To our knowledge, this is the largest study to examine movement abnormalities in a prodromal population, and the first to explore relationships between these movements and neurocognition. As predicted, there were significant negative associations between hyperkinetic movements and neuropsychological performance, and the combined sets of movement and neurocognitive markers showed good discriminative power when classifying those high-risk participants most in need of intervention. Taken together, results suggest that these domains share common neurological underpinnings.
This pattern is consistent with a “two hit” model, suggesting that a disruption of neurodevelopment increases the risk for developing schizophrenia (58
). As movement abnormalities are observable during early childhood in individuals who later go on to develop schizophrenia (23
), they are thought to be indicative of a constitutional vulnerability (60
). Specifically, hyperkinetic movements are believed to reflect abnormal striatal dopamine activity, resulting in reduced basal ganglia output to the thalamus and disinhibition of the thalamocortical neurons (16
). Indeed, investigators observed that signs of neuromotor impairment are associated with significant grey matter reductions in subcortical structures comprising the basal ganglia (61
). Because heightened striatal DA also characterizes schizophrenia (62
), and abnormal movements have been found to increase in severity during prodromal adolescence (63
), it is possible that hyperkinetic movements reflect an interaction between early basal ganglia dysfunction and later neural maturational processes (27
Present results support the idea that movement abnormalities and neurocognitive deficits in high-risk populations may be modulated to some degree by common underlying mechanisms. Notably, movement abnormalities were associated with deficits in several domains of neurocognitive function including verbal comprehension, perceptual organization, and based on these combined variables, the estimated FSIQ. Because the striatum serves as a connection point for pathways leading from the basal ganglia to the cortex (33
), dysfunction in this region may contribute to irregular movement behaviors as well as an array of cognitive dysfunction ranging from processes primarily regulated by the striatum (e.g., processing novel stimuli, signal preparation for or initiation of behavioral responses), to those governed by the prefrontal cortex (64
It should be noted that to date, there have only been a small number of studies that report relationships between cognition and movement in psychotic disorders. One possibility to consider is that a file door effect (where non significant findings are not published) may be contributing to the limited published support. Despite the limited extant direct support, there are several converging lines of research that do suggest such a relationship. For example, a study examining motor functioning abnormalities in a sample with schizotypal personality disorder, found that variable motor force was correlated with preservative responses on a card-sorting task (66
). D’Reaux and colleagues (67
) found that motor function (assessed via finger tapping) was strongly correlated with working memory performance in patients with schizophrenia. Further, researchers have also observed relationships between finger taping and social cognition (68
), as well as basal ganglia volumes (69
). In a relevant cohort study, researchers reported that delays in infant motor development were associated with adult cognition in the domains of executive function, verbal learning, and spatial memory in patients who developed schizophrenia in adulthood (70
). Finally, there is also evidence to suggest that oculomotor abnormalities (indicative of dysfunction in basal ganglia loops) are correlated with cognitive deficits in patients with schizophrenia (71
As noted, discrete cortico-striato-pallido-thalamic circuits act as a powerful regulator of different aspects of neurocognitive function (18
). Within these distinct circuits, DA moderates cognitive function, and altering of transmission could contribute to specific cognitive impairments (18
). This is supported by recent evidence of an inverse relationship of cognitive functioning (namely, verbal fluency) and the rate of striatal F-dopa uptake among patients with schizophrenia symptoms (1
). Researchers have also found that striatal D2 receptor density is associated with both immediate and delayed auditory memory (33
). Lichter and Cummings (72
) have noted that frontostriatal systems are involved in the integration of sensory and limbic phenomena, and play key roles in a number of functions underlying cognitive functioning such as motivation and goal selection for adaptive processes. Further, researchers have detailed how subcortical motor regions also play an important role in cognitive processes associated with prefrontal activity such as explicit and implicit category learning systems (73
), attention/working memory (67
) and social cognition (68
It is noteworthy that only upper-body region movements were associated with neurocognitive deficits. Because of the distinct and segregated cortical-striatal-thalamic circuitry, researchers have argued that orofacial dyskinesias appear to constitute a distinct syndrome when compared to involuntary upper-body movements (74
). Movement abnormalities in the facial region have been linked with the ventromedial area of the putamen, whereas such movements upper-body are associated with the dorsolateral sector and ventromedial area of the putamen (77
). Thus, the present findings suggest that these respective areas of the putamen may be affected in some individuals who develop psychosis.
Roughly 35% of high-risk participants convert to an Axis-I psychotic disorder in a two-year period (78
). A major goal of prodromal research is to develop strategies that can enhance detection of those individuals at the highest risk for conversion. While previous studies have examined specific biological markers and compared these to converters and non-converters, few have had the statistical power necessary to test models combining these markers. The results from the present collaborative study indicate that elevated upper-body region movements, and deficits in immediate, and delayed auditory memory, and FSIQ are significant defining factors of a group of high-risk participants who will eventually converted to Axis-I psychosis.
The present findings, suggesting that deficit immediate and delayed auditory memory and estimated FSIQ are significant discriminating factors between converting and non-converting high-risk participants, are consistent with a body of high-risk literature. For example, Simon and colleagues (14
) observed deficits in verbal fluency and declarative verbal memory when comparing early stage prodromal and late stage prodromal individuals. In another relevant study, Lencz and colleagues (10
) also observed those high-risk participants who converted over a one-year study period had significantly lower verbal memory scores than those prodromal patients who did not convert. Further, in a sizable study examining neuropsychological performance and conversion among a high-risk sample (n = 98), researchers observed that impairments in auditory memory were specific to the high-risk participants who converted (9
Supplementary analyses suggested that cognitive and movement abnormality variables alone did not correctly classify as many individuals as when both sets of variables where entered in the combined discriminant function analysis. However, the increase in prediction associated with a combined index relative to each domain separately was relatively small and the lack of a significant increase supports a common neurological underpinning underlying both movement and neurocognitive dysfunction. These results support the notion that incorporating susceptibility markers into programs for early identification enhance detection of those individuals at highest risk for conversion to psychotic disorder. Within the context of published high-risk studies, the sample size and number of converters available for study is quite high. However, it should also be noted that in terms of statistical modeling, the number of converters was relatively small, and as a result, the presented predictive model is limited.
A limitation of this study involved the use of videotaped interviews as the sole venue for measuring movement abnormalities. While the method has yielded consistent and important results in past studies (54
), the inability to measure lower-body movement represents a setback. However, it should be noted that previous examinations following movement abnormalities in schizophrenia-spectrum disorders have found that lower-body movements do not significantly distinguish high-risk individuals (80
It is also interesting to consider that while the converted group performed below average on both cognitive measures of perceptual organization, movement abnormalities in the upper-body region were significantly associated with the Block Design, but not the Matrix Reasoning task. One potential reason for this apparent phenomenon is that the task-specific cognitive factors for Block Design are particularly associated with the aberrant mechanisms also thought to underlie movement abnormalities. For example, while both measures are reliable and valid measures of perceptual organization (51
), the Block Design task holds several unique attributes in that it contains a visuoconstructive component, is timed, and is more abstract (48
). Future studies examining the relationships between movement abnormalities and these specific cognitive processes will be useful in clarifying this issue. It is also important to consider that because FSIQ estimate is in part contingent on these two measures, the magnitude between upper-body movement abnormalities and FSIQ at the EADP site (which used Block Design) is greater than the at the CAPPS site. As such, the present discriminative function may indeed be a conservative estimate of these potential markers; future studies utilizing FSIQ estimates based solely on Block Design are likely to have greater ability to classify converting from non-converting high-risk individuals.
Although medication was statistically controlled in the present analyses, and found not to be different between converting and non-converting participants, this does not entirely eliminate the potential confound of medication effects. Prescription of psychotropics is expected to be targeted to those with more severe behavioral dysfunction and, perhaps, concomitant movement abnormalities. Thus controlling for medication can affect the variance in ratings of disease progression and movements, thereby attenuating covariance between these two factors. However, it should also be noted that the increased use of psychotropic medication presents an opportunity to study a population less likely to meet the restrictive inclusion criteria of preventive trials, but more likely to represent individuals who are currently being seen in actual practice. Because of these constraints, the present results should be interpreted as preliminary, until advances in methodological design or significantly larger studies can lend to a supplemental analyses on medication-free proportions of the sample.