Ahmed A. Moustafa

Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson's patients

Parkinsons disease is characterized by the degeneration of dopaminergic pathways projecting to the striatum. These pathways are implicated in reward prediction. In this study, we investigated reward and punishment processing in young, never-medicated Parkinsons disease patients, recently medicated patients receiving the dopamine receptor agonists pramipexole and ropinirole and healthy controls. The never-medicated patients were also re-evaluated after 12 weeks of treatment with dopamine agonists. Reward and punishment processing was assessed by a feedback-based probabilistic classification task. Personality characteristics were measured by the temperament and character inventory. Results revealed that never-medicated patients with Parkinsons disease showed selective deficits on reward processing and novelty seeking, which were remediated by dopamine agonists. These medications disrupted punishment processing. In addition, dopamine agonists increased the correlation between reward processing and novelty seeking, whereas these drugs decreased the correlation between punishment processing and harm avoidance. Our finding that dopamine agonist administration in young patients with Parkinsons disease resulted in increased novelty seeking, enhanced reward processing, and decreased punishment processing may shed light on the cognitive and personality bases of the impulse control disorders, which arise as side-effects of dopamine agonist therapy in some Parkinsons disease patients.

Horizontal gene transfer of the algal nuclear gene psbO to the photosynthetic sea slug Elysia chlorotica

The sea slug Elysia chlorotica acquires plastids by ingestion of its algal food source Vaucheria litorea. Organelles are sequestered in the molluscs digestive epithelium, where they photosynthesize for months in the absence of algal nucleocytoplasm. This is perplexing because plastid metabolism depends on the nuclear genome for >90% of the needed proteins. Two possible explanations for the persistence of photosynthesis in the sea slug are (i) the ability of V. litorea plastids to retain genetic autonomy and/or (ii) more likely, the mollusc provides the essential plastid proteins. Under the latter scenario, genes supporting photosynthesis have been acquired by the animal via horizontal gene transfer and the encoded proteins are retargeted to the plastid. We sequenced the plastid genome and confirmed that it lacks the full complement of genes required for photosynthesis. In support of the second scenario, we demonstrated that a nuclear gene of oxygenic photosynthesis, psbO, is expressed in the sea slug and has integrated into the germline. The source of psbO in the sea slug is V. litorea because this sequence is identical from the predator and prey genomes. Evidence that the transferred gene has integrated into sea slug nuclear DNA comes from the finding of a highly diverged psbO 3′ flanking sequence in the algal and mollusc nuclear homologues and gene absence from the mitochondrial genome of E. chlorotica. We demonstrate that foreign organelle retention generates metabolic novelty (“green animals”) and is explained by anastomosis of distinct branches of the tree of life driven by predation and horizontal gene transfer.

Freezing of gait in Parkinson’s disease is associated with functional decoupling between the cognitive control network and the basal ganglia

Recent neuroimaging evidence has led to the proposal that freezing of gait in Parkinsons disease is due to dysfunctional interactions between frontoparietal cortical regions and subcortical structures, such as the striatum. However, to date, no study has employed task-based functional connectivity analyses to explore this hypothesis. In this study, we used a data-driven multivariate approach to explore the impaired communication between distributed neuronal networks in 10 patients with Parkinsons disease and freezing of gait, and 10 matched patients with no clinical history of freezing behaviour. Patients performed a virtual reality gait task on two separate occasions (once ON and once OFF their regular dopaminergic medication) while functional magnetic resonance imaging data were collected. Group-level independent component analysis was used to extract the subject-specific time courses associated with five well-known neuronal networks: the motor network, the right- and left cognitive control networks, the ventral attention network and the basal ganglia network. We subsequently analysed both the activation and connectivity of these neuronal networks between the two groups with respect to dopaminergic state and cognitive load while performing the virtual reality gait task. During task performance, all patients used the left cognitive control network and the ventral attention network and in addition, showed increased connectivity between the bilateral cognitive control networks. However, patients with freezing demonstrated functional decoupling between the basal ganglia network and the cognitive control network in each hemisphere. This decoupling was also associated with paroxysmal motor arrests. These results support the hypothesis that freezing behaviour in Parkinsons disease is because of impaired communication between complimentary yet competing neural networks.

The making of a photosynthetic animal

Summary Symbiotic animals containing green photobionts challenge the common perception that only plants are capable of capturing the suns rays and converting them into biological energy through photoautotrophic CO2 fixation (photosynthesis). ‘Solar-powered’ sacoglossan molluscs, or sea slugs, have taken this type of symbiotic association one step further by solely harboring the photosynthetic organelle, the plastid (=chloroplast). One such sea slug, Elysia chlorotica, lives as a ‘plant’ when provided with only light and air as a result of acquiring plastids during feeding on its algal prey Vaucheria litorea. The captured plastids (kleptoplasts) are retained intracellularly in cells lining the digestive diverticula of the sea slug, a phenomenon sometimes referred to as kleptoplasty. Photosynthesis by the plastids provides E. chlorotica with energy and fixed carbon for its entire lifespan of ∼10 months. The plastids are not transmitted vertically (i.e. are absent in eggs) and do not undergo division in the sea slug. However, de novo protein synthesis continues, including plastid- and nuclear-encoded plastid-targeted proteins, despite the apparent absence of algal nuclei. Here we discuss current data and provide hypotheses to explain how long-term photosynthetic activity is maintained by the kleptoplasts. This fascinating ‘green animal’ provides a unique model to study the evolution of photosynthesis in a multicellular heterotrophic organism.

A role for dopamine in temporal decision making and reward maximization in Parkinsonism

Converging evidence implicates striatal dopamine (DA) in reinforcement learning, such that DA increases enhance “Go learning” to pursue actions with rewarding outcomes, whereas DA decreases enhance “NoGo learning” to avoid non-rewarding actions. Here we test whether these effects apply to the response time domain. We employ a novel paradigm which requires the adjustment of response times to a single response. Reward probability varies as a function of response time, whereas reward magnitude changes in the opposite direction. In the control condition, these factors exactly cancel, such that the expected value across time is constant (CEV). In two other conditions, expected value increases (IEV) or decreases (DEV), such that reward maximization requires either speeding up (Go learning) or slowing down (NoGo learning) relative to the CEV condition. We tested patients with Parkinsons disease (depleted striatal DA levels) on and off dopaminergic medication, compared with age-matched controls. While medicated, patients were better at speeding up in the DEV relative to CEV conditions. Conversely, nonmedicated patients were better at slowing down to maximize reward in the IEV condition. These effects of DA manipulation on cumulative Go/NoGo response time adaptation were captured with our a priori computational model of the basal ganglia, previously applied only to forced-choice tasks. There were also robust trial-to-trial changes in response time, but these single trial adaptations were not affected by disease or medication and are posited to rely on extrastriatal, possibly prefrontal, structures.

Deep sequencing of 10,000 human genomes

Significance Large-scale initiatives toward personalized medicine are driving a massive expansion in the number of human genomes being sequenced. Therefore, there is an urgent need to define quality standards for clinical use. This includes deep coverage and sequencing accuracy of an individual’s genome. Our work represents the largest effort to date in sequencing human genomes at deep coverage with these new standards. This study identifies over 150 million human variants, a majority of them rare and unknown. Moreover, these data identify sites in the genome that are highly intolerant to variation—possibly essential for life or health. We conclude that high-coverage genome sequencing provides accurate detail on human variation for discovery and clinical applications. We report on the sequencing of 10,545 human genomes at 30×–40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.

Differential Gene Retention in Plastids of Common Recent Origin

The cyanobacterium-derived plastids of algae and plants have supported the diversification of much of extant eukaryotic life. Inferences about early events in plastid evolution must rely on reconstructing events that occurred over a billion years ago. In contrast, the photosynthetic amoeba Paulinella chromatophora provides an exceptional model to study organelle evolution in a prokaryote-eukaryote (primary) endosymbiosis that occurred approximately 60 mya. Here we sequenced the plastid genome (0.977 Mb) from the recently described Paulinella FK01 and compared the sequence with the existing data from the sister taxon Paulinella M0880/a. Alignment of the two plastid genomes shows significant conservation of gene order and only a handful of minor gene rearrangements. Analysis of gene content reveals 66 differential gene losses that appear to be outright gene deletions rather than endosymbiotic gene transfers to the host nuclear genome. Phylogenomic analysis validates the plastid ancestor as a member of the Synechococcus-Prochlorococcus group, and the cyanobacterial provenance of all plastid genes suggests that these organelles were not targets of interphylum gene transfers after endosymbiosis. Inspection of 681 DNA alignments of protein-encoding genes shows that the vast majority have dN/dS ratios <<1, providing evidence for purifying selection. Our study demonstrates that plastid genomes in sister taxa are strongly constrained by selection but follow distinct trajectories during the earlier phases of organelle evolution.

The cerebellum and psychiatric disorders.

The cerebellum has been considered for a long time to play a role solely in motor coordination. However, studies over the past two decades have shown that the cerebellum also plays a key role in many motor, cognitive, and emotional processes. In addition, studies have also shown that the cerebellum is implicated in many psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorders, schizophrenia, bipolar disorder, major depressive disorder, and anxiety disorders. In this review, we discuss existing studies reporting cerebellar dysfunction in various psychiatric disorders. We will also discuss future directions for studies linking the cerebellum to psychiatric disorders.

The role of frontostriatal impairment in freezing of gait in Parkinson's disease

Freezing of gait (FOG) is a disabling symptom of advanced Parkinsons disease (PD) that leads to an increased risk of falls and nursing home placement. Interestingly, multiple lines of evidence suggest that the manifestation of FOG is related to specific deficits in cognition, such as set shifting and the ability to process conflict-related signals. These findings are consistent with the specific patterns of abnormal cortical processing seen during functional neuroimaging experiments of FOG, implicating increased neural activation within cortical structures underlying cognition, such as the Cognitive Control Network. In addition, these studies show that freezing episodes are associated with abnormalities in the BOLD response within key structures of the basal ganglia, such as the striatum and the subthalamic nucleus. In this article, we discuss the implications of these findings on current models of freezing behavior and propose an updated model of basal ganglia impairment during FOG episodes that integrates the neural substrates of freezing from the cortex and the basal ganglia to the cognitive dysfunctions inherent in the condition.

Homocysteine levels in schizophrenia and affective disorders—focus on cognition

Although homocysteine (Hcy) has been widely implicated in the etiology of various physical health impairments, especially cardiovascular diseases, overwhelming evidence indicates that Hcy is also involved in the pathophysiology of schizophrenia and affective disorders. There are several mechanisms linking Hcy to biological underpinnings of psychiatric disorders. It has been found that Hcy interacts with NMDA receptors, initiates oxidative stress, induces apoptosis, triggers mitochondrial dysfunction and leads to vascular damage. Elevated Hcy levels might also contribute to cognitive impairment that is widely observed among patients with affective disorders and schizophrenia. Supplementation of vitamins B and folic acid has been proved to be effective in lowering Hcy levels. There are also studies showing that this supplementation strategy might be beneficial for schizophrenia patients with respect to alleviating negative symptoms. However, there are no studies addressing the influence of add-on therapies with folate and vitamins B on cognitive performance of patients with schizophrenia and affective disorders. In this article, we provide an overview of Hcy metabolism in psychiatric disorders focusing on cognitive correlates and indicating future directions and perspectives.