Date Published: August 13, 2012
Publisher: BioMed Central
Author(s): Laura E Downey, Colin J Mahoney, Martin N Rossor, Sebastian J Crutch, Jason D Warren.
An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as an important cause of frontotemporal dementia and motor neuron disease; however, the phenotypic spectrum of this entity and its pathophysiologic basis have yet to be fully defined. Psychiatric features may be early and prominent, although a putative cortico-thalamo-cerebellar network has been implicated in the pathogenesis of the clinical phenotype. Differentiation of self from others is a core cognitive operation that could potentially link network disintegration with neuropsychiatric symptoms in C9ORF72-associated frontotemporal dementia.
We undertook a detailed behavioral analysis of self-other attribution in a 67-year-old male patient with behavioral variant frontotemporal dementia (bvFTD) due to the C9ORF72 expansion by using a novel paradigm requiring differentiation of the effects of self- and non-self-generated actions. The patient’s performance was assessed in relation to two older male patients with bvFTD not attributable to the C9ORF72 expansion and four healthy older male subjects.
Compared with the healthy control group, the patient with the C9OFR72 mutation showed a deficit of self-other differentiation that was disproportionate to his otherwise relatively indolent clinical phenotype. The performance of the other patients with bvFTD was similar to that of healthy subjects.
We propose that impaired self-other differentiation is a candidate mechanism for neuropsychiatric decline in association with the C9ORF72 expansion. We offer this preliminary observation as a stimulus to further work.
An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as an important cause of frontotemporal dementia and motor neuron disease [1-3]; however, the phenotypic spectrum of this entity and its pathophysiologic basis have yet to be fully defined. Psychiatric manifestations including delusions, hallucinations, and severe anxiety disorders have been identified as frequent and prominent and may be presenting features [1,3,4]. Although detailed neuroanatomic-phenotypic correlation has yet to be undertaken in the C9ORF72 mutation spectrum, a culprit cortico-thalamo-cerebellar network has been identified as a potential substrate for certain clinical features, in particular, for neuropsychiatric symptoms . Differentiation of self from others is a core cognitive operation that could potentially link network disintegration with neuropsychiatric symptoms in C9ORF72-associated frontotemporal dementia. Disordered self-other differentiation has been implicated in the pathogenesis of various psychiatric conditions, including schizophrenia, out-of-body autoscopic experiences, anxiety, and depression [5-8]. Neuroimaging evidence in the healthy brain suggests that the cerebellum is a key component of distributed cortico-subcortical circuitry that represents and calibrates the effects of actions generated by oneself and others [5,9].
Results on the experimental behavioral test are summarized in Table 1. Compared with healthy controls, NT exhibited a significant deficit of self-other differentiation over all experimental conditions (t5 = -3.48; P < 0.021). Analyses of the three experimental conditions separately revealed that NT's performance was flawless for attribution of self-generated actions, whereas he performed significantly worse than healthy controls for attribution of both synchronous, non-self-generated actions (t5 = -4.05; P < 0.008) and asynchronous, non-self-generated actions (t5 = -5.5, P < 0.001). NT's errors were therefore entirely overattributions of the experimenter's actions on non-self trials as self-generated responses. Like NT, patients DC1 and DC2 correctly attributed all self-generated actions. However, in contrast to NT, DC1 and DC2 showed no significant differences in performance relative to healthy controls on either of the non-self conditions (DC1: overall t5 = 0.12, synchronous t5 = 0.45, asynchronous t5 = -0.78; DC2: overall t5 = -0.36, synchronous t5 = -1.34, asynchronous t5 = 0.78; all P > 0.05), and each patient’s performance fell within the control range for every condition.
It is evident from the range of scores (Table 1) that healthy controls and patients alike performed generally rather poorly on the synchronous non-self condition; performance differences were exposed largely in the asynchronous condition. This pattern of results suggests that the experimenter was able to control accurately the degree to which the external stimulus simulated (or did not simulate) the effect of a self-generated action.
Here we have shown that differentiation of the effects of one’s own versus others’ actions may become impaired in frontotemporal dementia associated with the C9ORF72 expansion. Indeed, the deficit of self-other differentiation appeared disproportionate to NT’s otherwise relatively mild cognitive phenotype. As this patient’s cognitive evolution was otherwise so indolent, we hypothesize that impaired self-other differentiation may be a key feature in the development of the complex behavioral disturbances that accompany the C9ORF72 expansion, or may to lead the development of more-typical cognitive deficits. The specificity of this finding for C9ORF72-associated frontotemporal dementia remains to be resolved. However, the present data suggest that the ability to distinguish one’s own from others’ actions is not comparably affected in other forms of frontotemporal dementia (including MAPT-associated disease); nor does it appear to be simply a consequence of more severe disease, as DC1 and DC2 were both substantially more cognitively impaired than was NT. Together, these findings raise the possibility that impaired self-other differentiation is a behavioral signal of C9ORF72 mutations. It is of interest that NT tended to “overattribute” others’ actions to his own agency. A similar overattribution bias to self for actions of ambiguous origin has been reported both in healthy individuals [12,13] and in schizophrenia . Both healthy controls and the two patients without the C9ORF72 expansion here made self-overattribution errors in the synchronous non-self condition, but (unlike NT) were able to use the increased temporal delay in the non-self asynchronous condition to identify the external origin of the action. Although the overattribution to self of external actions may seem somewhat paradoxic in a condition such as schizophrenia with delusions of external control, it has been argued  that such a deficit might lead to an impaired ability to model one’s own versus others’ actions and an abnormal sense of invasion by external forces masquerading as oneself.
BPVS: British Picture Vocabulary Scale; bvFTD: behavioral variant frontotemporal dementia; CBI: Cambridge Behavioural Inventory; D-KEFS: Delis-Kaplan Executive Function System; DS: digit span; GNT: Graded Naming Test; MRI: magnetic resonance imaging; NART: National Adult Reading Test; PIQ: Performance Intelligence Quotient; RMT: Recognition Memory Test; VIQ: Verbal Intelligence Quotient; VOSP: Visual Object and Space Perception; WASI: Wechsler Abbreviated Scale of Intelligence.
We have no financial competing interests to declare. LED, CJM, SJC, and JDW receive salary and research support from the Medical Research Council, Alzheimer Research UK, and the Wellcome Trust. MNR sits on the Data Monitoring Committee for Servier DMC Phase 2B AD Study S38093, and also sits on the Bapineuzumab Independent Safety Monitoring Committee for Janssen Al/Pfizer.
All authors read and approved the manuscript. LED was involved in study planning, design, and coordination, acquired and analyzed the behavioral data, and was involved in drafting and critically revising the article. CJM was involved in study design, acquisition of neuroimaging data, and drafting and critically revising the article. MNR assessed the patients clinically and was involved in study design and in drafting the article. SJC and JDW obtained funding for and supervised the study, and were involved in study planning and design, in data collection, and in drafting and critically revising the article.