John P. Ryan

Type 2 Diabetes and Cognitive Impairment Contributions From Neuroimaging

Type 2 diabetes mellitus (T2D) and Alzheimer disease (AD) are major public health burdens associated with aging. As the age of the population rapidly increases, a sheer increase in the incidence of these diseases is expected. Research has identified T2D as a risk factor for cognitive impairment and potentially AD, but the neurobiological pathways that are affected are only beginning to be understood. The rapid advances in neuroimaging in the past decade have added significant understanding to how T2D affects brain structure and function and possibly lead to AD. This article provides a review of studies that have utilized structural and functional neuroimaging to identify neural pathways that link T2D to impaired cognitive performance and potentially AD. A primary focus of this article is the potential for neuroimaging to assist in understanding the mechanistic pathways that may provide translational opportunities for clinical intervention.

A Neural Circuitry Linking Insulin Resistance to Depressed Mood

Objective Insulin resistance (IR) confers risk for Type 2 diabetes and is associated with depressed mood. Neurons within the ventral striatum (VS) are sensitive to insulin levels and show altered function in the context of both IR and depression. Hence, VS may represent a critical component of a neural circuitry linking IR to depressed mood. Methods Ninety adults (aged 30–50 years) free from major psychiatric illnesses and diabetes participated. Fasting blood was sampled, and participants completed a set of questionnaires (including the Beck Depression Inventory–II). Participants also underwent resting-state functional magnetic resonance imaging of the brain. Seed-based connectivity analyses, centered on VS, were conducted to examine how resting-state interregional connectivity patterns covaried with IR and depressed mood. Results Higher levels of IR covaried with increased connective strength between the left VS and two regions: the insula and the anterior midcingulate cortex (aMCC). Moreover, aMCC-VS connectivity predicted depressed mood (b = 0.93, standard error = 0.36, Fchange(1,81) = 6.54, p = .01). Finally, aMCC-VS connectivity was shown by Monte Carlo analysis to mediate the relationship between IR and depressed mood (a*b indirect effect = 0.16, confidence interval = 0.005–0.39, p = .03). Conclusions IR relates to changes in the functional connectivity between VS and aMCC. These changes in interregional communication partly account for the coupling of IR to depressed mood in otherwise healthy adults. These findings are relevant for understanding bidirectional associations between diabetes risk and depressed mood. Abbreviations ACC = anterior cingulate cortex aMCC = anterior midcingulate cortex BDI-II = Beck Depression Inventory–II HOMA = homeostatic model assessment IR = insulin resistance T2D = Type 2 diabetes VS = ventral striatum

Resting state functional connectivity within the cingulate cortex jointly predicts agreeableness and stressor-evoked cardiovascular reactivity.

Exaggerated cardiovascular reactivity to stress is a risk factor for cardiovascular disease. Further, individual differences in stressor-evoked cardiovascular reactivity covary with the functionality of corticolimbic brain systems, particularly areas of the cingulate cortex. What remains unclear, however, is how individual differences in personality traits interact with cingulate functionality in the prediction of stressor-evoked cardiovascular reactivity. Accordingly, we tested the associations between (i) a particular personality trait, Agreeableness, which is associated with emotional reactions to conflict, (ii) resting state functional connectivity within the cingulate cortex, and (iii) stressor-evoked blood pressure (BP) reactivity. Participants (N=39, 19 men, aged 20-37 years) completed a resting functional connectivity MRI protocol, followed by two standardized stressor tasks that engaged conflict processing and evoked BP reactivity. Agreeableness covaried positively with BP reactivity across individuals. Moreover, connectivity analyses demonstrated that a more positive functional connectivity between the posterior cingulate (BA31) and the perigenual anterior cingulate (BA32) covaried positively with Agreeableness and with BP reactivity. Finally, statistical mediation analyses demonstrated that BA31-BA32 connectivity mediated the covariation between Agreeableness and BP reactivity. Functional connectivity within the cingulate appears to link Agreeableness and a risk factor for cardiovascular disease, stressor-evoked BP reactivity.

Brainstem morphological changes in Alzheimer's disease.

As brainstem nuclei are interconnected with several cortical structures and regulate several autonomic, cognitive, and behavioral functions, it might be important to place the brainstem within an important pathologic core in the progression of Alzheimer’s disease (AD). Although there have been several postmortem studies reporting neuropathological alterations of the brainstem in AD, there has been no in-vivo structural neuroimaging study of the brainstem in the patients with AD. The aim of this study was to investigate differences in the brainstem volume and shape between patients with AD and elderly normal controls. Fifty AD patients (the Clinical Dementia Rating Scale≥1) and 50 normal controls were recruited, and the brainstem volumes and deformations were compared between the AD and the controls. Patients with AD showed significant total volume [(mean±SD) 21007±1640 mm3] reduction in the brainstem compared with the controls [(mean±SD) 22530±1750 mm3] (P<0.001). In addition, AD patients showed significant brainstem deformations in the upper posterior brainstem corresponding to the midbrain compared with the healthy individuals (false discovery rate corrected P<0.05). This study is the first to explore brainstem volume change and deformations in AD. These structural changes in the midbrain areas might be at the core of the underlying neurobiological mechanisms of brainstem dysfunction with relevance to their various cognitive and behavioral symptoms such as memory impairment, sleep, and emotional disturbance in AD. However, further longitudinal studies might be needed to confirm these findings.

Cerebral blood flow links insulin resistance and baroreflex sensitivity

Insulin resistance confers risk for diabetes mellitus and associates with a reduced capacity of the arterial baroreflex to regulate blood pressure. Importantly, several brain regions that comprise the central autonomic network, which controls the baroreflex, are also sensitive to the neuromodulatory effects of insulin. However, it is unknown whether peripheral insulin resistance relates to activity within central autonomic network regions, which may in turn relate to reduced baroreflex regulation. Accordingly, we tested whether resting cerebral blood flow within central autonomic regions statistically mediated the relationship between insulin resistance and an indirect indicator of baroreflex regulation; namely, baroreflex sensitivity. Subjects were 92 community-dwelling adults free of confounding medical illnesses (48 men, 30-50 years old) who completed protocols to assess fasting insulin and glucose levels, resting baroreflex sensitivity, and resting cerebral blood flow. Baroreflex sensitivity was quantified by measuring the magnitude of spontaneous and sequential associations between beat-by-beat systolic blood pressure and heart rate changes. Individuals with greater insulin resistance, as measured by the homeostatic model assessment, exhibited reduced baroreflex sensitivity (b = -0.16, p < .05). Moreover, the relationship between insulin resistance and baroreflex sensitivity was statistically mediated by cerebral blood flow in central autonomic regions, including the insula and cingulate cortex (mediation coefficients < -0.06, p-values < .01). Activity within the central autonomic network may link insulin resistance to reduced baroreflex sensitivity. Our observations may help to characterize the neural pathways by which insulin resistance, and possibly diabetes mellitus, relates to adverse cardiovascular outcomes.

Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife.

Objectives The development of Type 1 diabetes mellitus (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM. Methods Participants were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years, 32 men). Resting state blood oxygen level–dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid-attenuated inversion recovery images were analyzed to identify microstructural alterations and white-matter hyperintensity volumes. Results Later childhood onset of T1DM was associated with lower connectivity (F(8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F(8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white-matter hyperintensity volume, and lower microstructural integrity. Conclusions Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations.

Diabetes, Obesity, and the Brain: New Developments in Biobehavioral Medicine.

Diabetes and obesity, two major public health concerns, are associated with increased risk for problems in multiple organ systems, including the central nervous system. The adverse effects of diabetes and obesity on cognitive functioning are increasingly well recognized. This special issue of Psychosomatic Medicine features the latest research linking diabetes, obesity, and brain structure, function, and metabolism and follows a special meeting on this topic organized by the American Psychosomatic Society in October 2013. Evidence for the increased prevalence of diabetes and obesity is reviewed as it relates to cognitive decline. These articles indicate that the age of onset of Type 1 diabetes may be relevant to future cognitive function and that disease duration of Type 2 diabetes and sociocultural factors are related to cognitive decline during the aging process. The hypothalamus and other neural circuits, notably the dopaminergic system that underlies feeding and reward-related aspects of food intake, are among the key factors involved in obesity. Research on the associations between obesity and cognitive function is described using the positive effects of weight reduction following bariatric surgery or behavioral methods. This special issue concludes with a conceptual framework for linking obesity and diabetes with accelerated cognitive decline as related to the aging process. The collection of articles highlights the importance of using a life span perspective to understand the influence of both Type 1 and Type 2 diabetes on brain metabolism, function, and structure. Moreover, these studies show that distressing environmental circumstances can adversely influence neurocognitive dysfunction associated with obesity and diabetes.

Probing Prejudice with Startle Eyeblink Modification: A Marker of Attention, Emotion, or Both

In social neuroscience research, startle eyeblink modification can serve as a marker of emotion, but it is less clear whether it can also serve as a marker of prejudice. In Experiment 1, 30 White students viewed photographs of White and Black targets while the startle eyeblink reflex and facial EMG from the brow and cheek regions were recorded. Prejudice was related to facial EMG activity, but not to startle modification, which instead appeared to index attention to race. To test further whether racial categorizations are associated with differential attention, a dual-task paradigm was used in Experiment 2. Fifty-four White and fifty-five Black participants responded more slowly to a tone presented when viewing a racial outgroup member or a negative stimulus, indicating that both draw more attention than ingroup members or positive stimuli. We conclude that startle modification is useful to index differential attention to groups when intergroup threat is low.

Insulin sensitivity predicts brain network connectivity following a meal

&NA; There is converging evidence that insulin plays a role in food‐reward signaling in the brain and has effects on enhancing cognition. Little is known about how these effects are altered in individuals with insulin resistance. The present study was designed to identify the relationships between insulin resistance and functional brain connectivity following a meal. Eighteen healthy adults (7 male, 11 female, age: 41‐57 years‐old) completed a frequently‐sampled intravenous glucose tolerance test to quantify insulin resistance. On separate days at least one week apart, a resting state functional magnetic resonance imaging scan was performed: once after a mixed‐meal and once after a 12‐h fast. Seed‐based resting state connectivity of the caudate nucleus and eigenvector centrality were used to identify relationships between insulin resistance and functional brain connectivity. Individuals with greater insulin resistance displayed stronger connectivity within reward networks following a meal suggesting insulin was less able to suppress reward. Insulin resistance was negatively associated with eigenvector centrality in the dorsal anterior cingulate cortex following a meal. These data suggest that individuals with less sensitivity to insulin may fail to shift brain networks away from reward and toward cognitive control following a meal. This altered feedback loop could promote overeating and obesity. HighlightsInsulin plays a role in food‐reward signaling in the brain.It is not understood how insulin resistance affects insulins ability to modulate brain networks.We examined associations between insulin resistance and brain connectivity.Individuals with lower insulin sensitivity maintain reward connectivity after a meal.Higher insulin sensivity is associated with stronger connectivity in cognitive control regions.