Anup Sharma

Common Dimensional Reward Deficits Across Mood and Psychotic Disorders: A Connectome-Wide Association Study

OBJECTIVE Anhedonia is central to multiple psychiatric disorders and causes substantial disability. A dimensional conceptualization posits that anhedonia severity is related to a transdiagnostic continuum of reward deficits in specific neural networks. Previous functional connectivity studies related to anhedonia have focused on case-control comparisons in specific disorders, using region-specific seed-based analyses. Here, the authors explore the entire functional connectome in relation to reward responsivity across a population of adults with heterogeneous psychopathology. METHOD In a sample of 225 adults from five diagnostic groups (major depressive disorder, N=32; bipolar disorder, N=50; schizophrenia, N=51; psychosis risk, N=39; and healthy control subjects, N=53), the authors conducted a connectome-wide analysis examining the relationship between a dimensional measure of reward responsivity (the reward sensitivity subscale of the Behavioral Activation Scale) and resting-state functional connectivity using multivariate distance-based matrix regression. RESULTS The authors identified foci of dysconnectivity associated with reward responsivity in the nucleus accumbens, the default mode network, and the cingulo-opercular network. Follow-up analyses revealed dysconnectivity among specific large-scale functional networks and their connectivity with the nucleus accumbens. Reward deficits were associated with decreased connectivity between the nucleus accumbens and the default mode network and increased connectivity between the nucleus accumbens and the cingulo-opercular network. In addition, impaired reward responsivity was associated with default mode network hyperconnectivity and diminished connectivity between the default mode network and the cingulo-opercular network. CONCLUSIONS These results emphasize the centrality of the nucleus accumbens in the pathophysiology of reward deficits and suggest that dissociable patterns of connectivity among large-scale networks are critical to the neurobiology of reward dysfunction across clinical diagnostic categories.

A Neurotoxic Phosphoform of Elk-1 Associates with Inclusions from Multiple Neurodegenerative Diseases

Neurodegenerative diseases are characterized by a number of features including the formation of inclusions, early synaptic degeneration and the selective loss of neurons. Molecules serving as links between these shared features have yet to be identified. Identifying candidates within the diseased microenvironment will open up novel avenues for therapeutic intervention. The transcription factor Elk-1 resides within multiple brain areas both in nuclear and extranuclear neuronal compartments. Interestingly, its de novo expression within a single dendrite initiates neuronal death. Given this novel regionalized function, we assessed whether extranuclear Elk-1 and/or phospho-Elk-1 (pElk-1) protein might be associated with a spectrum of human neurodegenerative disease cases including Lewy body Disease (e.g. Parkinsons), Alzheimers disease, and Huntingtons Disease. We first determined the importance of Elk-1 post-translational modifications on its ability to initiate regionalized cell death. We next screened human cases from three major neurodegenerative diseases to look for remarkable levels of Elk-1 and/or pElk-1 protein as well as their association with inclusions characteristic of these diseases. We compared our findings to age-matched control cases. We find that the ability of Elk-1 to initiate regionalized neuronal death depends on a specific phosphosite, T417. Furthermore, we find that T417+ Elk-1 uniquely associates with several types of inclusions present in cases of human Lewy body Disease, Alzheimers disease, and Huntingtons Disease. These results suggest a molecular link between the presence of inclusions and neuronal loss that is shared across a spectrum of neurodegenerative disease.

A Breathing-Based Meditation Intervention for Patients With Major Depressive Disorder Following Inadequate Response to Antidepressants: A Randomized Pilot Study.

OBJECTIVE To evaluate feasibility, efficacy, and tolerability of Sudarshan Kriya yoga (SKY) as an adjunctive intervention in patients with major depressive disorder (MDD) with inadequate response to antidepressant treatment. METHODS Patients with MDD (defined by DSM-IV-TR) who were depressed despite ≥ 8 weeks of antidepressant treatment were randomized to SKY or a waitlist control (delayed yoga) arm for 8 weeks. The primary efficacy end point was change in 17-item Hamilton Depression Rating Scale (HDRS-17) total score from baseline to 2 months. The key secondary efficacy end points were change in Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) total scores. Analyses of the intent-to-treat (ITT) and completer sample were performed. The study was conducted at the University of Pennsylvania between October 2014 and December 2015. RESULTS In the ITT sample (n = 25), the SKY arm (n = 13) showed a greater improvement in HDRS-17 total score compared to waitlist control (n = 12) (-9.77 vs 0.50, P = .0032). SKY also showed greater reduction in BDI total score versus waitlist control (-17.23 vs -1.75, P = .0101). Mean changes in BAI total score from baseline were significantly greater for SKY than waitlist (ITT mean difference: -5.19; 95% CI, -0.93 to -9.34; P = .0097; completer mean difference: -6.23; 95% CI, -1.39 to -11.07; P = .0005). No adverse events were reported. CONCLUSIONS Results of this randomized, waitlist-controlled pilot study suggest the feasibility and promise of an adjunctive SKY-based intervention for patients with MDD who have not responded to antidepressants. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02616549.

S -Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research

OBJECTIVE A systematic review on S-adenosylmethionine (SAMe) for treatment of neuropsychiatric conditions and comorbid medical conditions. DATA SOURCES Searches were conducted in PubMed, EMBASE, PsycINFO, Cochrane Library, CINAHL, and Google Scholar databases between July 15, 2015, and September 28, 2016, by combining search terms for SAMe (s-adenosyl methionine or s-adenosyl-l-methionine) with terms for relevant disease states (major depressive disorder, MDD, depression, perinatal depression, human immunodeficiency virus, HIV, Parkinsons, Alzheimers, dementia, anxiety, schizophrenia, psychotic, 22q11.2, substance abuse, fibromyalgia, osteoarthritis, hepatitis, or cirrhosis). Additional studies were identified from prior literature. Ongoing clinical trials were identified through clinical trial registries. STUDY SELECTION Of the 174 records retrieved, 21 were excluded, as they were not original investigations. An additional 21 records were excluded for falling outside the scope of this review. Of the 132 studies included in this review, 115 were clinical trials and 17 were preclinical studies. DATA EXTRACTION A wide range of studies was included in this review to capture information that would be of interest to psychiatrists in clinical practice. RESULTS This review of SAMe in the treatment of major depressive disorder found promising but limited evidence of efficacy and safety to support its use as a monotherapy and as an augmentation for other antidepressants. Additionally, preliminary evidence suggests that SAMe may ameliorate symptoms in certain neurocognitive, substance use, and psychotic disorders and comorbid medical conditions. CONCLUSIONS S-adenosylmethionine holds promise as a treatment for multiple neuropsychiatric conditions, but the body of evidence has limitations. The encouraging findings support further study of SAMe in both psychiatric and comorbid medical illnesses.

Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. In the metastatic setting, the majority of patients respond to initial therapies but eventually develop resistance and progress. In this study, we test the hypothesis that priming with epigenetic therapy sensitizes CRC cell lines, which were previously resistant to subsequent chemotherapeutic agents. When multiple CRC cell lines are first exposed to 500 nM of the DNA demethylating agent, 5-aza-cytidine (AZA) in-vitro, and the cells then established as in-vivo xenografts in untreated NOD-SCID mice; there is an enhanced response to cytotoxic chemotherapy with agents commonly used in CRC treatment. For irinotecan (IRI), growth diminished by 16–62 fold as assessed, by both proliferation (IC50) and anchorage independent cell growth soft agar assays. Treatment of resistant HCT116 cell line along with in-vivo, for CRC line xenografts, AZA plus IRI again exhibits this synergistic response with significant improvement in survival and tumor regression in the mice. Genome-wide expression correlates changes in pathways for cell adhesion and DNA repair with the above responses. A Phase 1/2 clinical trial testing this concept is already underway testing the clinical efficacy of this concept in IRI resistant, metastatic CRC (NCT01896856).

Divergent relationship of depression severity to social reward responses among patients with bipolar versus unipolar depression

Neuroimaging studies of mood disorders demonstrate abnormalities in brain regions implicated in reward processing. However, there is a paucity of research investigating how social rewards affect reward circuit activity in these disorders. Here, we evaluated the relationship of both diagnostic category and dimensional depression severity to reward system function in bipolar and unipolar depression. In total, 86 adults were included, including 24 patients with bipolar depression, 24 patients with unipolar depression, and 38 healthy comparison subjects. Participants completed a social reward task during 3T BOLD fMRI. On average, diagnostic groups did not differ in activation to social reward. However, greater depression severity significantly correlated with reduced bilateral ventral striatum activation to social reward in the bipolar depressed group, but not the unipolar depressed group. In addition, decreased left orbitofrontal cortical activation correlated with more severe symptoms in bipolar depression, but not unipolar depression. These differential dimensional effects resulted in a significant voxelwise group by depression severity interaction. Taken together, these results provide initial evidence that deficits in social reward processing are differentially related to depression severity in the two disorders.

Nucleic Acid Introduction into Primary Neurons and Glia

By modifying gene expression within the nervous system and following its impact on brain function, neuroscientists have gained insight into brain functionality in a variety of different contexts. Within the past couple of decades, several different methodologies have been developed for gene delivery and modified for efficient gene transfer into postmitotic neurons and mitotic glial cells. Exogenous genes can now be expressed in single cells, large population of cultured cells, cultured slices, and organisms. In this article, we discuss these methodologies and also highlight novel methods of gene delivery.

Diminished Cortical Thickness Is Associated with Impulsive Choice in Adolescence

Adolescence is characterized by both maturation of brain structure and increased risk of negative outcomes from behaviors associated with impulsive decision-making. One important index of impulsive choice is delay discounting (DD), which measures the tendency to prefer smaller rewards available soon over larger rewards delivered after a delay. However, it remains largely unknown how individual differences in structural brain development may be associated with impulsive choice during adolescence. Leveraging a unique large sample of 427 human youths (208 males and 219 females) imaged as part of the Philadelphia Neurodevelopmental Cohort, we examined associations between delay discounting and cortical thickness within structural covariance networks. These structural networks were derived using non-negative matrix factorization, an advanced multivariate technique for dimensionality reduction, and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear developmental effects. We found that impulsive choice, as measured by greater discounting, was most strongly associated with diminished cortical thickness in structural brain networks that encompassed the ventromedial prefrontal cortex, orbitofrontal cortex, temporal pole, and temporoparietal junction. Furthermore, structural brain networks predicted DD above and beyond cognitive performance. Together, these results suggest that reduced cortical thickness in regions known to be involved in value-based decision-making is a marker of impulsive choice during the critical period of adolescence. SIGNIFICANCE STATEMENT Risky behaviors during adolescence, such as initiation of substance use or reckless driving, are a major source of morbidity and mortality. In this study, we present evidence from a large sample of youths that diminished cortical thickness in specific structural brain networks is associated with impulsive choice. Notably, the strongest association between impulsive choice and brain structure was seen in regions implicated in value-based decision-making; namely, the ventromedial prefrontal and orbitofrontal cortices. Moving forward, such neuroanatomical markers of impulsivity may aid in the development of personalized interventions targeted to reduce risk of negative outcomes resulting from impulsivity during adolescence.

RNA analysis in neuronal dendrites: insights into Parkinson's disease.

Parkinson’s disease (PD) is a neurodegenerative movement disorder that occurs following selective neuronal loss within the substantia nigra pars compacta. A number of symptoms result, including resting tremor, rigidity, akinesia and postural instability. In addition to neuronal loss, the disease is characterized by widespread Lewy body pathology, which implies the presence of intracellular Lewy bodies and dystrophic Lewy neurites. Lewy bodies are neuronal, intracytoplasmic spherical inclusions that contain an eosinophilic core surrounded by a pale halo. They are associated with coarse dystrophic neurites called Lewy neurites. Given the correlation between Lewy body pathology and neurodegeneration, much work has focused on defining the properties of these filamentous inclusions, including their biochemical composition, mechanisms of aggregation and effects on cell viability [1]. In addition to understanding Lewy body pathology, there has been an emphasis on identifying and characterizing the genes associated with rare, familial forms of PD [2,3]. These strategies have served as entrance points in understanding the pathogenesis of PD. Similar strategies are employed for the study of other neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. While these strategies continue to yield insights into the pathogenesis of PD, as well as other neurodegenerative diseases, we believe they contain some significant limitations and need to be complemented with other approaches. The emphasis on rare, familial forms of the disease does allow for unobstructed ana lysis of clinically relevant, single gene defects. However, the vast majority of PD cases are sporadic and likely dependent upon multigenic and environmental effects. The study of inclusions and their components does identify areas of disease pathogenesis that likely impact aspects of neurodegeneration. However, a more thorough survey of the diseased cellular microenvironment is needed. Recently, there has been a greater emphasis on systems-based genomic approaches to analyze gene-expression changes in PD. A number of studies have analyzed gene expression in methylphenyltetrahydropyridine-treated mice, genetic models of PD in insects and rodents, as well as from post-mortem PD tissue [4]. The former analyze changes due to known causes of PD, with greater accessibility to different brain regions and stages of disease. The latter provide RNA from actual sporadic cases, but with limited accessibility to diverse tissue. The hope is that a consensus expression profile unique to a specific brain region and stage of disease can emerge, from which one can identify biomarkers, better understand pathogenesis and pinpoint therapeutic targets.