20][21][22][23][24][25][26], autism spectrum disorders [27], and sleep disordered breathing [7]. Most of these studies did not employ a healthy comparison group, instead looking at associations within the clinical group. ...
... Less commonly the PCA and BA were assessed. Six articles employing fTCD were included, all measuring bilaterally from the MCA [2][3][4][27][28][29]. A broad range of behavioural and cognitive domains were assessed such as the intelligence quotient (IQ; including the Wechsler Intelligence Scale for Children, Wechsler Preschool and Primary Scale of Intelligence and the Woodcock-Johnson Psycho-Educational Battery), neonatal behaviour (e.g. ...
The contribution of cerebrovascular function to cognitive performance is gaining increased attention. Transcranial doppler (TCD) is portable, reliable, inexpensive and extremely well tolerated by young and clinical samples. It enables measurement of blood flow velocity in major cerebral arteries at rest and during cognitive tasks.
We systematically reviewed evidence for associations between cognitive performance and cerebrovascular function in children (0-18 years), as measured using TCD. A total of 2778 articles were retrieved from PsychInfo, Pubmed, and EMBASE searches and 25 relevant articles were identified.
Most studies investigated clinical groups, where decreased blood flow velocities in infants were associated with poor neurological functioning, and increased blood flow velocities in children with Sickle cell disease were typically associated with cognitive impairment and lower intelligence. Studies were also identified assessing autistic behaviour, mental retardation and sleep disordered breathing. In healthy children, the majority of studies reported cognitive processing produced lateralised changes in blood flow velocities however these physiological responses did not appear to correlate with behavioural cognitive performance.
Poor cognitive performance appears to be associated with decreased blood flow velocities in premature infants, and increased velocities in Sickle cell disease children using TCD methods. However knowledge in healthy samples is relatively limited. The technique is well tolerated by children, is portable and inexpensive. It therefore stands to make a valuable contribution to knowledge regarding the underlying functional biology of cognitive performance in childhood.
... When a neurotypical person has to focus on a task or generate speech (in other words, when the brain has to do work), there is an increase in blood flow to the brain, supplying more blood, oxygen, and glucose (fuel) [12]. However, several studies have now demonstrated that not only do some autistic children have diminished blood flow at baseline, they also do not get an increase in blood flow when brain cells have to do more work, such as when the chil-dren have to focus on a task or generate a sentence [13][14][15]. In fact, sometimes cerebral blood flow goes down and this appears to be mediated, in part, by inappropriate vasoconstriction instead of vasodilatation [15]. ...
... However, several studies have now demonstrated that not only do some autistic children have diminished blood flow at baseline, they also do not get an increase in blood flow when brain cells have to do more work, such as when the chil-dren have to focus on a task or generate a sentence [13][14][15]. In fact, sometimes cerebral blood flow goes down and this appears to be mediated, in part, by inappropriate vasoconstriction instead of vasodilatation [15]. The interesting thing about these studies demonstrating cerebral hypoperfusion in autism is that no one has stopped to ask why the diminished blood flow exists in the first place. ...
HBOT and Autism Overview At first glance, the use of hyperbaric oxy-gen therapy (HBOT) in autism appears out of the ordinary. That is what I first thought when I heard about HBOT and autism almost 2 years ago. At the time, no studies existed on the use of HBOT in au-tistic individuals (there was one published case re-port [1]). In fact, many people who were propo-nents for this therapy could not give a theoretical reason why it should/could even work. We began using HBOT in autistic children with a great deal of skepticism. After seeing improvements in some of these children, we decided that further study was needed. Just over 2 years later, we have finished our third study on the use of HBOT in autism. Many of the underlying pathophysiological findings in autism might be ameliorable with HBOT and these have been reviewed in another publication [2]. HBOT in children is generally regarded as safe [3]. Cerebral Hypoperfusion in Autism To understand how or why HBOT works in autistic children, we need to review some basic, but newly described, fundamental problems found in many autistic individuals. There are now numer-ous studies in the medical literature [4-11] demon-strating cerebral hypoperfusion (decreased blood flow in the brain) in as many as 86% of autistic individuals [4]. In one study, this hypoperfusion typically worsened as the age of the autistic child increased, and become "quite profound" in older children compared to younger [5]. Furthermore, this diminished blood flow typically correlates with many core autistic symptoms (see Table 1). When a neurotypical person has to focus on a task or gen-erate speech (in other words, when the brain has to do work), there is an increase in blood flow to the brain, supplying more blood, oxygen, and glucose (fuel) [12]. However, several studies have now demonstrated that not only do some autistic children have diminished blood flow at baseline, they also do not get an increase in blood flow when brain cells have to do more work, such as when the chil-dren have to focus on a task or generate a sentence [13-15]. In fact, sometimes cerebral blood flow goes down and this appears to be mediated, in part, by in-appropriate vasoconstriction instead of vasodilatation [15]. The interesting thing about these studies demon-strating cerebral hypoperfusion in autism is that no one has stopped to ask why the diminished blood flow exists in the first place. This cerebral hypoperfusion appears to lead to cerebral hypoxia (impaired oxygen delivery) to the brain in some autistic individuals. In fact, several studies have demonstrated a reduction of Bcl-2 and an increase of p53 in the brain of some au-tistic individuals [80, 81]. Elevated p53 is caused by hypoxia [82] and an increase in Bcl-2 normally pro-tects from cell death provoked by hypoxia; a reduction is associated with increased damage caused by hy-poxia [83].
... As determined by ultrasonography, blood flow to the auditory cortex during sound stimulus decreased in ASDs [143]. The finding suggests inversion of normal neurovascular coupling, which matches local blood flow to metabolic activity. ...
... It is also known that experimental inversion of neurovascular coupling is mediated by activation of potassium channels [249]. These data suggest that possible inversion of the neurovascular couple in ASDs [143] could result from altered potassium currents in the pNTS, as mediated by adenosine and pericytes. ...
Electrophysiological findings implicate site-specific impairment of the nucleus tractus solitarius (NTS) in autism. This invites hypothetical consideration of a large role for this small brainstem structure as the basis for seemingly disjointed behavioral and somatic features of autism. The NTS is the brain's point of entry for visceral afference, its relay for vagal reflexes, and its integration center for autonomic control of circulatory, immunological, gastrointestinal, and laryngeal function. The NTS facilitates normal cerebrovascular perfusion, and is the seminal point for an ascending noradrenergic system that modulates many complex behaviors. Microvascular configuration predisposes the NTS to focal hypoxia. A subregion-the "pNTS"-permits exposure to all blood-borne neurotoxins, including those that do not readily transit the blood-brain barrier. Impairment of acetylcholinesterase (mercury and cadmium cations, nitrates/nitrites, organophosphates, monosodium glutamate), competition for hemoglobin (carbon monoxide, nitrates/nitrites), and higher blood viscosity (net systemic oxidative stress) are suggested to potentiate microcirculatory insufficiency of the NTS, and thus autism.
... We combined n-back testing (n values ranging from 0 to 4) with bilateral TCD during incremental upright tilt at 0, 15, 30, 45, 60, and 75°. We measured changes in cerebrovascular function by measuring CBF velocity (CBFV) using a two-parameter analysis that incorporates critical closing pressure (CCP; corresponding to vasomotor tone) (1,7,16,42) and the resistance-area product (corresponding to proximal resistance) and compared these with the Gosling pulsatility index (PI) (6,24). We assessed the response of CBFV during cognitive activation (34,43,48) to model blood flow linkage to neuronal activation (20,45). ...
... Gosling PI. PI was calculated using the following formula: PI ϭ (maximum CBFV Ϫ minimum CBFV)/(mean CBFV) (6,24), where maximum CBFV is the maximum systolic velocity, minimum CBFv is the minimum diastolic velocity, and mean CBFV is the CBFV averaged over the entire cardiac cycle. Averaging over multiple cardiac cycles was performed. ...
Neurocognition is impaired in chronic fatigue syndrome (CFS). We propose that the impairment relates to postural cerebral hemodynamics. Twenty-five CFS subjects and twenty control subjects underwent incremental upright tilt at 0, 15, 30, 45, 60, and 75° with continuous measurement of arterial blood pressure and cerebral blood flow velocity (CBFV). We used an n-back task with n ranging from 0 to 4 (increased n = increased task difficulty) to test working memory and information processing. We measured n-back outcomes by the number of correct answers and by reaction time. We measured CBFV, critical closing pressure (CCP), and CBFV altered by neuronal activity (activated CBFV) during each n value and every tilt angle using transcranial Doppler ultrasound. N-back outcome in control subjects decreased with n valve but was independent of tilt angle. N-back outcome in CFS subjects decreased with n value but deteriorated as orthostasis progressed. Absolute mean CBFV was slightly less than in control subjects in CFS subject at each angle. Activated CBFV in control subjects was independent of tilt angle and increased with n value. In contrast, activated CBFV averaged 0 in CFS subjects, decreased with angle, and was less than in control subjects. CCP was increased in CFS subjects, suggesting increased vasomotor tone and decreased metabolic control of CBFV. CCP did not change with orthostasis in CFS subjects but decreased monotonically in control subjects, consistent with vasodilation as compensation for the orthostatic reduction of cerebral perfusion pressure. Increasing orthostatic stress impairs neurocognition in CFS subjects. CBFV activation, normally tightly linked to cognitive neuronal activity, is unrelated to cognitive performance in CFS subjects; the increased CCP and vasomotor tone may indicate an uncoupling of the neurovascular unit during orthostasis.
... The over-connectivity in networks involving the auditory cortex and the hippocampus is intriguing. Auditory processing deficits in ASD are well documented and range from a lack of lateralization to a general delay in network maturation (Bruneau et al. 1992;Edgar et al. 2015), although the functional behavioral consequences of these deficits are not clear. Furthermore, over-responsivity to sensory stimuli is frequently observed in ASD patients, can affect all sensory modalities and appears to be positively correlated with the severity of autistic traits (reviewed in Tavassoli et al. 2014;Sinclair et al. 2017). ...
Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorder (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at midgestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8+/- mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.
... A study has shown that neurologically healthy children present a drop in the resistance of the middle cerebral artery upon auditory stimulation, which indicates that the artery relaxes and blood flood flow increases, delivering more oxygen to this part of the brain. Conversely, upon the same stimulus, the resistance in the middle cerebral artery increased in children diagnosed with ASD, indicating that the artery contracts and thereby limits blood flow and oxygen delivery (Bruneau et al. 1992). The origin of this lack of the compensatory response (increased blood flow) upon a stimulus in the autistic brain is unknown, but it is likely to be related to an absence of the signal/receptor involved in vasodilatation in the brain (Ohnishi et al. 2000). ...
Cerebral hypoperfusion, or insufficient blood flow in the brain, occurs in many areas of the brain in patients diagnosed with autism spectrum disorder (ASD). Hypoperfusion was demonstrated in the brains of individuals with ASD when compared to normal healthy control brains either using positron emission tomography (PET) or single‑photon emission computed tomography (SPECT). The affected areas include, but are not limited to the: prefrontal, frontal, temporal, occipital, and parietal cortices; thalami; basal ganglia; cingulate cortex; caudate nucleus; the limbic system including the hippocampal area; putamen; substantia nigra; cerebellum; and associative cortices. Moreover, correlations between symptom scores and hypoperfusion in the brains of individuals diagnosed with an ASD were found indicating that the greater the autism symptom pathology, the more significant the cerebral hypoperfusion or vascular pathology in the brain. Evidence suggests that brain inflammation and vascular inflammation may explain a part of the hypoperfusion. There is also evidence of a lack of normal compensatory increase in blood flow when the subjects are challenged with a task. Some studies propose treatments that can address the hypoperfusion found among individuals diagnosed with an ASD, bringing symptom relief to some extent. This review will explore the evidence that indicates cerebral hypoperfusion in ASD, as well as the possible etiological aspects, complications, and treatments.
... The vast majority of studies that have investigated this question have used handedness as a proxy (i.e., the studies that are included in the present meta-analyses). A study that examined blood flow response to auditory stimulation using transcranial Doppler ultrasonography found a less asymmetrical pattern of blood flow in ID compared to TD children (Bruneau et al., 1992), supporting the idea of a shift of language functions to the right hemisphere in ID individuals. ...
Understanding the relationship between cerebral laterality and intelligence is important in elucidating the neurological underpinnings of individual differences in cognitive abilities. A widely used, behavioral indicator for cerebral laterality, mainly of language, is handedness. A number of studies have compared cognitive abilities between groups of left-and right-handers, while others have investigated the handedness prevalence between groups of different cognitive abilities. The present study comprises five meta-analyses of studies that have assessed the handedness prevalence in (a) individuals with intellectual disability (ID) of unknown/idiopathic nature compared to typically developing (TD) individuals, and (b) individuals with intellectual giftedness (IG) compared to TD individuals. Nineteen data sets totaling 16,076 participants (5,795 ID, 8,312 TD, and 1,969 IG) were included in the analyses. Elevated levels of atypical handedness were found to be robust only for the ID to TD comparison. Findings constrain the range of acceptable theories on the handedness distribution for different intelligence levels.
Copyright © 2015 Elsevier Ltd. All rights reserved.
... Cependant, plusieurs études ont montré que non seulement des enfants autistes avaient un débit sanguin de base diminué, mais qu'il n'y avait pas d'augmentation du débit sanguin quand les cellules cérébrales devaient fournir plus de travail. Cette diminution du débit sanguin cérébral (DSC) pourrait être médiée en partie, par une vasoconstriction inappropriée et/ou des modifications de la résistance des artères cérébrales [3]. ...
Various therapies take place in autism treatment. Cerebral hypoperfusion, neuro-inflammation and oxidative stress findings in autistic children have led clinicians to experiment hyperbaric oxygen therapy. To date, except two single case descriptions, only available results are about five case series, three of whom very briefly described, and two randomized comparative studies. Improvement in cerebral perfusion is found in one study but results concerning oxidative stress are not significant. Globally, these studies seem to show an improvement in autistic symptoms, but their validity is not demonstrated because of their small samples and their questionable methods. Further studies are currently carried out. Analysis and results interpretation will be distorted by oxygen concentrations and pressure variability from one study to another one. To date, hyperbaric oxygen therapy should be considered as an experimental therapeutic modality and should be used only in the context of a well defined research.
... The finding that light reflectance varies at frequencies which parallel moment-to-moment electrical changes has substantial implications for interpretation of optical imaging studies. Physiological processes typically linked to alterations in neural activation include neurally and metabolically mediated changes in vascular perfusion, with differential reflectance originating from hemoglobin oxygenation states or changes in relative flow [1,5,18,24,38,46], and are suggested as potential sources for cortical light reflectance variation observed during sensory stimulation [9,11]. None of the potential vascular influences change sufficiently fast to accommodate the highest frequencies observed (12 Hz) in this study; a maximal rate of 0.5 Hz could be expected [20] . ...
We assessed the correspondence of 660 nm light reflectance changes from the dorsal hippocampus with slow wave electroencephalographic (EEG) activity during quiet sleep (QS) and rapid eye movement (REM) sleep in four cats. An optic probe, attached to a charge-coupled-device (CCD) video camera, was placed on the dorsal hippocampal surface to collect reflectance images simultaneously with EEG, which was measured by macroelectrodes placed around the probe circumference. Spectral estimates of EEG and light reflectance amplitude indicated that reflectance changes occurred in a similar frequency range as EEG changes. Dividing the image into 10 subregions revealed that reflectance changes at the rhythmical slow wave activity band (RSA, 4–6 Hz) persisted in localized regions during QS and REM sleep, but regional changes showed considerable wave-by-wave independence between areas and from slow wave electrical activity. Peak frequencies for reflectance changes corresponded to fast RSA frequencies observed in the EEG. Optical changes most likely derive from fast-acting physical phenomena, rather than from alterations in blood perfusion, and provide increased spatial resolution over that offered by electrical measurements.
... Children with autism have impaired CNS blood circulation and resulting hypoxia (Ichim et al., 2007). Defects include basal hypoperfusion (Ichim et al., 2007;Ryu et al., 1999), and decreased perfusion in response to stimuli that usually upregulate perfusion (Bruneau, Dourneau, Garreau, Pourcelot, & Lelord, 1992). The areas affected by hypoperfusion seem to correlate with regions of the brain that were responsible for functionalities that are abnormal in autism, for example, specific lobe areas associated with face recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in autistic but not control children (Ichim et al., 2007) (Table 9). ...
Anatomic, histopathologic, and MRI/SPET studies of autistic spectrum disorders (ASD) patients’ brains confirm existence of very early developmental deficits. In congenital and chronic murine toxoplasmosis several cerebral anomalies also have been reported, and worldwide, approximately two billion people are chronically infected with T. gondii with largely yet unknown consequences. The aim of the study was therefore to compare brain abnormalities in ASD patients with those found in mice with cerebral toxoplasmosis (CT) because this may help in understanding pathophysiology of ASD. Data from available published studies were analyzed to compare postmortem pathologic changes found in the brains of ASD patients with those of mice developed after intraperitoneal T. gondii infection. Patients with ASD had the following brain abnormalities: active neuroinflammatory process notably in cerebellum, microglial nodules, accumulation of perivascular macrophages, decreased number and size of Purkinje cells in cerebellar nuclei and inferior olive, hypoperfusion of brain. Mice with congenital toxoplasmosis also had persistent neuroinflammation and ventricular enlargement, periventricular edema, meningeal and perivascular inflammation, and focal loss of Purkinje and granule cells. In murine acquired CT, the brain anomalies included: ventricular dilatation probably reflecting loss of brain parenchyma; perivascular inflammation particularly in hippocampus, and periaqueductal/periventricular areas, Purkinje cell layer markedly disfigured with focal loss of cells; perivascular cuffing by mononuclear cells and localized microglial/inflammatory nodules. Infection of mice with different strains of T. gondii resulted in distinctive neuropathological changes and various stadium of maturity of cysts and the parasite itself, which is in line with the diversity of the autistic phenotypes. Also, the abnormalities in behavior and clinical features associated with autism resembled that reported in chronic latent toxoplasmosis in humans and rodents. All these similarities suggest that T. gondii should be regarded as an important infectious factor that may trigger development of ASD and some other neurodegenerative diseases, such as obsessive–compulsive and attention-deficit/hyperactivity disorders, and cryptogenic epilepsy. Thus, all these patients should be tested for T. gondii infection.
... Studies have examined the effect of pharmacological agents (Rosengarten et al., 2002a), Type I diabetes (Rosengarten et al., 2002b), Alzheimer's disease (Rosengarten et al., 2007), voluntary movements (Sitzer et al., 1994;Orlandi and Murri, 1996), hemispheric language lateralization (Markus and Boland, 1992;Knecht et al., 1998a,b;Dorst et al., 2008), emotional processing (Troisi et al., 1999), and attentional processes (Schnittger et al., 1996(Schnittger et al., , 1997Knecht et al., 1997;Helton et al., 2007) on neurovascular coupling. It has also been well characterized in clinical populations (Njemanze, 1991;Bruneau et al., 1992;Thie et al., 1992;Silvestrini et al., 1993Silvestrini et al., , 1995Silvestrini et al., , 1998Silvestrini et al., , 2000, and may be a useful paradigm for the evaluation of cerebrovascular function in certain disease states (Boms et al., 2010). ...
There is considerable utility in the use of transcranial Doppler ultrasound (TCD) to assess cerebrovascular function. The brain is unique in its high energy and oxygen demand but limited capacity for energy storage that necessitates an effective means of regional blood delivery. The relative low cost, ease-of-use, non-invasiveness, and excellent temporal resolution of TCD make it an ideal tool for the examination of cerebrovascular function in both research and clinical settings. TCD is an efficient tool to access blood velocities within the cerebral vessels, cerebral autoregulation, cerebrovascular reactivity to CO(2), and neurovascular coupling, in both physiological states and in pathological conditions such as stroke and head trauma. In this review, we provide: (1) an overview of TCD methodology with respect to other techniques; (2) a methodological synopsis of the cerebrovascular exam using TCD; (3) an overview of the physiological mechanisms involved in regulation of the cerebral blood flow; (4) the utility of TCD for assessment of cerebrovascular pathology; and (5) recommendations for the assessment of four critical and complimentary aspects of cerebrovascular function: intra-cranial blood flow velocity, cerebral autoregulation, cerebral reactivity, and neurovascular coupling. The integration of these regulatory mechanisms from an integrated systems perspective is discussed, and future research directions are explored.
... It is likely that severe focal or general defects will affect the patterns or the latencies and amplitudes of cognitively evoked flow, because intact metabolic cou pling in the respective brain areas is required to produce the characteristic' 'normal" response. Whether such pos sible abnormalities, as they have been described after auditory stimulation (Bruneau et aI., 1992 ...
This study describes the dynamics of flow activation by reading and investigates the potential use of repeated flow velocity measurements for the lateralization of speech. Using simultaneous transcranial Doppler recordings from both middle cerebral arteries and averaging techniques in 25 healthy volunteers, we describe the changes in blood flow velocity caused by repetitive reading tasks of variable duration in comparison with a resting state. Reading aloud evoked a characteristic temporal flow pattern in both hemispheres, consisting of three relative maxima in flow velocity during and after activation. Flow velocities lower than baseline were common during longer lasting activation. The amplitudes of two of the observed peaks decreased depending on the duration of the task. Reading silently produced a markedly different temporal pattern of activation than reading aloud. There were individually reproducible significant side to side differences. Right-handed persons (n = 15) almost without exception showed a significantly higher increase in flow velocity on the left hemisphere (e.g., reading silently 8.7% versus 5.3%; P < 0.0001). Three out of ten left-handed individuals, however, exhibited no significant side to side difference or exhibited lateralization to the right during one or more of the tasks. These findings suggest that reading induces task-specific temporal patterns of regional neuronal activity, which show habituation with longer duration of activation. Additionally, the observed side to side differences could be useful to predict language dominance.
... Our results are also in accordance with other data reporting a right hemisphere dominance in the processing of verbal and non-verbal auditory stimuli by autistic subjects. Such evidence derives from dichotic listening studies (Prior and Bradshaw, 1979 ), neuropsychological testing (Hoffmann and Prior, 1982), electrophysiological studies using EEG (Small, 1975), auditory responses during sleep (Tanguay et al., 1976 ), auditory responses to verbal stimulation (Dawson et al., 1982Dawson et al., , 1988) and cerebral blood ¯ow studies (Bruneau et al., 1992). These results argue for a reorganization of the respective roles of the left and right hemispheres for auditory information processing during early brain development rather than dysfunction of the left hemisphere alone. ...
Auditory processing at the cortical level was investigated with late auditory evoked potentials (N1 wave-T complex) in 4-8-year-old autistic children with mental retardation and compared to both age-matched normal and mentally retarded children (16 children in each group).
Two negative peaks which occurred in the 80-200 ms latency range were analyzed according to stimulus intensity level (50 to 80 dB SPL): the first culminated at fronto-central sites (N1b) and the second at bitemporal sites (N1c, equivalent to Tb of the T complex). The latter wave was the most prominent and reliable response in normal children at this age.
Our results in autistic children indicated abnormalities of this wave with markedly smaller amplitude at bitemporal sites and pronounced peak latency delay (around 20 ms). Moreover, in both reference groups the intensity effect was found on both sides whereas in autistic children it was absent on the left side but present on the right.
These findings in autistic children showing very disturbed verbal communication argue for dysfunction in brain areas involved in N1c generation i.e., the auditory associative cortex in the lateral part of the superior temporal gyrus, with more specific left side defects when auditory stimulus have to be processed.
... Posterior associative temporal areas were activated on the left side in normal children and on the right side in children with autism. A lack of cerebral blood flow modifications in response to tone stimulations had also previously been shown in autistic children using transcranial Doppler ultrasonography (Bruneau et al., 1992). Modifications of AEP observed when stimulus intensity increases, are usually interpreted as reflecting better synchronisation of single trial responses, which lead to greater mean amplitude and shorter latency of peaks. ...
The purpose of the present study was to investigate the relations between late auditory evoked potentials (AEPs) recorded at temporal sites (the N1c wave or Tb) and verbal and non-verbal abilities in children with autism. The study was performed in 26 mentally retarded children with autism (AUT) aged 4-8 years (mean age +/- S.E.M. = 71 +/- 2 months; mean verbal and non-verbal developmental quotient +/- S.E.M. = 36 +/- 4 and 48 +/- 3). The stimuli used were 750 Hz tone bursts of 200 ms duration delivered binaurally at different intensity levels (50, 60, 70, 80 dB SPL) with 3-5 s interstimulus intervals. Temporal AEPs were first compared to those of a group of 16 normal children (NOR) in the same age range (mean age +/- S.E.M. = 69 +/- 3 months). We then focused on the AUT group and considered relations between temporal AEPs and the severity of disorders of verbal and non-verbal communication assessed using a behavior rating scale. AEPs recorded on left and right temporal sites were of smaller amplitude in the AUT group than in the NOR group. Increasing intensity-related amplitude was observed on both sides in NOR and only on the right side in AUT. The lack of intensity effect on the left side resulted in a particular pattern of asymmetry at the highest level of intensity (80 dB SPL) with greater N1c amplitude on the right than on the left side (the reverse was found in the NOR group). Electro-clinical correlations indicated that the greater the amplitude of the right temporal N1c responses, the higher the verbal and non-verbal communication abilities. This suggests a developmental reorganization of left-right hemisphere functions in autism, with preferential activation of the right hemisphere for functions usually allocated to the left hemisphere, particularly those involving the secondary auditory areas situated on the lateral surface of the superior temporal gyrus where the N1c/Tb wave is generated.
... One of the first studies measuring cerebral blood flow in autistic children utilized transcranial Doppler ultrasound and showed decreased blood flow and concomitantly increased middle cerebral arterial resistance upon auditory stimulation . Conversely, control neurotypical and mentally retarded children showed opposite results [45]. The mechanism of this abnormal change in cerebral arterial resistance in autistic children is unknown . ...
Autism is a neurodevelopmental disorder that currently affects as many as 1 out of 166 children in the United States. Recent research has discovered that some autistic individuals have decreased cerebral perfusion, evidence of neuroinflammation, and increased markers of oxidative stress. Multiple independent single photon emission computed tomography (SPECT) and positron emission tomography (PET) research studies have revealed hypoperfusion to several areas of the autistic brain, most notably the temporal regions and areas specifically related to language comprehension and auditory processing. Several studies show that diminished blood flow to these areas correlates with many of the clinical features associated with autism including repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) has been used with clinical success in several cerebral hypoperfusion syndromes including cerebral palsy, fetal alcohol syndrome, closed head injury, and stroke. HBOT can compensate for decreased blood flow by increasing the oxygen content of plasma and body tissues and can even normalize oxygen levels in ischemic tissue. In addition, animal studies have shown that HBOT has potent anti-inflammatory effects and reduces oxidative stress. Furthermore, recent evidence demonstrates that HBOT mobilizes stem cells from human bone marrow, which may aid recovery in neurodegenerative diseases. Based upon these findings, it is hypothesized that HBOT will improve symptoms in autistic individuals. A retrospective case series is presented that supports this hypothesis.
... Control children also have an increase in cerebral blood flow when listening to tones and generating sentences; whereas autistic children typically have a decrease in cerebral blood flow [27]. Upon an auditory stimulation, ''normal'' children have a drop in the left middle cerebral artery resistance index as measured by transcranial doppler ultrasound (which means blood flow increases); while autistic children have an increase in resistance index, which causes blood flow to decrease [28]. These findings might indicate that the brain metabolic rate and function are diminished in autistic children because blood flow is tightly coupled with these two parameters [29,30]. ...
Autism is a neurodevelopmental disorder currently affecting as many as 1 out of 166 children in the United States. Numerous studies of autistic individuals have revealed evidence of cerebral hypoperfusion, neuroinflammation and gastrointestinal inflammation, immune dysregulation, oxidative stress, relative mitochondrial dysfunction, neurotransmitter abnormalities, impaired detoxification of toxins, dysbiosis, and impaired production of porphyrins. Many of these findings have been correlated with core autistic symptoms. For example, cerebral hypoperfusion in autistic children has been correlated with repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) might be able to improve each of these problems in autistic individuals. Specifically, HBOT has been used with clinical success in several cerebral hypoperfusion conditions and can compensate for decreased blood flow by increasing the oxygen content of plasma and body tissues. HBOT has been reported to possess strong anti-inflammatory properties and has been shown to improve immune function. There is evidence that oxidative stress can be reduced with HBOT through the upregulation of antioxidant enzymes. HBOT can also increase the function and production of mitochondria and improve neurotransmitter abnormalities. In addition, HBOT upregulates enzymes that can help with detoxification problems specifically found in autistic children. Dysbiosis is common in autistic children and HBOT can improve this. Impaired production of porphyrins in autistic children might affect the production of heme, and HBOT might help overcome the effects of this problem. Finally, HBOT has been shown to mobilize stem cells from the bone marrow to the systemic circulation. Recent studies in humans have shown that stem cells can enter the brain and form new neurons, astrocytes, and microglia. It is expected that amelioration of these underlying pathophysiological problems through the use of HBOT will lead to improvements in autistic symptoms. Several studies on the use of HBOT in autistic children are currently underway and early results are promising.
... Children with autism have been consistently shown to have impaired, or subnormal CNS circulation, as well as resulting hypoxia. Defects include basal hypoperfusion [3], and decreased perfusion in response to stimuli that under normal circumstances upregulates perfusion [4]. In numerous studies the areas affected by hypoperfusion seem to correlate with regions of the brain that are responsible for functionalities that are abnormal in autism. ...
Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions whose incidence is reaching epidemic proportions, afflicting approximately 1 in 166 children. Autistic disorder, or autism is the most common form of ASD. Although several neurophysiological alterations have been associated with autism, immune abnormalities and neural hypoperfusion appear to be broadly consistent. These appear to be causative since correlation of altered inflammatory responses, and hypoperfusion with symptology is reported. Mesenchymal stem cells (MSC) are in late phases of clinical development for treatment of graft versus host disease and Crohn's Disease, two conditions of immune dysregulation. Cord blood CD34+ cells are known to be potent angiogenic stimulators, having demonstrated positive effects in not only peripheral ischemia, but also in models of cerebral ischemia. Additionally, anecdotal clinical cases have reported responses in autistic children receiving cord blood CD34+ cells. We propose the combined use of MSC and cord blood CD34+cells may be useful in the treatment of autism.
In the present study, we made use of dual-wavelength laser speckle imaging (DW-LSI) to assess cerebral blood flow in the BTBR genetic mouse model of Autism Spectrum Disorder, as well as control (C57Bl/6J) mice. Since the deficits in social behavior demonstrated by BTBR mice are attributed to changes in neural tissue structure and function, we postulated that these changes can be detected optically using DW-LSI. BTBR mice demonstrated reductions in both cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2 ), as suggested by studies using conventional neuroimaging technologies to reflect impaired neuronal activation and cognitive function. To validate the monitoring of CBF by DW-LSI, measurements with laser Doppler flowmetry (LDF) were also performed which confirmed the lowered CBF in the autistic-like group. Furthermore, we found in vivo cortical CBF measurements to predict the rate of hippocampal neurogenesis, measured ex vivo by the number of neurons expressing doublecortin (DCX) or the cellular proliferation marker Ki-67 in the dentate gyrus (DG), with a strong positive correlation between CBF and neurogenesis markers (Pearson, r= 0.78; 0.9, respectively). These novel findings identifying cortical CBF as a predictive parameter of hippocampal neurogenesis highlight the power and flexibility of the DW-LSI and LDF setups for studying neurogenesis trends under normal and pathological conditions.
The title of the work by Dr. Bernard Garreau “Neuroimaging in childhood psychiatric disorders” may appear quite ambitious, if not presumptuous. Are not psychiatric childhood disorders both too subtle and too complex to be detected by of the examinations brain? Are these examinations useful in childhood mental disorders? Is not clinical medicine still the only valid discipline in this field? These questions are still posed by many child psychiatrists today.
Autism is a life-long severe developmental disorder which impairs the acquisition of some of the most important skills in life (Kanner, 1943). The major signs of the syndrome are deficits in social interaction, verbal and nonverbal communication and imaginative activity (APA, 1987; Rutter, 1978). Autism was believed to be a “psychological” disorder but over the past 20 years it has become clear that it must have a biological origin. The understanding of brain mechanisms which underlie such a severe disorder remains a major challenge for research in this field. Neuropathological studies of infantile autism are few and have revealed abnormalities in the limbic system and cerebellar circuits (Bauman and Kemper, 1988; Ritvo, 1986; Williams, 1980). Structural neuroimaging investigations, including CT and MRI, have indicated various sites of anatomical abnormalities including the cerebral cortex, ventricular system and the cerebellum of autistic adults, and relatively old autistic children (Campbell, 1982; Cour-chesne, 1994; Courchesne, 1988; Damasio, 1980; Gill-berg and Svendsen, 1983; Hier, 1979; Piven, 1990). However, these findings are still inconsistent and none accounts fully for the clinical expression of autism. Thus, we have little evidence of structural brain abnormalities in autism, despite the various theories proposed to explain it.
Most childhood psychiatric syndromes appear at a well defined stage of development (Fig. 1) which in part determines their clinical picture. Thus, autism appears very early and affects all adaptive functions: perception, posture-motility, language and communication (Sauvage, 1984). Clinicians justly use the term “pervasive developmental disorders”. Schizophrenia appears later and does not affect motor or perception functions and is limited to disorders in consistency of thought (Bleuler, 1911). The first signs of the Gilles de 1a Tourette syndrome appear only around the age of 7 years and eating disorders such as anorexia bulimia at the onset of adolescence. In addition, symptoms progress with age and childhood psychiatric syndromes are thus intimately linked with the development of the central nervous system in both their genesis and their advancement (Evrard et al., 1992). The causes of these syndromes may be endogenous, e.g. a defect in the expression of development genes, or exogenous such as congenital rubella or certain environmentally-linked disorders. It is clear that these endogenous or exogenous causes affect cerebral development, but the aetiological search in childhood psychiatric syndromes remains problematic. Applying imaging and developmental neurophysiology techniques contributes to this procedure, in addition to the value of these techniques for physiopathological analysis.
IntroductionPhysiological backgroundHow to perform a fTCD investigation: technical considerations and practical recommendationsValidation studiesLimitationsApplications of fTCDConclusions
References
The neurophysiology of sensory and cognitive processing can be studied with a high degree of temporal resolution by recording evoked potentials (EPs) on the scalp. These potentials are extracted from the EEG by averaging a number of EEG samples time-locked to the event. They offer the possibility of measuring the function of numerous neural systems in a completely noninvasive fashion. Moreover, evoked potentials can be assessed in paradigms which do not require the active participation of the subject. These advantages make them easily applicable to children and therefore particularly suitable for the study of normal and abnormal brain development. One of the most important uses of EPs is assessment of auditory function. Applications are quite extensive, particularly in developmental disorders. Indeed, in disorders such as those including language and communicative impairment, it is important to identify the possible disturbances which can affect various levels of the central auditory system.
In der vorliegenden Arbeit werden am Beispiel visuell evozierter Flussgeschwindigkeitsänderungen die Anpassung der zerebralen Hämodynamik an Änderungen der Gehirnaktivität untersucht. Dazu wurde das nichtinvasive Verfahren der transkraniellen Dopplersonographie angewendet. Ziele der Arbeit waren das Erstellen von Normwerten der Latenzen und Amplituden visuell evozierter Geschwindigkeitsänderungen an einer Gruppe von Normalprobanden sowie die Prüfung der Sensitivität der zeitlichen Auflösung dieses Verfahrens. Die Untersuchungen wurden an einer Gruppe von 20 Normalprobanden und an einer Gruppe von 16 Patienten, welche eine Leitungsverzögerung im vorderen Sehbahnbereich (nachgewiesen mit den Visuell Evozierten Potentialen anhand der P100) zeigten, vorgenommen. Die Lichtstimulation erfolgte mit einer LED-Blitzbrille und einer Stimulationszeit von jeweils 10 s "on" und "off" mit einer Frequenz von 15 Hz bei konstanter Lichtintensität. In der Kontrollgruppe ermittelten wir einen reaktiven Geschwindigkeitsanstieg von 16 %. Der Anstieg der Flussgeschwindigkeit erfolgte nach 1,4 s bzw. nach 1 s bei Flussantworten, die gleich mit einem Anstieg der Geschwindigkeit begannen. Das initiale Maximum wurde nach 5,6 s erreicht, 2,9 s nach Stimulationsende begann die Geschwindigkeit wieder abzufallen. Außer bei den Latenzwerten bis zum Anstieg ohne vorherigen Abfall der Flussgeschwindigkeit gab es keine signifikanten Unterschiede zwischen den beiden untersuchten Gruppen. Die von uns ermittelten Werte lagen in den Größenordnungen der Ergebnisse anderer Studien mit ähnlichem Versuchsaufbau. Auch die unterschiedlichen Verläufe der Flussantworten wurden bis auf das "initiale undershoot" auch von anderen Autoren beschrieben. Als Erklärung dafür diskutierten wir Aktivierungen anderer Hirnareale und eine Umverteilung des Blutflusses dorthin zu Beginn. Die zeitliche Auflösung der Dopplersonographie ist gut geeignet zeitliche Abläufe der zerebralen Hämodynamik zu untersuchen. Sie ist aber nicht sensitiv genug Leitungsverzögerungen im vorderen Sehbahnbereich zu erfassen. Die Möglichkeiten der Anwendung in der klinischen Routine liegen daher in der Untersuchung von Störungen der neurovaskulären Kopplung.
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The difficulty that a person with autism has in establishing relationships, maintaining them (communicating and responding appropriately) is a common experience of those close to them., That impaired perceptual and cognitive processing can underlie this difficulty and the interactions of people with autism with the material environment has been established in the laboratory. The consequences at a psychological level of analysis may converge in the inadequacy of second-order representations of the world. An attenuation of such endogenous monitoring processes could also indirectly account for features of withdrawal and the stereotypies often observed. At another level of analysis there are delays in neurotransmission, in the CNS and a lack of flexibility of physiological response shown by evoked potential recordings. Tomographic studies of blood flow and metabolism illustrate a lack of correlation between information processing centres in the brain that may sometimes arise from diffuse gray matter atrophy. A "stop-go" form of modulation of central processing is mediated by anomalous ascending serotonergic and dopaminergic function (transmitters with inhibitory and switching functions). On these bases it is no wonder that representations are not formed and inappropriate and repetitive behaviors follow, although the link remains somewhat speculative. Both levels of analysis are useful for an explanation. As behavioral and pharmacotherapy, though helpful, are severely limited in their efficacy, more effort is required to synthesize the different levels of analysis into a psycho-biological approach, to remedial programs and new forms of therapy.
The first part of this review on event-related potentials (ERPs) in children summarizes the role of ERPs in the study of normal cognitive development. The ERPs vary both as a function of the age of the child and also as a function of the cognitive processes that are required by the tasks. Topographical studies allow one to identify cortical regions involved in specific cognitive processes, and monitor their age-related changes. The second part of this paper reviews two examples of abnormal cognitive development (attention deficit hyperactivity disorder and childhood autism) where the ERPs allow a better understanding of the dysfunction underlying the observed cognitive disorders.
Transcranial Doppler sonography (TCD) can assess blood flow velocity changes induced by focal brain activation. Therefore, TCD may have the potential to identify hemispheric dominance for cognitive tasks.
Using a system with two TCD probes ("stereo" TCD), we monitored simultaneously both middle cerebral arteries (MCAs) of 14 healthy right-handed volunteers while they performed cognitive tasks. The averaged blood flow velocity ratio of the two MCAs and the hemispheric blood flow velocity shift induced by the cognitive task were calculated.
In every subject, language tasks resulted in blood flow velocity shift to the left compared with visuospatial tasks. Mean MCA blood flow velocity shift to the left was 1.67%, 2.01%, and 2.31% in three language tasks. Mean blood flow velocity shift to the right was 1.67% and 2.31% in two visuospatial tasks.
Bilateral simultaneous MCA blood flow velocity monitoring and averaging during cognitive tasks can help to identify hemispheric dominance for cognitive tasks in individuals.
Cortical auditory evoked potentials (N1 wave) were studied in 24 adults (12 men, 12 women) and 20 children (12 boys, 8 girls; age: 4-8 years). In adults, this wave was recorded with maximal amplitude at frontocentral sites, peaking at about 100 ms poststimulation, whereas in children the auditory response displayed maximal amplitude at the midtemporal sites, with a positive wave at about 100 ms and a large negative wave at approximately 170 ms. Moreover, the modulatory effects of intensity on N1 amplitude were prominent at frontocentral sites in adults and at temporal sites in children. Frontocentral negative response was also recorded in children but was smaller in amplitude and longer in peak latency (around 140 ms) than in adults; responses were of greater amplitude at the frontal site than at the vertex before 6 years of age, whereas the reverse was more often found after this age. These data suggest great differences with age in the neural generators contributing to auditory evoked potentials recorded in the N1 latency range.
The aim of this study was to investigate side-to-side differences of simultaneously measured middle cerebral artery (MCA) blood flow velocities during various hemisphere-specific tasks. Using a transcranial Doppler device, flow velocity changes of 24 healthy, right-handed subjects were monitored simultaneously in the left and right MCA during different hemisphere-specific tasks. Mean flow velocity (MFV) curves were averaged for each individual subject and task. Simultaneously, heart rate, blood pressure and end-tidal carbon dioxide (CO2) were measured in a subgroup of six subjects. When compared with the resting state, all stimuli produced significant (p < 0.001) bilateral MFV increases, ranging from 2.5-9.2%. A lateralization of MFV increases with a significantly (p < 0.001) more pronounced increase in MFV in the hemisphere contralateral to the performing band was observed both during simple sequential finger movements and a complex spatial task. During the complex spatial task, consistently higher MFV increases were observed in the right MCA (p < 0.001), regardless of the side of task performance. Recognition of pictorial material presented as part of a memory task, also resulted in a side-to-side difference of respective MFV increases (right > left, p < 0.001), whereas memorization did not. Whereas bilateral MFV elevations observed during stimulation with white noise were only discrete and not lateralized, exposure to overt speech produced significantly higher (p < 0.001) MFV increases in the left MCA. The time course of the MFV reaction showed a rapid increase with an initial maximum after 4-5 s. Heart rate, blood pressure, and end-tidal CO2 showed only subtle changes during the stimulation periods. In conclusion, the observed side-to-side differences of MFV reaction in the left and right MCA concur with current functional imaging data. Bilateral simultaneous repetitive transcranial Doppler monitoring is a sensitive method to detect cerebral perfusion asymmetries caused by hemisphere-specific activation, and thus may be helpful for noninvasive assessment of hemispheric dominance for language.
We examined the brain organization for language and auditory functions in five high-functioning autistic and five normal adults, using [15O]-water positron emission tomography (PET). Cerebral blood flow was studied for rest, listening to tones, and listening to, repeating, and generating sentences. The autism group (compared to the control group) showed (a) reversed hemispheric dominance during verbal auditory stimulation; (b) a trend towards reduced activation of auditory cortex during acoustic stimulation; and (c) reduced cerebellar activation during nonverbal auditory perception and possibly expressive language. These results are compatible with findings of cerebellar anomalies and may suggest a tendency towards atypical dominance for language in autism.
Neuroimaging studies of neurobehavioral disorders are using new imaging modalities. In dyslexia, anatomic imaging studies demonstrate an abnormal symmetry of the planum temporale. Functional imaging supports the hypothesis that developmental dyslexia is frequently the result of deficits in phonologic processing and that normal reading requires a patent network organization of a number of anterior and posterior brain areas. In autism, anatomic imaging studies are conflicting. Functional imaging demonstrates temporal lobe abnormalities and abnormal interaction between frontal and parietal brain areas. In attention-deficit-hyperactivity disorder, imaging studies suggest an abnormality in the prefrontal and striatal regions. Neuroimaging studies are often contradictory, but trends, especially with functional imaging analysis, are evolving. Because neurobehavioral disorders seem to be a result of a dysfunction in brain circuits, no one region will be abnormal in all patients studied. Further studies with well-defined patient populations and appropriate activation paradigms will better elucidate the pathophysiology of these conditions.
Functional transcranial Doppler sonography (fTCD) allows the noninvasive and uncomplicated registration of intracranial blood flow parameters under defined conditions of stimulation. Although local distribution patterns of regional blood perfusion can be measured with high spatial resolution through neuroimaging methods (e.g., PET or SPECT), these methods are limited by their low temporal resolution. The high temporal resolution provided by fTCD, however, allows the recording of the dynamic component of cerebral blood perfusion by continuously measuring the cerebral blood flow velocity in the basal cerebral arteries. Hence, this method is especially appropriate for the investigation of fast neuronal activation processes, which are generally accompanied by changes in local blood perfusion. In this review, we present methodical issues regarding fTCD, as well its application in the field of psychology, especially psychophysiology. The relevant studies available to date investigate processes of attention and perception, higher cognitive functions, and emotional and psychomotor processes. Considering the current state of methodology and research, fTCD can be seen to be an important complement to the other psychophysiological methods for studying brain function.
Transcranial Doppler ultrasonography (TCD) permits the assessment of cognitively induced cerebral blood flow velocity (BFV) changes. We sought to investigate the lateralization of BFV acceleration induced by auditory stimulation and speech in a normal population. TCD monitoring of BFV in the middle cerebral arteries (MCA) was performed in 30 normal right-handed volunteers (average age = 31.7 years). Noise stimulation, speech, and instrumental music were administered during 60 sec to both ears by means of earphones. Auditory stimulation induced a significant BFV increase in the ipsilateral MCA compared to BFV during the preceding rest periods. Left MCA BFV increased by an average of 7.1% (noise), 8.4% (language), and 5.2% (melody) over baseline values, and right MCA BFV increased 5.1%, 3.1%, and 4.2%, respectively. Speech stimulation produced a significant increase in BFV in the left hemisphere MCA (from 49.86 to 54.03 cm/sec; p < .0001). Left MCA BFV response to speech stimulation may reflect the dominance of the left hemisphere in language processing by right-handed individuals. Due to the high temporal resolution of TCD we were able show a habituation effect during the 60-sec stimulation period.
The objective of this study was to compare autistic adults and matched control subjects in their ability to focus attention selectively on a sound source in a noisy environment. Event-related brain potentials (ERPs) were recorded while subjects attended to a fast paced sequence of brief noise bursts presented in free-field at a central or peripheral location. Competing sequences of noise bursts at adjacent locations were to be ignored. Both behavioral measures of target detection and auditory ERP amplitudes indicated that control subjects were able to focus their attention more sharply on the relevant sound source than autistic subjects. These findings point to a fundamental deficit in the spatial focusing of auditory attention in autism, which may be a factor that impedes social interactions and sensory-guided behavior, particularly in noisy environments.
The present study aimed to find out how different stages of cortical auditory processing (sound encoding, discrimination, and orienting) are affected in children with autism. To this end, auditory event-related potentials (ERP) were studied in 15 children with autism and their controls. Their responses were recorded for pitch, duration, and vowel changes in speech stimuli, and for corresponding changes in the non-speech counterparts of the stimuli, while the children watched silent videos and ignored the stimuli. The responses to sound repetition were diminished in amplitude in the children with autism, reflecting impaired sound encoding. The mismatch negativity (MMN), an ERP indexing sound discrimination, was enhanced in the children with autism as far as pitch changes were concerned. This is consistent with earlier studies reporting auditory hypersensitivity and good pitch-processing abilities, as well as with theories proposing enhanced perception of local stimulus features in individuals with autism. The discrimination of duration changes was impaired in these children, however. Finally, involuntary orienting to sound changes, as reflected by the P3a ERP, was more impaired for speech than non-speech sounds in the children with autism, suggesting deficits particularly in social orienting. This has been proposed to be one of the earliest symptoms to emerge, with pervasive effects on later development.
Investigations made in previous decades about irregularities in auditory perception in individuals with autism are reviewed and revised clinical and theoretical implications are provided. Emphasis is placed on the fact that these auditory perception irregularities of people with autism are very important for the understanding of the symptoms, for the search of its etiology, for the implementation of an adequate treatment program, and for the formulation of an adequate theoretical explanation of the syndrome.
Flow velocities in the basal cerebral arteries were studied by transcranial Doppler sonography. A longitudinal study was undertaken on 25 healthy newborn babies during the first 20 days of life, and a cross sectional study was performed on 112 healthy children between 1 day and 18 years of age. A rapid linear increase of flow velocities was found within the first 20 days with higher velocities in neonates of higher birth weight and gestational age. Maximal values were recorded at the age of 5 to 6 years. After that the velocities decreased linearly to 70% of their maximum at the age of 18 years. Reference values were derived from the data considering age and birth weight. The increasing flow velocities probably reflect the increasing cerebral blood flow during the first years of life. Our results also support the hypothesis of a decrease in cerebrovascular resistance during infancy. With the technique of transcranial Doppler sonography and the introduced reference values normal and abnormal intracranial flow velocities can now be assessed by non-invasive methods in all paediatric age groups.
The end-tidal carbon dioxide partial pressure (PCO2) response curves for the flow velocity in the middle cerebral artery were studied in 31 normal subjects with transcranial Doppler techniques. An exponential curve with an exponent of 0.034 mm Hg-1 was found to be a good fit to the recorded data. By means of this relationship, recordings of flow velocity in cerebral arteries can be normalized to a standard value of PCO2. Physiological aspects of cerebrovascular reactivity to PCO2 and the clinical implications of the PCO2 response curve are discussed. The normal material provides a reference for assessing pathological responses.
Every few years a dissertation comes to the area of clinical application of medical technology which carries us forward as on a magic carpet into new regions of understanding and patient care. This book is such a magic carpet. It brings together, in a clear and incisive fashion, important hemodynamic principles with a simple noninvasive method of application to a part of the cerebral vasculature which has been relatively inaccessible. To the lucky and perceptive person who reads this book, a feeling of excitement and hope for progress is engendered. The diligent application of the potentials of transcranial Doppler ultrasound brings new power to our efforts in understanding the cerebral circulation and the causes, treatment and prevention of cerebrovascular disorders. Merrill P. Spencer, M. D. Director Institute of Applied Physiology and Medicine Seattle, Wash. , July 1986 Acknowledgements I am greatly indebted to Prof. He1ge Nornes, Oslo, who introduced me to the fascinating study of cerebral hemodynamics in the early 1970's and since then continually encouraged my interest in this field. It was through his pioneering work on the cerebral circulation-using peroperative electromagnetic flowmetry and Doppler techniques-that the basis was laid for the noninvasive trans cranial approach to the circle of Willis described in this book. I also gratefully acknowledge the stimulating case discussions with Prof. Peter Huber, Berne, at the very early introduction of trans cranial Doppler, the inspiring exchange of ideas with Dr. Merrill P.
A total of 64 healthy children were studied with transcranial Doppler ultrasound (TCD). The purpose was to determine the relative influence of age and hematocrit (HCT) on intracranial arterial velocities and to establish approximate normal ranges for TCD findings based on age. Blood velocities decreased with advancing age and increasing HCT; velocities were highest in young children (aged 4-8) and declined toward adult levels by age 16. Unexpected findings included a significantly higher velocity in girls compared with boys, which was associated with a higher pulse rate but no difference in HCT. Modest left-to-right asymmetries (12 ± 10%) were observed in middle cerebral artery (MCA) velocities. Knowledge of the hematocrit did not add to the prediction of MCA velocities after age and sex were considered. We conclude that intracranial arterial velocities decline with increasing age and HCT in early childhood but that knowledge of the HCT is not necessary to interpret TCD findings in children without severe anemia. Side-to-side asymmetries of up to 30% do not necessarily represent abnormal conditions. Such information will be useful in the application of TCD to the detection of intracranial vessel stenosis in such diseases as moyamoya, sickle cell anemia, and arteritis.
• To test the hypothesis that regional cerebral blood flow (rCBF) is normally regulated by regional metabolic activity, rCBF and the regional cerebral metabolic rate for oxygen (rCMRO2) were compared in selected human subjects. In normal subjects and patients with chronic, stable diseases of brain, rCBF correlated well with rCMRO2. In one individual with mild dementia, rCBF and rCMRO2 were measured before and during exercise of the hand and forearm contralateral to the hemisphere studied. Appropriate parallel changes occurred in both rCBF and rCMRO2 during hand exercise. In patients with acute diseases affecting the hemisphere studied, however, the correlation between rCBF and rCMRO2 was unpredictable.
the purpose of this presentation is to extend the sensory-processing dysfunction hypothesis to an information-processing dysfunction hypothesis by utilizing the Jacksonian principle that higher levels of the nervous system represent and re-represent, but do not replace, lower levels
through an analysis of recent experimental neurophysiological findings, I attempt to demonstrate (1) the influence of the brain stem and diencephalic regions involved in the modulation of sensory input on those cortical centers involved with information processing; (2) the relevance of the functions of those higher centers to autistic behavior; and (3) the way in which these higher centers might elaborate an autistic dysfunction of sensory processing to a disorder of information processing (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Thirty normal children (aged 3–68 months) and 16 autistic children (aged 36–62 months) were recorded during nonmedicated sleep and data pertaining to rapid eye movements (REM) were measured during the first three REM periods of the night. When time of night from which data were gathered was held constant, normal children showed a significant relationship between age and the organization of eye movements into discrete bursts. When autistic children were compared to age-matched normal controls, they showed an immaturity in this phenomena, their results being similar to those found in children less than 18 months of age. Such an immaturity could result from dysfunction at a number of diverse levels and sites in the central nervous system.
Thirteen autistic and 10 control children were studied with high resolution computerized tomographic (CT) scans. Linear and volumetric measurements of ventricles, subarachnoid cisterns and head size were made. Evidence of subtle differences between autistic and control children with marked variance within the autistic group when compared to the control group was revealed. This study confirms previous reports of heterogeneity in brain structure in autism. New and more sophisticated technology now permits a more quantitative approach to regional brain structural features than has been feasible in the past.
Sixty-three children with an unequivocal diagnosis of infantile psychosis who attended the Maudsley Hospital between 1950 and 1958 were individually matched for age, sex, IQ and year of attendance with a control group of clinic children with non-psychotic disorders. Both groups were re-examined in 1963–4 and given individual psychiatric, neurological, social and psychological assessments. At follow-up (mean age 15 years 7 months) the psychotic children showed low scores on tests of verbal ability and higher scores on performance tests. They showed a characteristic WISC subtest pattern of high scores on the Block Design, Object Assembly and Digit Span subtests combined with a very low score on Comprehension; this pattern was more marked among the children with a pronounced language retardation. Similar patterns of Wechsler Performance Scale scores have been found in deaf children with poor language and in children with developmental disorders of language. This was interpreted in terms of the hypothesis that infantile psychosis develops on the basis of a central disorder of language and of perception of sounds.
The psychotic children as a group were inferior to the controls in terms of social competence. Among the psychotics the mean SQ was significantly lower than their Non-Verbal IQ, whereas, among the controls, the two scores were approximately the same.
Data were summarized from clinical EEG studies and investigations of evoked responses and quantitative EEG analysis in autistic and normal children. Most of the data from clinical EEG studies showed that autistic children have a high incidence of abnormal EEG's, providing objective indication of central nervous system dysfunction in this condition. Moreover, in these studies abnormal EEG findings were significantly related to other indications of impaired CNS functioning, such as lower intelligence, positive neurological signs, and poorer followup status. Data from studies of evoked potentials recording during waking and sleep generally indicated that autistic children were less neurophysiologically responsive both to internal regulatory mechanisms and to external stimuli. Limited evidence from voltage integration and auto and cross correlation of the waking EEG suggested that spontaneous waking EEG activity in autistic children is not as variable, differentiated, or fluctuant as it is in normals.
Thirty normal children (aged 3--68 months) and 16 autistic children (aged 36--62 months) were recorded during nonmedicated sleep and data pertaining to rapid eye movements (REM) were measured during the first three REM periods of the night. When time of night from which data were gathered was held constant, normal children showed a significant relationship between age and the organization of eye movements into discrete bursts. When autistic children were compared to age-matched normal controls, they showed an immaturity in this phenomena, their results being similar to those found in children less than 18 months of age. Such an immaturity could result from dysfunction at a number of diverse levels and sites in the central nervous system.
Recent research in childhood autism has provided support for the hypothesis that a central cognitive deficit involving severe language impairment underlies this disorder. In this study a group of autistic children were tested for handedness and for lateralization of speech function using a dichotic listening task. Contrary to earlier reports there were no left-handed children in the group although a number showed mixed preference. In the dischotic listening task using pairs of single syllable words the autistic group performed similarly to a matched group of normal children in terms of numbers of correct responses but over all did not show the right ear advantage characteristic of the normal children. There was a significant excess of right hemisphere dominance for verbal stimuli amongst the autistic children suggesting that for some at least, language functions had developed in the right hemisphere. Lateralization was shown to be related to presence or absence of speech before the age of 5 years and to IQ level.
Utilizing computerized brain tomography, left-right morphologic asymmetries of the parietooccipital region were judged in 16 autistic patients, 44 mentally retarded patients, and 100 miscellaneous neurological patients. In 57% of the autistic patients the right parietooccipital region was wider than the left, while this pattern of cerebral asymmetry was found in only 23% of the mentally retarded patients and 25% of the neurological patients. It is suggested that unfavorable morphologic asymmetries of the brain near the posterior language zone may contribute to the difficulties autistic children experience in acquiring language.
To test the hypothesis that regional cerebral blood flow (rCBF) is normally regulated by regional metabolic activity, rCBF and the regional cerebral metabolic rate for oxygen (rCMRO2) were compared in selected human subjects. In normal subjects and patients with chronic, stable diseases of brain, rCBF correlated well with rCMRO2. In one individual with mild dementia, rCBF and rCMRO2 were measured before and during exercise of the hand and forearm contralateral to the hemisphere studied. Appropriate parallel changes occurred in both rCBF and rCMRO2 during hand exercise. In patients with acute diseases affecting the hemisphere studied, however, the correlation between rCBF and rCMRO2 was unpredictable.
Pneumoencephalographic findings are described in a group of 18 children who presented to us with a history of retarded language development and autistic behaviour disturbances. None had specific diagnosable neurological diseases nor gross motor disorders. PEG findings included, most prominently, pathological enlargement of the left temporal horn in 15 cases; some cases showed enlargement of both temporal horns or mild variable enlargement of the lateral ventricles, especially the left. Comparisons between infantile autism and recognized patterns of temporal lobe disease (especially Korsakoff syndrome and Kluver-Bucy syndrome) are drawn. We have suggested that medial temporal lobe dysfunction may be a major factor in the pathogenesis of the syndrome of infantile autism.
The authors investigated a possible cortical brain dysfunction associated with infantile autism.
They measured regional cerebral blood flow with single photon emission computed tomography (SPECT) and xenon-133 in 21 children with primary autism (according to DSM-III-R criteria). Five cortical brain areas including frontal, temporal, and sensory association cortices were examined in order to test the recent hypothesis of cerebral dysfunction in primary autism. Anatomical references for each subject were obtained with computerized tomography or magnetic resonance imaging and were used to delimit the regions of interest for SPECT analysis.
When the results from the group with primary autism were compared with an age-matched group of nonautistic children with slight to moderate language disorders (N = 14), no cortical regional abnormalities were found.
It appears that there is no regional cortical dysfunction in primary autism; however, in light of methodological limitations, one cannot exclude the possibility of more localized or subcortical brain dysfunctions in autism.
Transcranial pulsed Doppler analysis of blood velocity in the middle cerebral artery was performed in 120 healthy volunteers (age 20-70 y, 12 male and 12 female subjects per decade), meeting strict selection criteria. The intention was to create normative reference data, both at rest and during hyperventilation, for the assessment of abnormality in patients with cerebral vascular disorders. The measured blood velocity at rest decreased significantly with increasing age. Females up to 50 years of age had significantly higher blood velocity values than males. Blood velocity diminution was induced by means of voluntary hyperventilation, under capnographic control. An age related decline of blood velocity as present at rest was not found during hyperventilation, thus the relative value of hyperventilation induced changes diminished with increasing age. The pCO2 related change in the blood velocity index appeared not to be a constant value, as suggested by previous authors. The blood velocity index was largest in the change from resting condition to 4 kPa pCO2, and smallest in the change 3 kPa pCO2 to 2 kPa pCO2. When examining the blood velocity in the MCA, the age, sex and end-tidal pCO2 pressure have to be taken into account for a correct interpretation of the data obtained.
Isotope tracer methods for measuring regional cerebral blood flow or metabolism do not provide data on the dynamics of the fast adjustment of local cerebral blood flow. Measuring intracranial flow patterns of the posterior cerebral artery by means or 2 MHz pulsed transcranial Doppler ultrasonography demonstrated that detailed dynamic effects of various visual patterns on local cerebral perfusion can be recorded, and that visual stimuli of different complexity as well as the strategy of stimulus perception cause distinct flow velocity changes in the occipital cortex involved in information processing. This type of on--line analysis may become a powerful tool for detecting fast autoregulatory mechanisms in relation to purely functional cerebral changes.
Blood velocities have been measured transcranially, at small Doppler angles, in the middle cerebral artery of normal volunteers. Cerebral blood flow was changed by varying carbon dioxide tension. In four volunteers, the relationships between arterial pCO2 and percentage change in intensity weighted mean, median, and maximum Doppler-shifted frequencies in the internal carotid and middle cerebral arteries were linear with slopes of 2.5 and 2.8% per mm Hg change in pCO2. In 38 volunteers, the relationship between end-expiratory pCO2 and time-averaged maximum Doppler frequency was linear over the range of pCO2 20-60 mm Hg with slopes of 2.5 and 2.9 percentage change per mm Hg, for internal carotid and middle cerebral, respectively. These results are very similar to those reported using direct methods of measuring cerebral blood flow. As the transcranial Doppler method is reproducible, this indicates that changes in middle cerebral blood velocity may be used to monitor changes in flow.
Correlations between regional cerebral metabolic rates for glucose (rCMRglc), determined by positron emission tomography using 18F-2-deoxy-2-fluoro-D-glucose, provide a measure of the functional associations between brain regions. We compared correlations between ratios of resting rCMRglc to global brain metabolism from 14 healthy autistic men (ages, 18 to 39 years) with those from 14 matched control subjects. The autistic group showed significantly fewer large positive correlations between frontal and parietal regions, particularly those with the left inferior frontal region and its right hemispheric homologue, and significantly lower correlations of the thalamus, caudate nucleus, lenticular nucleus, and insula with frontal and parietal regions, with many correlations negative in the autistic group that were positive in the control group. These results are compatible with functionally impaired interactions between frontal/parietal regions and the neostriatum and thalamus, regions that subserve directed attention.
The dynamics of the metabolic mechanism that regulates cerebral blood flow was studied in 10 normal human subjects using a noninvasive transcranial ultrasonic Doppler method. Flow volume in the posterior cerebral artery, supplying the visual cortex, increased 20.2% in response to light stimulation of the retina, while flow velocity in the same artery increased 16.4%. The regulation of blood flow was very rapid; only 2.3 seconds elapsed from application of the light stimulus to 50% of full response. Full regulation (90% of full response) took 4.6 seconds. The blood flow response adapted slightly after about 10 seconds. Flow velocity in the middle cerebral artery increased significantly, by 3.3%, while flow in the superior cerebellar artery showed no significant change in response to this stimulus. These findings suggest the mechanism of very fast metabolic regulation of cerebral blood flow in humans.
Brain glucose metabolism was measured in 18 autistic children, using high resolution positron emission tomography. Global brain glucose utilization in the autistic population was slightly more elevated than in young adult volunteers but did not differ significantly from that of control children. Regional metabolic maps were also normal, although there was evidence for heterogeneities, particularly at the level of prefrontal and parieto-temporo-occipital association areas: 6 children showed a relative hyperfrontality whilst hypofrontality was found in 2 cases; these heterogeneities were not correlated with clinical symptoms. These data suggest that both the rate and the regional distribution of brain glucose metabolism are normal in autistic children. Variations in terms of relative metabolic rates in association cortex remains to be investigated further.
Electroencephalographic measures of the neurophysiological dysfunction underlying autism have been nonspecific and incomplete. Studies using electroencephalographic methods have been fraught with subject sampling bias, a lack of standardized techniques and measures, and a lack of appropriate control groups. Low-functioning autistic children with age-matched normals, age-matched mentally handicapped, and mentally age-matched normal toddlers were tested using a computerized electroencephalographic technique. The autistic children showed significantly more slow wave activity and less alpha, as well as less inter- and intrahemispheric asymmetry than either normal or mentally handicapped children. In general, electroencephalographic features of autistic children closely resembled those of the toddlers, supporting a model of maturational lag as the key descriptor for autistic CNS functioning. A model of diminished cortical differentiation is proposed to account for the low level of intellectual functioning.
The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic rates (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions.
Neurophysiologic hypotheses of infantile autism fall into two broad categories. One is a caudally directed sequence of pathophysiologic influence originating in telencephalic structures. The other is a rostrally directed sequence of pathophysiologic influence originating in brainstem and diencephalic structures. This paper relates each hypothesis to relevant aspects of autistic behavior, reviews neurophysiologic research relevant to each hypothesis, and describes recently completed studies of vestibular nystagmus, relating these new findings to the brainstem-diencephalic hypothesis. Those studies that delineate subgroups of autistic children are distinguished from those that characterize the entire group of autistic children. Those results that point toward maturational delays are distinguished from those that characterize deviant neurophysiologic abnormalities.
With a split image focusing technique, it has been demonstrated by angiography that the human cerebral arteries dilate rapidly under the influence of Urografin 60%. The effect is most pronounced on the smallest measurable arteries, which have diameters from 0.5 to 1.0 mm, whereas the larger arteries of the more elastic type do not change their diameters significantly. The dilatation of the smallest arteries averages approximately 25%. It is assumed that this dilatation is due to the hypertonicity of the contrast material since a similar dilatation was observed following the injection of a hypertonic solution of glucose (50%). A similar degree of dilatation occurred following CO2 inhalation which elevated the arterial pCO2 to levels around 58 mm Hg and following injections of papaverine (30mg) into the carotid artery. This dilatation of 25% of the arteries with a diameter between 0.5 and 1.0 mm does not represent the maximum possible dilatation since Urografin 60% causes a further small increase in diameter of these pre-dilated arteries. On the other hand, Urografin 60% has nearly its full dilatory effect on arteries which are pre-dilated in a lesser degree with, for instance, a small dose of intravenous papaverine (40 mg).
A group of 36 children with infantile autism and various neurological disorders matched closely on age, sex, and handedness underwent computerized tomographic (CT) scanning of the brain. All CT scans were assessed blindly and independently by a neuroradiologist. Two techniques modified from two published CT studies concerning cerebral asymmetries were used for measuring frontal and parieto-occipital asymmetries. The present study found that the CT pattern of cerebral asymmetries in autistic children is the same as observed in the neurological patients. Contradictory results were noted when the distributions of such asymmetries between the present autistic group and normal adults included in two previous studies were compared. One of the striking findings in this study is that the brains of the present autistic patients seem to be more symmetric than those of the normals. This finding, however, is also noted in the present matched controls as well as in the dyslexic children previously studied by other investigators. Further sophisticated studies are needed to explain the difference in the brain morphology between normals and children with a developmental disorder or a neurological disorder.
Early infantile autism was found to be associated with an atypical pattern of cerebral lateralization. Based on EEG measures of hemispheric activation during cognitive processing, it was found that 7 of the 10 autistic individuals tested showed a pattern of hemispheric specialization rarely seen in the normal population; namely, a “reversal” in lateralization reflective of a lack of left-hemisphere specialization for linguistic functions. Furthermore, the autistic individuals' pattern of cognitive strengths and weakness is suggestive of a selective impairment of the left cerebral hemisphere.
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