Systems and Diseases

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Depression Impairs Learning, whereas the Selective Serotonin Reuptake Inhibitor, Paroxetine, Impairs Generalization in Patients with Major Depressive Disorder
(Elsevier, 2014-11-01) Herzallah, Mohammad M.; Moustafa, Ahmed A.; Natsheh, Joman Y.; Danoun, Omar A.; Simon, Jessica R.; Tayem, Yasin I.; Sehwail, Mahmud A.; Amleh, Ivona; Bannoura, Issam; Petrides, Georgios; Myers, Catherine E.; Gluck, Mark A.
To better understand how medication status and task demands affect cognition in Major Depressive Disorder (MDD), we evaluated medication-naïve patients with MDD, medicated patients with MDD receiving the Selective Serotonin Reuptake Inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naïve MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampaldependent generalization of past learning to novel contexts, not otherwise seen in the medicationnaïve MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures critical for generalization.
Diabetes mellitus: The epidemic of the century
(Baishideng Publishing Group Inc., 2015-06-25) Kharroubi, Akram T; Darwish, Hisham M
The epidemic nature of diabetes mellitus in different regions is reviewed. The Middle East and North Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific region has the highest number of adults diagnosed with diabetes and has countries with the highest prevalence of diabetes (37.5%). Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. The molecular genetics of diabetes received extensive attention in recent years by many prominent investigators and research groups in the biomedical field. A large array of mutations and single nucleotide polymorphisms in genes that play a role in the various steps and pathways involved in glucose metabolism and the development, control and function of pancreatic cells at various levels are reviewed. The major advances in the molecular understanding of diabetes in relation to the different types of diabetes in comparison to the previous understanding in this field are briefly reviewed here. Despite the accumulation of extensive data at the molecular and cellular levels, the mechanism of diabetes development and complications are still not fully understood. Definitely, more extensive research is needed in this field that will eventually reflect on the ultimate objective to improve diagnoses, therapy and minimize the chance of chronic complications development.
Diabetes mellitus: The epidemic of the century
(Baishideng Publishing Group Inc., 2015-06-25) Kharroubi, Akram T; Darwish, Hisham M
The epidemic nature of diabetes mellitus in different regions is reviewed. The Middle East and North Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific region has the highest number of adults diagnosed with diabetes and has countries with the highest prevalence of diabetes (37.5%). Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. The molecular genetics of diabetes received extensive attention in recent years by many prominent investigators and research groups in the biomedical field. A large array of mutations and single nucleotide polymorphisms in genes that play a role in the various steps and pathways involved in glucose metabolism and the development, control and function of pancreatic cells at various levels are reviewed. The major advances in the molecular understanding of diabetes in relation to the different types of diabetes in comparison to the previous understanding in this field are briefly reviewed here. Despite the accumulation of extensive data at the molecular and cellular levels, the mechanism of diabetes development and complications are still not fully understood. Definitely, more extensive research is needed in this field that will eventually reflect on the ultimate objective to improve diagnoses, therapy and minimize the chance of chronic complications development.
Dissociating the Cognitive Effects of Levodopa versus Dopamine Agonists in aNeurocomputational Model of Learning in Parkinson's Disease
(Karger AG, Basel, 2012-11-01) Moustafa, Ahmed A.; Herzallah, Mohammad M.; Gluck, Mark A.
Background/Aims: Levodopa and dopamine agonists have different effects on the motor, cognitive, and psychiatric aspects of Parkinson’s disease (PD). Methods: Using a computational model of basal ganglia (BG) and prefrontal cortex (PFC) dopamine, we provide a theoretical synthesis of the dissociable effects of these dopaminergic medications on brain and cognition. Our model incorporates the findings that levodopa is converted by dopamine cells into dopamine, and thus activates prefrontal and striatal D 1 and D 2 dopamine receptors, whereas antiparkinsonian dopamine agonists directly stimulate D 2 receptors in the BG and PFC (although some have weak affinity to D 1 receptors). Results: In agreement with prior neuropsychological studies, our model explains how levodopa enhances, but dopamine agonists impair or have no effect on, stimulus-response learning and working memory. Conclusion: Our model explains how levodopa and dopamine agonists have differential effects on motor and cognitive processes in PD.
Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331 288 participants.
(2015-06-22) Abdeen, Ziad
Background Diabetes has been defi ned on the basis of diff erent biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA1c. We assessed the eff ect of diff erent diagnostic defi nitions on both the population prevalence of diabetes and the classifi cation of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in diff erent regions. Methods We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defi ning diabetes. Diabetes was defi ned using HbA1c (HbA1c ≥6·5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT defi nitions (FPG ≥7·0 mmol/L or 2hOGTT ≥11·1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using diff erent defi nitions graphically and by regression analyses. We calculated sensitivity and specifi city of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specifi city in each survey, and then pooled results using a random-eff ects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Findings Population prevalence of diabetes based on FPG-or-2hOGTT was correlated with prevalence based on FPG alone (r=0·98), but was higher by 2–6 percentage points at diff erent prevalence levels. Prevalence based on HbA1c was lower than prevalence based on FPG in 42·8% of age–sex–survey groups and higher in another 41·6%; in the other 15·6%, the two defi nitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA1c-based prevalences was partly related to participants’ age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specifi c communities. Diabetes defi ned as HbA1c 6·5% or more had a pooled sensitivity of 52·8% (95% CI 51·3–54·3%) and a pooled specifi city of 99·74% (99·71–99·78%) compared with FPG 7·0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defi ned based on FPGor- 2hOGTT was 30·5% (28·7–32·3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA1c versus FPG.
Hippocampal BOLD Response During Category Learning Predicts Subsequent Performanceon Transfer Generalization
(Wiley Periodicals, Inc., 2014-10-13) Fera, Francesco; Passamonti, Luca; Myers, Catherine E.; Veltri, Pierangelo; Morganti, Giuseppina; Quattrone, Aldo; Gluck, Mark A.; Herzallah, Mohammad
To test a prediction of our previous computational model of cortico-hippocampal interaction (Gluck and Myers [1993, 2001]) for characterizing individual differences in category learning, we studied young healthy subjects using an fMRI-adapted category-learning task that has two phases, an initial phase in which associations are learned through trial-and-error feedback followed by a generalization phase in which previously learned rules can be applied to novel associations (Myers et al. [2003]). As expected by our model, we found a negative correlation between learning-related hippocampal responses and accuracy during transfer, demonstrating that hippocampal adaptation during learning is associated with better behavioral scores during transfer generalization. In addition, we found an inverse relationship between Blood Oxygenation Level Dependent (BOLD) activity in the striatum and that in the hippocampal formation and the orbitofrontal cortex during the initial learning phase. Conversely, activity in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal lobes dominated over that of the hippocampal formation during the generalization phase. These findings provide evidence in support of theories of the neural substrates of category learning which argue that the hippocampal region plays a critical role during learning for appropriately encoding and representing newly learned information so that that this learning can be successfully applied and generalized to subsequent novel task demands.
Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants
(2013-09-23) Herzallah, Mohammad M.; Moustafa, Ahmed A.; Natsheh, Joman Y.; Abdellatif, Salam M.; Taha, Mohamad B.; Tayem, Yasin I.; Sehwail, Mahmud A.; Amleh, Ivona; Petrides, Georgios; Myers, Catherine E.; Gluck, Mark A.
One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject's relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky's (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not "normal" when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naïve state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs.
A model of reversal learning and working memory in medicated and unmedicated patients with Parkinsons disease
(Elsevier, 2014-10-18) Herzallah, Mohammed; Moustafa, Ahmed; Gluck, Mark
Wepresent a neural network model of cognition in medicated and unmedicated patients with Parkinson’s disease (PD) in various learning and memory tasks. The model extends our prior models of the basal ganglia and PD with further modeling of the role of prefrontal cortex (PFC) dopamine in stimulus–response learning, reversal, and working memory. In our model, PD is associated with decreased dopamine levels in the basal ganglia and PFC, whereas dopamine medications increase dopamine levels in both brain structures. Simulation results suggest that dopamine medications impair stimulus–response learning in agreement with experimental data (Breitenstein et al., 2006; Gotham, Brown, & Marsden, 1988). Weshow how decreased dopamine levels in the PFC in unmedicated PD patients are associated with impaired working memory performance, as seen experimentally (Costa et al., 2003; Lange et al., 1992; Moustafa, Sherman, & Frank, 2008; Owen, Sahakian, Hodges, Summers, & Polkey, 1995). Further, our model simulations illustrate how increases in tonic dopamine levels in the PFC due to dopamine medications will enhance working memory, in accord with previous modeling and experimental results (Cohen, Braver, & Brown, 2002; Durstewitz, Seamans, & Sejnowski, 2000; Wang, Vijayraghavan, & Goldman-Rakic, 2004). The model is also consistent with data reported in Cools, Barker, Sahakian, and Robbins (2001), who showed that dopamine medications impair reversal learning. In addition, our model shows that extended training of the reversal phase leads to enhanced reversal performance in medicated PD patients, which is a new, and as yet untested, prediction of the model. Overall, our model provides a unified account for performance in various behavioral tasks using common computational principles.
A neural model of hippocampalstriatal interactions in associative learningand transfer generalization in various neurological and psychiatric patients
(Elsevier, 2010-08-21) Herzallah, Mohammed; Moustafa, Ahmed; Keri, Szabolcs; Myers, Catherine; Gluck, Mark
Building on our previous neurocomputational models of basal ganglia and hippocampal region function (and their modulation by dopamine and acetylcholine, respectively), we show here how an integration of these models can inform our understanding of the interaction between the basal ganglia and hippocampal region in associative learning and transfer generalization across various patient populations. As a common test bed for exploring interactions between these brain regions and neuromodulators, we focus on the acquired equivalence task, an associative learning paradigm in which stimuli that have been associated with the same outcome acquire a functional similarity such that subsequent generalization between these stimuli increases. This task has been used to test cognitive dysfunction in various patient populations with damages to the hippocampal region and basal ganglia, including studies of patients with Parkinson’s disease (PD), schizophrenia, basal forebrain amnesia, and hippocampal atrophy. Simulation results show that damage to the hippocampal region—as in patients with hippocampal atrophy (HA), hypoxia, mild Alzheimer’s (AD), or schizophrenia—leads to intact associative learning but impaired transfer generalization performance. Moreover, the model demonstrates how PD and anterior communicating artery (ACoA) aneurysm—two very different brain disorders that affect different neural mechanisms— can have similar effects on acquired equivalence performance. In particular, the model shows that simulating a loss of dopamine function in the basal ganglia module (as in PD) leads to slow acquisition learning but intact transfer generalization. Similarly, the model shows that simulating the loss of acetylcholine in the hippocampal region (as in ACoA aneurysm) also results in slower acquisition learning. We argue from this that changes in associative learning of stimulus–action pathways (in the basal ganglia) or changes in the learning of stimulus representations (in the hippocampal region) can have similar functional effects.
Prevalence and awareness of osteoporosis among postmenopausal Palestinian women
(Springer, 2010-05-18) Abd-Alhameed, Intissar; Saba, Elias; Darwish, Hisham M.
Summary The prevalence and awareness of postmenopausal osteoporosis was assessed among 569 postmenopausal women randomly selected from the population. Osteoporosis was assessed based on bone mineral density (BMD) values at three indicative sites. The results indicate a significant prevalence of the disease among this fraction of the population with a poor knowledge of its risk factors. Introduction Postmenopausal osteoporosis is a major health problem at the individual and population levels. Assessment of its prevalence and awareness of risk factors provide the basis for health plans to control the disease. No previous studies have been done in our population. A cross-sectional study including 569 postmenopausal women showed a significant prevalence of osteoporosis with a poor awareness of risk factors. Methods Included in the study were 569 randomly selected postmenopausal women (≥49 years of age). BMD was measured in 505 subjects at the lumbar spine, femoral neck and total hip using dual energy x-ray absorptiometry. Awareness was evaluated using a special questionnaire. Results Osteoporosis affected the lumbar spine, femoral neck and total hip in 24%, 14% and 29.7% of subjects, respectively. There was a significant negative correlation (p<0.001) between age and number of years since menopause and BMD at all the sites evaluated. Conversely, BMD increased at the three sites as weight, height and BMI increased. There was a significant positive correlation between BMD at the three sites and the physical characteristics of the subjects (weight, height and BMI) (p<0.001 at the hip and femoral neck, and p=0.05 at the lumbar spine). BMD was higher at the lumbar spine and femoral neck among subjects aware of the disease (0.893 and 0.746 g/cm2, respectively) than among subjects unaware of the disease (0.835 and 0.712 g/cm2, respectively). This investigation is the first among Palestinian women in this region. It indicates the urgent need for a comprehensive national programme to reduce the incidence of osteoporosis. Conclusion Postmenopausal osteoporosis is significant among the Palestinian population and there is a poor awareness of the risk factors.
Serum 25-hydroxyvitamin D and bone turnover markers in Palestinian postmenopausal osteoporosis and normal women
(Springer, 2017-01-26) Kharroubi, Akram; Saba, Elias; Smoom, Riham; Bader, Khaldoun; Darwish, Hisham
Summary This study evaluated the association of vitaminD and bone markers with the development osteoporosis in Palestinian postmenopausal women. Even though vitamin D deficiency was very high for the recruited subjects, it was not associated with osteoporosis except for bones of the hip. Age and obesity were the strongest determining factors of the disease. Purpose The purpose of this study was to investigate the association of bone mineral density (BMD) with serum vitamin D levels, parathyroid hormone (PTH), calcium, obesity, and bone turnover markers in Palestinian postmenopausal women. Methods Three hundred eighty-two postmenopausal women (≥45 years) were recruited from various women clinics for BMD assessment (131 women had osteoporosis and 251 were normal and served as controls). Blood samples were obtained for serum calcium, PTH, 25(OH)D, bone formation (N-terminal propeptide (PINP)), and bone resorption (serum Cterminal telopeptide of type I collagen (CTX1)) markers. Results Women with osteoporosis had statistically significant lower mean weight, height, body mass index (BMI), and serum calcium (p < 0.05) compared to controls. No significant differences were detected between the mean values of bone turnover markers (CTX and PINP), 25(OH)D, and PTH of the two groups. Women with vitamin D deficiency (severe and insufficiency) represented 85.9% of the study subjects. Multiple and logistic regression showed that age and BMI significantly affected BMD and vitamin D had a significant association with BMD only at the lumbar spine. BMI was positively correlated with BMD and PTH but negatively correlated with vitamin D. Logistic regression showed that the odds ratio (OR) for having osteoporosis decreased with increasing BMI (overweight OR = 0.11, p = 0.053; obese OR = 0.05, p = 0.007). Conclusions There was no direct correlation between BMD and PTH, bone turnover markers, and vitamin D except at the lumbar spine. A negative correlation between BMD and age and a positive correlation with BMI were observed. The protective effect of obesity on osteoporosis was complicated by the effect of obesity on vitamin D and PTH.
Total Antioxidant Status in Type 2 Diabetic Patients in Palestine
(Hindawi Publishing Corporation, 2015-05-12) Kharroubi, Akram T.; Darwish, Hisham M.; Akkawi, Mutaz A.; Ashareef, Abdelkareem A.; Almasri, Zaher A.; Bader, Khaldoun A.; Khammash, Umaiyeh M.
The objective of this study was to compare the level of total antioxidant status (TAS) in type 2 diabetic and normal Palestinian subjects as well as the major factors influencing TAS levels. A sample of convenience composed of 212 type 2 diabetic and 208 normal subjects above the age of 40 were recruited. Only 9.8% of the subjects had normal bodymass index (BMI) levels (<25), 29% were overweight (≥25 to <30), and 61.2% were obese (≥30). The mean levels of TAS were significantly higher in diabetic compared to control subjects (2.18 versus 1.84mM Trolox, P = 0.001) and in hypertensive subjects compared to subjects with normal blood pressure (BP).Mean TAS levels were higher in obese compared to nonobese subjects (2.12 versus 1.85mMTrolox, P = 0.001).Mean TAS levels were similarly higher in subjects with high fasting plasma glucose (FPG) compared to normal FPG (2.19 versus 1.90mM Trolox) and high HbA1c (≥6.5%) compared to HbA1c < 6.5% (2.14 versus 1.91mMTrolox).Multivariate analysis revealed that only diabetic status (P = 0.032) and the level of education (P = 0.036) were significantly associated with TAS. In conclusion diabetic patients had 18.5% increase in TAS levels compared to control subjects.

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