The experience of agency, i.e., the registration that I am the initiator of my actions, is a basic and constant underpinning of our interaction with the world. Whereas several accounts have underlined predictive processes as the central mechanism (e.g., the comparator model by C. Frith), others emphasized postdictive inferences (e.g., post-hoc inference account by D. Wegner). Based on increasing evidence that both predictive and postdictive processes contribute to the experience of agency, we here present a unifying but at the same time parsimonious approach that reconciles these accounts: predictive and postdictive processes are both integrated by the brain according to the principles of optimal cue integration. According to this framework, predictive and postdictive processes each serve as authorship cues that are continuously integrated and weighted depending on their availability and reliability in a given situation. Both sensorimotor and cognitive signals can serve as predictive cues (e.g., internal predictions based on an efferency copy of the motor command or cognitive anticipations based on priming). Similarly, other sensorimotor and cognitive cues can each serve as post-hoc cues (e.g., visual feedback of the action or the affective valence of the action outcome). Integration and weighting of these cues might not only differ between contexts and individuals, but also between different subject and disease groups. For example, schizophrenia patients with delusions of influence seem to rely less on (probably imprecise) predictive motor signals of the action and more on post-hoc action cues like e.g., visual feedback and, possibly, the affective valence of the action outcome. Thus, the framework of optimal cue integration offers a promising approach that directly stimulates a wide range of experimentally testable hypotheses on agency processing in different subject groups.

The experience of being the initiator of one's own actions seems to be infallible at first glance. Misattributions of agency of one's actions in certain neurological or psychiatric patients reveal, however, that the central mechanisms underlying this experience can go astray. In particular, delusions of influence in schizophrenia might result from deficits in an inferential mechanism that allows distinguishing whether or not a sensory event has been self-produced. This distinction is made by comparing the actual sensory information with the consequences of one's action as predicted on the basis of internal action-related signals such as efference copies. If this internal prediction matches the actual sensory event, an action is registered as self-caused; in case of a mismatch, the difference is interpreted as externally produced. We tested the hypothesis that delusions of influence are based on deficits in this comparator mechanism. In particular, we tested whether patients’ impairments in action attribution tasks are caused by imprecise predictions about the sensory consequences of self-action. Schizophrenia patients and matched controls performed pointing movements in a virtual-reality setup in which the visual consequences of movements could be rotated with respect to the actual movement. Experiment 1 revealed higher thresholds for detecting experimental feedback rotations in the patient group. The size of these thresholds correlated positively with patients’ delusions of influence. Experiment 2 required subjects to estimate their direction of pointing visually in the presence of constantly rotated visual feedback. When compared to controls, patients’ estimates were significantly better adapted to the feedback rotation and exhibited an increased variability. In interleaved trials without visual feedback, i.e. when pointing estimates relied solely on internal action-related signals, this variability was likewise increased and correlated with both delusions of influence and the size of patients’ detection thresholds as assessed in the first experiment. These findings support the notion that delusions of influence are based on imprecise internal predictions about the sensory consequences of one's actions. Moreover, we suggest that such imprecise predictions prompt patients to rely more strongly on (and thus adapt to) external agency cues, in this case vision. Such context-dependent weighted integration of imprecise internal predictions and alternative agency cues might thus reflect the common basis for the various misattributions of agency in schizophrenia patients.

The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.

Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot–Marie–Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.