FRONTOSTRIATAL CIRCUITS are neural pathways that connect frontal lobe regions with the basal ganglia (striatum) that mediate motor, cognitive, and behavioural functions within the brain and thus modulate information processing. Control of executive functions include: selection and perception of important information, manipulation of information in working memory, planning and organization, behavioral control, adaptation to changes, and decision making.
These circuits originate in the prefrontal cortex and project to the striatum followed by globus pallidus and substantia nigra and finally to the thalamus. There are also feedback loops from thalamus back to the prefrontal cortex completing closed loop circuits. Also, there are open connections to these circuits integrating information from other areas of the brain.
There are five defined frontostriatal circuits: motor and oculomotor circuits originating in the frontal eye fields are involved in motor functions; while dorsolateral prefrontal, orbital frontal, and anterior cingulate circuits are involved in executive functions, social behavior and motivational states. These five circuits share same anatomical structures.
It was found that self-esteem is related to the connectivity of frontostriatal circuits, suggesting that feelings of self-worth may emerge from neural systems which integrate information about the self with positive affect and reward.
These circuits are involved in neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease as well as neuropsychiatric disorders including schizophrenia, depression, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and autism.
Ventromedial prefrontal circuit. Connects the pre-frontal cortex to the ventral striatum and amygdala and is important in affective-emotional processing. They are responsible for the elaboration of the plan of actions responsible for goal-directed behavior.
Eye movement circuit. Connects the prefrontal cortex and anterior cingulate cortex for the cognitive control of attention and eye movements, while striatum and brainstem initiate the eye movements.
Dorsolateral prefrontal circuit.This circuit is important in executive functions including complex problem solving, learning new information, planning ahead, recalling remote memories, responding with appropriate behavior, and chronological ordering of events.
Orbital frontal circuit. This circuit connects the frontal monitoring systems to the limbic system. Dysfunction of this circuit often results in personality change including behavioral disinhibition, emotional lability, aggressive outbursts, poor judgment, and lack of interpersonal sensitivity.
Anterior cingulate circuit. This circuit mediates motivated behavior, response selection, error detection, performance, and competition monitoring, working memory, and novelty detection. Dysfunction in this circuit leads to decreased motivation including prominent apathy, indifference to pain, thirst or hunger, lack of spontaneous movements, and verbalization.
SENSORIMOTOR GATING is the normal protective mechanism in the brain by which a neural system screens or ‘gates’ irrelevant external (sensory) and internal (cognitive, motor) information from higher-order processing. This prevents information overload, the misinterpretation of sensory information, and facilitates mental and behavioral integration. This enables coherent thought – the uninterrupted processing of the most salient aspects of the external and internal environment.
Filtering out relevant from irrelevant information is deficient in multiple neuropsychiatric disorders including autism and Asperger’s syndrome, schizophrenia and obsessive-compulsive disorder.
Prepulse inhibition (PPI) is a measure of sensorimotor gating, in which response, or startle, to a stimulus (pulse) is diminished when the stimulus is preceded by a smaller stimulus (prepulse). Disruption of this normal inhibition of startle is consistent with deficient sensorimotor gating.
An important mechanism involved in regulating sleep is sensory gating. In mammals, the thalamus is thought to gate sensory input, such that sensory information is processed at a subcortical level during sleep and wakefulness. Such mechanisms would protect sleep continuity as stimuli from minor noises would be filtered out and not reach the cortex to disturb sleep.
Schizophrenia. A key cognitive symptom in patients with schizophrenia is impaired sensroy gating, defined as reduced ability to suppress processing of irrelevant and uninformative sensory input. “Sensory gating” is said to be the central event in explaining the underlying pathophysiology of delusions and hallucinations in schizophrenia. It is measured by PPI in which the prepulse is thought to evoke inhibitory mechanisms that limit response to further stimulation until the stimulation is fully processed.
Obsessive-Compulsive Disorder (OCD) is a severe, chronic psychiatric disorder with 2–3% prevalence worldwide. Sensorimotor gating as measured by prepulse inhibition (PPI) is abnormal in OCD. Obsessions are thought to arise from the inability to inhibit undesired thoughts and images, and compulsions from the inability to inhibit repetitive acts or reactions to uncontrollable obsessive thoughts.
Asberger’s Syndrome
Abstract
Asperger’s syndrome (an autistic disorder) is characterized by stereotyped and obsessional behaviours, and pervasive abnormalities in socio‐emotional and communicative behaviour. These symptoms lead to social exclusion and a significant healthcare burden; however, their neurobiological basis is poorly understood.
There are few studies on brain anatomy of Asperger’s syndrome, and no focal anatomical abnormality has been reliably reported from brain imaging studies of autism, although there is increasing evidence for differences in limbic circuits. These brain regions are important in sensorimotor gating, and impaired ‘gating’ may partly explain the failure of people with autistic disorders to inhibit repetitive thoughts and actions.
Thus, we compared brain anatomy and sensorimotor gating in healthy people with Asperger’s syndrome and controls. We included 21 adults with Asperger’s syndrome and 24 controls. All had normal IQ and were aged 18–49 years. We studied brain anatomy using quantitative MRI, and sensorimotor gating using prepulse inhibition of startle in a subset of 12 individuals with Asperger’s syndrome and 14 controls.
We found significant age‐related differences in the volume of cerebral hemispheres and caudate nuclei. Controls, but not people with Asperger’s syndrome, had age‐related reductions in volume. Also, people with Asperger’s syndrome had significantly less grey matter in frontostriatal and cerebellar regions than controls, and widespread differences in white matter.
Moreover, sensorimotor gating was significantly impaired in Asperger’s syndrome. People with Asperger’s syndrome most likely have generalized alterations in brain development, but this is associated with significant differences from controls in the anatomy and function of specific brain regions implicated in behaviours characterizing the disorder. We hypothesize that Asperger’s syndrome is associated with abnormalities in fronto‐striatal pathways resulting in defective sensorimotor gating, and consequently characteristic difficulties inhibiting repetitive thoughts, speech and actions.
Developmental disorders that lie on the autistic spectrum, including the genetically related subtypes of classical autism and Asperger’s syndrome, are characterized by stereotyped and obsessional behaviours, and pervasive abnormalities in socio‐emotional and communicative behaviour. Individuals with classical autism have delayed language development, and most have mental retardation (learning disability). Individuals with Asperger’s syndrome have no history of language delay and have normal or superior intellectual abilities, but still show characteristic impairments in reciprocal social interaction. Thus, in Asperger’s syndrome, there is the dissociation between cognitive and social skills. However, the neurobiological determinants of the behavioural phenotype of Asperger’s syndrome are poorly understood.
In one of the very few studies of Asperger’s syndrome, Abell et al. (1999) investigated grey matter differences between a group of adults with Asperger’s and matched controls. They noted grey matter anomalies in the cerebellum, and in medial temporal and frontal lobe structures. These findings fit broadly with a growing consensus that limbic system and cerebellar abnormalities may be important determinants of autism. For example, Damasio and Maurer (1978) suggested that developmental abnormalities in a limbic circuit comprising medial prefrontal cortex and temporal lobe, striatum and limbic thalamus underlie autism. This theory has been supported by studies reporting: delayed metabolic maturation and dysfunction of frontal and temporal circuitry; decreased correlated metabolic activity between frontal‐parietal and cortical‐subcortical regions; and volume differences in fronto‐temporal regions and caudate nuclei. We therefore restricted the present study to adults with Asperger’s syndrome to clarify neuroanatomical changes in an autistic spectrum disorder uncomplicated by confounds of IQ.
The limbic circuitry, proposed by some as the biological substrate of autism, plays an important role in sensorimotor gating. We use this mechanism to supress motor responses to irrelevant stimuli, and it is possible that similar processes underlie cognitive gating. A measure of sensorimotor gating is prepulse inhibition of startle (PPI), in which the startle response to a strong stimulus is muted or inhibited when momentarily preceded by a weak stimulus (the prepulse). We hypothesized that people with an autistic spectrum disorder may have defective sensorimotor gating, reflecting their characteristic inability to inhibit or ‘gate’ repetitive thoughts, speech and actions. However, to date, there have been no studies using PPI in adults with Asperger’s syndrome.
Thus there is evidence that people with an autistic spectrum disorder may have abnormalities in brain anatomy, including regions responsible for sensorimotor gating. However, there are relatively few studies of healthy, non‐learning disabled people who lie on this spectrum. We therefore used quantitative MRI in what we believe to be the first comprehensive study of brain anatomy in unmedicated, intellectually able adults with Asperger’s syndrome and healthy controls of comparable age, IQ, gender and handedness. We also carried out a pilot study of sensorimotor gating using PPI. We hypothesized that people with Asperger’s syndrome would have differences in the anatomy and function of limbic circuitry.
Discussion
We believe that this is the first study to quantify MRI differences in both regional brain volumes and grey and white matter volumes in Asperger’s syndrome and to investigate age-related differences in these parameters. Similar to others (Courchesne et al., 1999), we found that megaloencephaly is not a universal feature of autistic spectrum disorders, and we detected no bulk regional brain volume differences between Asperger’s syndrome and controls using manual tracing. Past reports of megaloencephaly in autism may therefore reflect an effect of disease severity (e.g. mental retardation) that is not evident in the Asperger’s sample we studied. We also found that age‐related differences in whole brain and grey matter volume in the controls were not evident in people with Asperger’s syndrome. The reason for this is unknown, but may include neurodevelopmental differences in neurogenesis and programmed cell death.
Our main findings were that people with Asperger’s syndrome had significant reductions in grey matter volume of frontostriatal and cerebellar regions. In addition, people with Asperger’s syndrome had white matter excesses bilaterally around the basal ganglia, whereas they had deficits mainly in the left hemisphere. The concentration of abnormalities in frontostriatal circuitry we observed most likely has functional consequences. PPI is thought to depend in part on intact fronto‐striatal pathways, and we report for the first time a significant impairment in sensorimotor gating in Asperger’s syndrome.
Fronto‐striatal systems in Asperger’s syndrome. Our finding of reduced grey matter in the medial frontal lobe of people with Asperger’s syndrome is in agreement with other neuroanatomical studies of autism. In contrast, a recent MRI study of basal ganglia size in autism found that volume of the caudate nucleus was increased in subjects with autism and this increase was proportional to an increase in total brain volume. However, we observed a reduction in grey matter in the basal ganglia in people with Asperger’s syndrome and no increase in caudate or whole-brain volume. Important differences between our studies may explain these disparate findings. The Sears et al. (1999) study included children and adults with performance IQs ranging from 52 to 136; the control group had IQs >70. We only studied adults with an IQ >75, and we also identified significant age‐related differences in brain anatomy between people with Asperger’s and controls. Thus our results may differ due to the specific population we studied, in addition to confounds introduced by age and IQ.
Frontal and striatal brain regions are reciprocally connected to each other and the thalamus proposed that dysfunction in a system incorporating the basal ganglia and mesial frontal lobe is responsible for the clinical symptoms of autism, including motor disturbances such as dystonia, bradykinesia and hyperkinesias, and impaired social communication. Their model also predicted temporal lobe abnormalities in autism. Although we did not identify grey matter deficits in the temporal lobe at the level of significance we adopted, we did observe extensive white matter deficits in the left temporal lobe. Ours is the first study to report abnormalities in the anatomy of this entire neural system in people with an autistic spectrum disorder, and we suggest that our anatomical findings are consistent with Damasio and Maurer’s model.
The fronto‐striatal regions we identified as abnormal are known to have intimate and reciprocal links with the cerebellum, and the cerebellum has been implicated in higher-order cognitive functions, including executive functions such as planning and shifting attention. Thus, the anomalies we found within the cerebellum, a region anatomically and functionally related to the basal ganglia and frontal cortex, are not surprising. Our study, therefore, lends tentative support for the hypothesis that abnormalities in the cerebellum may be related to the behavioural phenotype of people with an autistic spectrum disorder, but in our view cerebellar pathology may best be viewed in the context of system‐wide pathology, rather than in isolation.
Sensorimotor gating in Asperger’s syndrome. There is consensus that alterations in fronto‐striatal regions (as found in our study of people with Asperger’s syndrome) underlie impaired sensorimotor gating in a range of neuropsychiatric conditions such as obsessive compulsive disorder, Huntington’s disease, Tourette’s syndrome, and schizophrenia spectrum disorders. The argument is perhaps most persuasive for Huntington’s disease, as this is associated with significant damage to the caudate nucleus. Recent functional imaging data support this position, with activation in the prefrontal cortex and caudate nuclei being observed during PPI in healthy individuals. We suggest that the reduction in grey matter volume of fronto‐striatal regions we identified in people with Asperger’s may also explain our finding of impaired PPI in this group. Our findings are unlikely to be explained by differences in schizotypal traits, as the control and Asperger’s groups were comparable in this regard.
We explored PPI in a population of intellectually able, healthy, adult men with Asperger’s and found significant impairment of PPI in the 120 ms/16 db condition. Again, we may find differences where others do not due to differences in our study populations.
The occurrence of sensorimotor gating abnormalities in a number of disorders, as noted above, could simply mean that PPI is a task sensitive to fronto‐striatal damage, but differences may not be specific to Asperger’s syndrome.
However, sensorimotor gating deficits in autism may reflect similar difficulties with cognitive gating, rendering the individual unable to inhibit or ‘gate’ the repetitive thoughts, speech and actions characteristic of the disorder. The subsequent information ‘overload’ may lead to higher cognitive difficulties, such as executive function and ‘theory of mind’ (ToM) abnormalities, reported by others in autism.
ToM and executive function accounts of autism together explain quite well the socio‐communicative and flexibility problems in this disorder. However, neither account can explain why people with autism are so good at certain tasks.
Autism presents a strikingly uneven cognitive profile, with typical peaks on Wechsler block design and digit span. One theoretical account of autism attempts to explain these skills in terms of a bias towards featural versus configural processing. This cognitive style of ‘weak central coherence’ is demonstrated through success of individuals with autism on tasks favouring detail focus, and relative inability on tasks requiring processing of information in context for global form or meaning. Impaired sensorimotor gating permits stimuli indiscriminate access to response output systems without regard for the context of presentation. This is reflected in reduced PPI: the startle response to a given stimulus is not modulated by preceding stimuli. Conceivably, the stimulus which elicits inappropriate startle has been subject to a form of featural processing. We therefore suggest that abnormal gating may contribute to the physiological basis of weak central coherence in autistic spectrum disorders.
White matter deficits and excesses in Asperger’s syndrome. We found widespread white matter anomalies in the brain of people with Asperger’s syndrome; indeed white matter projections to and from abnormal grey matter structures might be expected to be deviant. However, while white matter excesses were distributed bilaterally, deficits appeared to be more prominent in the left hemisphere. This hemisphere normally develops later than the right and, perhaps as a consequence of evolving speech pathways, fronto‐temporal pathways reach maturation later than those linking lower order regions. Thus neuro‐developmental delay in autism may particularly impact on the left hemisphere and consequently explain some of the developmental language anomalies found in the disorder. For example, we found significant fronto‐temporal white matter deficits in people with Asperger’s syndrome, including the left superior temporal lobe speech area.
Courchesne et al. (2001) recently investigated developmental changes in grey and white matter volume in autistic boys. They noted that expanded white matter volumes in 2–3 year old children with autism were not found in adolescents with autism. In conjunction with the present findings, this suggests that the autistic brain matures differently, and has a complex and anomalous trajectory affecting both brain development and aging. Courchesne’s group of autistic children had IQs ranging from 36 to 122, while the control group had IQs in the normal range, so it is unclear to what extent the presence of learning disability impacted on their results. Clearly the question of structural brain changes throughout the lifespan of autistic individuals deserves further investigation in well‐matched groups.
Conclusions
We found that, compared with controls, people with Asperger’s syndrome have age‐related differences in brain anatomy, structural abnormalities in fronto‐striatal systems and the cerebellum, and impaired sensorimotor gating. We suggest that Asperger’s syndrome probably arises from a generalized abnormality in brain development (causing widespread white matter abnormalities). This neurodevelopmental abnormality may, in turn, be modulated by environmental factors such as social isolation. Some regions are more affected than others, and our findings support the hypothesis that a proportion of autistic symptomatology may be explained by frontostriatal disorder. Further studies are required to examine changes in brain anatomy and function across the lifespan, and to explore their relationship to the behavioural phenotype in people with Asperger’s syndrome.
