The basal ganglia are neural structures within the motor and cognitive control circuits in the mammalian forebrain and are interconnected with the neocortex by multiple loops. Dysfunction in these parallel loops caused by damage to the striatum results in major defects in voluntary movement, exemplified in Parkinson's disease and Huntington's disease. These parallel loops have a distributed modular architecture resembling local expert architectures of computational learning models. During sensorimotor learning, such distributed networks may be coordinated by widely spaced striatal interneurons that acquire response properties on the basis of experienced reward.

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ObjectiveWe hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates.MethodsA total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.ResultsOverall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance.InterpretationMutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685

This article presents a three-factor anatomical model of human idea generation and creative drive, focusing on interactions between the temporal lobes, frontal lobes, and limbic system. Evidence is drawn from functional imaging, drug studies, and lesion analysis. Temporal lobe changes, as in hypergraphia, often increase idea generation, sometimes at the expense of quality. Frontal lobe deficits may decrease idea generation, in part because of rigid judgments about an idea's worth. These phenomena are clearest in verbal creativity, and roughly parallel the pressured communication of temporal lobe epilepsy, mania, and Wernicke's aphasia-compared to the sparse speech and cognitive inflexibility of depression, Broca's aphasia, and other frontal lobe lesions. The phenomena also shape non-linguistic creativity, as in that of frontotemporal dementia. The appropriate balance between frontal and temporal activity is mediated by mutually inhibitory corticocortical interactions. Mesolimbic dopamine influences novelty seeking and creative drive. Dopamine agonists and antagonists have opposite effects on goal-directed behavior and hallucinations. Creative drive is not identical to skill-the latter depends more on neocortical association areas. However, drive correlates better with successful creative output than skill does. Traditional neuroscientific models of creativity, such as the left brain - right brain hemispheric model, emphasize skills primarily, and stress art and musical skill at the expense of language and mathematics. The three-factor model proposed here predicts findings in a broad range of normal and pathological states and can be tested in many experimental paradigms.