Cerebellar Connectivity and Glutamatergic Metabolite Concentration in ASD As Assessed By fcMRI/MRS

Background:  Cerebellar pathology is observed in ASD.  Atypical cortico-cerebellar functional connectivity has also recently been reported in ASD.  Furthermore, several lines of evidence have suggested atypical excitatory-to-inhibitory (E/I) balance in ASD, with an imbalance between glutamate and GABA, observed in brain regions including the cerebellum.  

Objectives:  We examined the relationship between E/I balance using magnetic resonance spectroscopy (MRS) and functional integrity of cerebrocerebellar connections in ASD for language-associated cerebellar regions and their cortical projections.

Methods:  Twelve adults with ASD and 12 gender, age, and IQ -matched controls participated.  Social communication was assessed with the Social Responsiveness Scale (SRS), maladaptive behaviors with the Aberrant Behavior Checklist (ABC), and language competence with the Test of Language Competence (TLC).  MRI was performed at 3T and BOLD sequences were collected at rest. Functional connectivity (FC) analyses were performed with conservative motion correction. Single voxel spectroscopy spin-echo sequences were used to detect glutamate, and J-coupling edited sequences were used to detect GABA. Voxels were localized in each participant in the right postereolateral cerebellar hemisphere junction of crus I&II (RCere) and the left dorsolateral prefrontal cortex (LDLPFC). Metabolite levels were quantified with LCModel. 

Results:  ASD participants were impaired on the SRS, ABC, and TLC.  Within the ASD group, LDLPFC-RCere connectivity was associated with listening comprehension (r=0.588, p=0.027).  Furthermore, RCere-LFLPFC FC was significantly associated with RCere E/I, regardless of diagnosis.

Conclusions:  Significant variability exists in the literature regarding FC and MRS of glutamate and GABA in ASD.  Our data suggests connectivity and pharmacopathology may be interrelated in ASD.  Furthermore, this may relate to behavior, as FC to the portion of the cerebellum most involved with language was related to language comprehension performance.  Future studies will need to explore whether these might serve as markers for or predictors of response to pharmacological agents targeting E/I balance in ASD.