Genetic variation in CNTNAP2 alters brain function during linguistic processing in healthy individuals.

Language impairments are a characteristic feature of autism and related autism spectrum disorders (ASDs). Autism is also highly heritable and one of the most promising candidate genes implicated in its pathogenesis is contactin-associated protein-like 2 (CNTNAP2), a gene also associated with language impairment. In the current study we investigated the functional effects of variants of CNTNAP2 associated with autism and language impairment (rs7794745 and rs2710102; presumed risk alleles T and C, respectively) in healthy individuals using functional magnetic resonance imaging (fMRI) during performance of a language task (n = 66). Against a background of normal performance and lack of behavioral abnormalities, healthy individuals with the putative risk allele versus those without demonstrated significant increases in activation in the right inferior frontal gyrus (Broca's area homologue) and right lateral temporal cortex. These findings demonstrate that risk associated variation in the CNTNAP2 gene impacts on brain activation in healthy non-autistic individuals during a language processing task providing evidence of the effect of genetic variation in CNTNAP2 on a core feature of ASDs.

Episodic memory and episodic future thinking impairments in high-functioning autism spectrum disorder: an underlying difficulty with scene construction or self-projection?

OBJECTIVE: There appears to be a common network of brain regions that underlie the ability to recall past personal experiences (episodic memory) and the ability to imagine possible future personal experiences (episodic future thinking). At the cognitive level, these abilities are thought to rely on "scene construction" (the ability to bind together multimodal elements of a scene in mind--dependent on hippocampal functioning) and temporal "self-projection" (the ability to mentally project oneself through time--dependent on prefrontal cortex functioning). Although autism spectrum disorder (ASD) is characterized by diminished episodic memory, it is unclear whether episodic future thinking is correspondingly impaired. Moreover, the underlying basis of such impairments (difficulties with scene construction, self-projection, or both) is yet to be established. The current study therefore aimed to elucidate these issues. METHOD: Twenty-seven intellectually high-functioning adults with ASD and 29 age- and IQ-matched neurotypical comparison adults were asked to describe (a) imagined atemporal, non-self-relevant fictitious scenes (assessing scene construction), (b) imagined plausible self-relevant future episodes (assessing episodic future thinking), and (c) recalled personally experienced past episodes (assessing episodic memory). Tests of narrative ability and theory of mind were also completed. RESULTS: Performances of participants with ASD were significantly and equally diminished in each condition and, crucially, this diminution was independent of general narrative ability. CONCLUSIONS: Given that participants with ASD were impaired in the fictitious scene condition, which does not involve self-projection, we suggest the underlying difficulty with episodic memory/future thinking is one of scene construction.

White matter correlates of cognitive dysfunction after mild traumatic brain injury.

OBJECTIVE: To relate neurophysiologic changes after mild/moderate traumatic brain injury to cognitive deficit in a longitudinal diffusion tensor imaging investigation. METHODS: Fifty-three patients were scanned an average of 6 days postinjury (range = 1-14 days). Twenty-three patients were rescanned 1 year later. Thirty-three matched control subjects were recruited. At the time of scanning, participants completed cognitive testing. Tract-Based Spatial Statistics was used to conduct voxel-wise analysis on diffusion changes and to explore regressions between diffusion metrics and cognitive performance. RESULTS: Acutely, increased axial diffusivity drove a fractional anisotropy (FA) increase, while decreased radial diffusivity drove a negative regression between FA and Verbal Letter Fluency across widespread white matter regions, but particularly in the ascending fibers of the corpus callosum. Raised FA is hypothesized to be caused by astrogliosis and compaction of axonal neurofilament, which would also affect cognitive functioning. Chronically, FA was decreased, suggesting myelin sheath disintegration, but still regressed negatively with Verbal Letter Fluency in the anterior forceps. CONCLUSIONS: Acute mild/moderate traumatic brain injury is characterized by increased tissue FA, which represents a clear neurobiological link between cognitive dysfunction and white matter injury after mild/moderate injury.

Spatial navigation impairments among intellectually high-functioning adults with autism spectrum disorder: exploring relations with theory of mind, episodic memory, and episodic future thinking.

Research suggests that spatial navigation relies on the same neural network as episodic memory, episodic future thinking, and theory of mind (ToM). Such findings have stimulated theories (e.g., the scene construction and self-projection hypotheses) concerning possible common underlying cognitive capacities. Consistent with such theories, autism spectrum disorder (ASD) is characterized by concurrent impairments in episodic memory, episodic future thinking, and ToM. However, it is currently unclear whether spatial navigation is also impaired. Hence, ASD provides a test case for the scene construction and self-projection theories. The study of spatial navigation in ASD also provides a test of the extreme male brain theory of ASD, which predicts intact or superior navigation (purportedly a systemizing skill) performance among individuals with ASD. Thus, the aim of the current study was to establish whether spatial navigation in ASD is impaired, intact, or superior. Twenty-seven intellectually high-functioning adults with ASD and 28 sex-, age-, and IQ-matched neurotypical comparison adults completed the memory island virtual navigation task. Tests of episodic memory, episodic future thinking, and ToM were also completed. Participants with ASD showed significantly diminished performance on the memory island task, and performance was positively related to ToM and episodic memory, but not episodic future thinking. These results suggest that (contra the extreme male brain theory) individuals with ASD have impaired survey-based navigation skills--that is, difficulties generating cognitive maps of the environment--and adds weight to the idea that scene construction/self-projection are impaired in ASD. The theoretical and clinical implications of these results are discussed.

The neural basis of familial risk and temperamental variation in individuals at high risk of bipolar disorder.

BACKGROUND: Bipolar disorder is a highly heritable psychiatric disorder characterized by episodic elevation or depression of mood. Bipolar disorder is associated with structural and functional brain abnormalities but it is unclear whether these are present in relatives of affected individuals and if they are associated with subclinical symptoms or traits associated with the disorder. METHODS: Functional magnetic resonance imaging scans were conducted on 93 unrelated relatives of bipolar disorder patients and 70 healthy comparison subjects performing the Hayling sentence completion paradigm. Examination of comparison subjects versus high-risk individuals was followed by assessments of associations with depression scores and measures of cyclothymic temperament. RESULTS: Examination of comparison subjects versus high-risk subjects revealed increased activation in the high-risk group in the left amygdala. No interaction effects were observed between the groups for scores of depression or cyclothymia and activation in any region. Significant associations were found across the groups with depression ratings and activation in the ventral striatum and with cyclothymia and activation in ventral prefrontal regions, however no interaction effects were observed between the groups. CONCLUSIONS: Differences in activation in the left amygdala in those at familial risk may represent a heritable endophenotype of bipolar disorder. Activation in striatal and ventral prefrontal regions may, in contrast, represent a distinct biological basis of subclinical features of the illness regardless of the presence of familial risk.

White matter integrity in individuals at high genetic risk of bipolar disorder.

BACKGROUND: Bipolar disorder is a familial psychiatric disorder associated with reduced white matter integrity, but it is not clear whether such abnormalities are present in young unaffected relatives and, if so, whether they have behavioral correlates. We investigated with whole brain diffusion tensor imaging whether increased genetic risk for bipolar disorder is associated with reductions in white matter integrity and whether these reductions are associated with cyclothymic temperament. METHODS: Diffusion tensor imaging data of 117 healthy unaffected relatives of patients with bipolar disorder and 79 control subjects were acquired. Cyclothymic temperament was measured with the cyclothymia scale of the Temperament Evaluation of Memphis, Pisa and San Diego auto-questionnaire. Voxel-wise between-group comparisons of fractional anisotropy (FA) and regression of cyclothymic temperament were performed with tract-based spatial statistics. RESULTS: Compared to the control group, unaffected relatives had reduced FA in one large widespread cluster. Cyclothymic temperament was inversely related to FA in the internal capsules bilaterally and in left temporal white matter, regions also found to be reduced in high-risk subjects. CONCLUSIONS: These results show that widespread white matter integrity reductions are present in unaffected relatives of bipolar patients and that more localized reductions might underpin cyclothymic temperament. These findings suggest that white matter integrity is an endophenotype for bipolar disorder with important behavioral associations previously linked to the etiology of the condition.