Greg Allen

Autism and Abnormal Development of Brain Connectivity

It has been said that people with autism suffer from a lack of “central coherence,” the cognitive ability to bind together a jumble of separate features into a single, coherent object or concept ([Frith, 1989][1]). Ironically, the same can be said of the field of autism research, which all too

A total score for the CERAD neuropsychological battery

Objective: To develop a total or composite score for the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery. Method: CERAD total scores were obtained by summing scores from the individual CERAD subtests (excluding the Mini-Mental State Examination [MMSE]) into a total composite (maximum score = 100). The method of tabulating the total score was constructed using normal controls (NCs; n = 424) and patients with AD (n = 835) from the CERAD registry database. The utility of the total score was further tested in independent samples of mild AD (n = 95), mild cognitive impairment (MCI; n = 60), and NC (n = 95) subjects. Results: The CERAD total score was highly accurate in differentiating NC and AD subjects in the CERAD registry. Age, gender, and education effects were observed, and demographic correction scores were derived through multiple regression analysis. Demographically corrected CERAD total scores showed excellent test-retest reliability across samples (r = 0.95) and were highly correlated with the MMSE (r = 0.89) and Clinical Dementia Rating Scale (r = −0.83) in mixed AD and NC samples and with the Blessed Dementia Rating Scale in an AD sample (r = −0.40). The CERAD total score was highly accurate in differentiating independent samples of NC, MCI, and AD subjects. Conclusion: Results provide support for the validity of a Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total score that can be used along with the normative data to provide an index of overall level of cognitive functioning from the CERAD neuropsychological battery.

Magnetic resonance imaging of cerebellar–prefrontal and cerebellar–parietal functional connectivity

Recent studies of the cerebellum indicated its involvement in a diverse array of functions, and analyses of non-human primate neuroanatomy have revealed connections between cerebellum and cerebral cortex that might support cerebellar contributions to a wider range of functions than traditionally thought. These include cortico-ponto-cerebellar projections originating throughout cerebral cortex, in addition to projections from the dentate nucleus of the cerebellum to prefrontal and posterior parietal cortices via the thalamus. Such projections likely serve as important substrates for cerebellar involvement in human cognition, assuming their analogues are prominent in the human brain. These connections can be examined from a functional perspective through the use of functional connectivity MRI (FCMRI), a technique that allows the in vivo examination of coherence in MR signal among functionally related brain regions. Using this approach, low-frequency fluctuations in MR signal in the dentate nucleus correlated with signal fluctuations in cerebellar, thalamic, limbic, striatal, and cerebrocortical regions including parietal and frontal sites, with prominent coherence in dorsolateral prefrontal cortex. These findings indicate that FCMRI is a useful tool for examining functional relationships between the cerebellum and other brain regions, and they support the findings from non-human primate studies showing anatomic projections from cerebellum to regions of cerebral cortex with known involvement in higher cognitive functions. To our knowledge, this represents the first demonstration of functional coherence between the dentate nucleus and parietal and prefrontal cortices in the human brain, suggesting the presence of cerebellar-parietal and cerebellar-prefrontal functional connectivity.

Cerebellar function in autism: Functional magnetic resonance image activation during a simple motor task

BACKGROUND The cerebellum is one of the most consistent sites of neuroanatomic abnormality in autism, yet it is still unclear how such pathology impacts cerebellar function. In normal subjects, we previously demonstrated with functional magnetic resonance imaging (fMRI) a dissociation between cerebellar regions involved in attention and those involved in a simple motor task, with motor activation localized to the anterior cerebellum ipsilateral to the moving hand. The purpose of the present investigation was to examine activation in the cerebella of autistic patients and normal control subjects performing this motor task. METHODS We studied eight autistic patients and eight matched normal subjects, using fMRI. An anatomic region-of-interest approach was used, allowing a detailed examination of cerebellar function. RESULTS Autistic individuals showed significantly increased motor activation in the ipsilateral anterior cerebellar hemisphere relative to normal subjects, in addition to atypical activation in contralateral and posterior cerebellar regions. Moreover, increased activation was correlated with the degree of cerebellar structural abnormality. CONCLUSIONS These findings strongly suggest dysfunction of the autistic cerebellum that is a reflection of cerebellar anatomic abnormality. This neurofunctional deficit might be a key contributor to the development of certain diagnostic features of autism (e.g., impaired communication and social interaction, restricted interests, and stereotyped behaviors).

Atypical patterns of cerebral motor activation in autism: a functional magnetic resonance study

BACKGROUND Early neurodevelopmental pathogenesis in autism potentially affects emerging functional maps, but little imaging evidence is available. METHODS We studied eight male autistic and eight matched normal subjects, using functional magnetic resonance imaging during visually paced finger movement, compared to a control condition (visual stimulation in the absence of motor response). RESULTS Groupwise analyses showed activation in contralateral perirolandic cortex, basal ganglia, and thalamus, bilateral supplementary motor area, and ipsilateral cerebellum for both groups. However, activations were less pronounced in the autism group. Direct group comparisons demonstrated greater activation in perirolandic and supplementary motor areas in the control group and greater activation (or reduced deactivation) in posterior and prefrontal cortices in the autism group. Intraindividual analyses further showed that strongest activations were consistently located along the contralateral central sulcus in control subjects but occurred in locations differing from individual to individual in the autism group. CONCLUSIONS Our findings, though based on a rather small sample, suggest abnormal individual variability of functional maps and less distinct regional activation/deactivation patterns in autism. The observations may relate to known motor impairments in autism and are compatible with the general hypothesis of disturbances of functional differentiation in the autistic cerebrum.

The cerebellum and non-motor function : clinical implications

The recent demonstration that the human cerebellum is involved in attention operations independent of sensory input or motor output highlights the inadequacy of traditional concepts of cerebellar function, and calls for psychiatrists, neurologists, and neuropsychologists to reconsider the possible contribution of cerebellar abnormalities to disorders characterized by non-motor symptoms.

Functional connectivity between the left and right inferior frontal lobes in a small sample of children with and without reading difficulties.

Individuals with dyslexia often demonstrate bilateral inferior frontal lobe activation while performing basic reading tasks. To investigate these findings, functional connectivity analyses were conducted on fMRI data collected from children with dyslexia, who did and did not respond well to treatment, and from non-impaired readers. Analysis of active and resting-state fMRI data across 15 participants revealed functional connections between the inferior frontal regions in non-impaired readers and treatment responders, but not in treatment non-responders. Analyses incorporating DTI data revealed associations with anterior corpus callosum structures. These results suggest that bilateral frontal functional connectivity is normative and may facilitate treatment response.

Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer's disease: preliminary report.

We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimers disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls.

Neural bases of the foreign accent syndrome: a functional magnetic resonance imaging case study.

Foreign accent syndrome (FAS) is a rare disorder characterized by the emergence of a perceived foreign accent following brain damage. Despite decades of study, little is known about the neural substrates involved in this disorder. In this case study, MRI images of the brain were obtained during a speech task for an American English-speaking monolingual female who presented with FAS of unknown etiology and was thought to sound ‘Swedish’ or ‘Eastern European’. On the basis of MR structural imaging, the patient was noted to have frontal lobe atrophy. An fMRI picture-naming task designed to broadly engage the speech motor network revealed predominantly left-hemisphere involvement, including activation of the (1) left superior temporal and medial frontal structures, (2) bilateral subcortical structures and thalamus, and (3) left cerebellum. The results suggest an instance of substantial brain reorganization for speech motor control.

Differential activation on fMRI of monozygotic twins discordant for AD

This is the first report of fMRI in monozygotic twins discordant for AD. FMRI brain activation patterns were examined during visuospatial and verbal working memory tasks. The affected twin had greater parietal involvement bilaterally during both working memory tasks and reduced left dorsolateral prefrontal cortex activity on the visuospatial memory task. Thus, fMRI may identify additional brain regions recruited in patients with AD to perform a given cognitive task.