Abstract: “Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition.”
Grace AA and Gomes FV: The Circuitry of Dopamine System Regulation and its Disruption in Schizophrenia: Insights Into Treatment and Prevention. Schizophr. Bull.[Epub ahead of print, Jan. 29, 2018; doi: 10.1093/schbul/sbx199.].
“The effects of neurodegenerative syndromes extend beyond cognitive function to involve key physiological processes, including eating and metabolism, autonomic nervous system function, sleep, and motor function. Changes in these physiological processes are present in several conditions, including frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer disease and the parkinsonian plus conditions. Key neural structures that mediate physiological changes across these conditions include neuroendocrine and hypothalamic pathways, reward pathways, motor systems and the autonomic nervous system.” In this review, the key changes in physiological processing in neurodegenerative syndromes are highlighted. The authors suggest that changes and similarities between disorders might provide novel insights into the human neural correlates of physiological functioning. These changes may provide biomarkers to aid in the early diagnosis of neurodegenerative diseases and treatment.
Ahmed RM, Ke YD, Vucic S, Ittner LM, Seeley W, Hodges JR, Piguet O, Halliday G, Kiernan MC Physiological changes in neurodegeneration – mechanistic insights and clinical utility. Nature Rev. Neurol. [Epub ahead of print, March 23, 2018; doi: 10.1038/nrneurol.2018.23].
This study shows that the number of mature neurons in the human amygdala increases from childhood into adulthood. The authors suggest that this trajectory may be due to the incorporation of immature neurons from the paralaminar nucleus in the ventral amygdala. In contrast, individuals with autism spectrum disorder show an initial excess of mature neurons followed by a decline into adulthood. The results suggest a degenerative component in autism spectrum disorder and highlight the need for a more comprehensive understanding of the protracted cellular development of the human amygdala for multiple psychiatric disorders.
Avino TA, Barger N, Vargas MV, Carlson EL, Amaral DG, Bauman MD, Schumann CM: Neuron numbers increase in the human amygdala from birth to adulthood, but not in autism. PNAS 115 (14) 3710-3715 (2018).
Bipolar disorder is considered to be a leading cause of global disability. Its biological basis is unknown, and its treatment is not optimal. Here, Harrison and colleagues review two recent areas of progress.” First, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target. Second, facilitated by new technologies, it is increasingly apparent that the bipolar phenotype is more complex and nuanced than simply one of recurring manic and depressive episodes. One such feature is persistent mood instability, and efforts are underway to understand its mechanisms and its therapeutic potential. Bipolar disorder illustrates how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches.”
Harrison PJ, Geddes JR, Tunbridge EM: The Emerging Neurobiology of Bipolar Disorder. Trends Neurosci. 41(1):18-30 (2018).
The current report analyzed mitochondrial complex I activity in bipolar disorder patients, schizophrenics, and control subjects and in the presence of antipsychotic and antidepressant medications.
Complex I activity in the prefrontal cortex was decreased by 45% in schizophrenics compared to controls. No significant difference was found in bipolar disorder. Complex I activity was also significantly decreased in pooled cases (schizophrenic and bipolar) that had detectable psychotropic medications compared to pooled cases with no detectable drug levels.
The study concluded that complex I deficiency is found in schizophrenic brain tissue, and that psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.
Rollins BL, Morgan L, Hjelm BE, Sequeira A, Schatzberg AF, Barchas JD, Lee FS, Myers RM, Watson SJ, Akil H, Potkin SG, Bunney WE, Vawter MP: Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence. Mol. Neuropsychiatry 3(3) 157-169 (2018).
“Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis.” Here, Tomasella and colleagues “show that selective dopamine D2 receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. (These) findings show that dopamine D2 receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.”
Tomasella E, Bechelli L, Ogando MB, Mininni C, Di Guilmi MN, De Fino F, Zanutto S, Elgoyhen AB, Marin-Burgin A, Gelman DM: Deletion of dopamine D2 receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes. Proc. Natl. Acad. Sci. USA pii: 201719897. doi: 10.1073/pnas.1719897115. [Epub ahead of print, March 12, 2018].
The purpose of this study was to investigate whether greater cardiovascular fitness in midlife is associated with decreased dementia risk in women followed for 44 years. A population-based sample of 1,462 women 38 to 60 years of age was examined in 1968. Of these, a systematic subsample comprising 191 women completed a stepwise-increased maximal ergometer cycling test to evaluate cardiovascular fitness. Subsequent examinations of dementia incidence were done in 1974, 1980, 1992, 2000, 2005, and 2009.
The study found that high cardiovascular fitness in midlife was associated with decreased risk of dementia. High compared to medium fitness decreased the risk of dementia by 88%. The authors suggest that promotion of high cardiovascular fitness may be included in strategies to combat dementia. Findings are not causal, and future research is needed on whether improved fitness could have positive effects on dementia risk and when during the life course a high cardiovascular fitness is the most important.
Hörder H, Johansson L, Guo X, Grimby G, Kern S, Östling S, Skoog I: Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology: pii: 10.1212/WNL.0000000000005290. doi: 10.1212/WNL.0000000000005290. [Epub ahead of print, March 14, 2018].
“New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons.” Here Sorrells and colleagues report that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. They also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years), young neurons were not detected in the dentate gyrus.
The authors concluded that “recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.”
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF, Gutierrez AJ, Kriegstein AR, Mathem GW, Oldham MC, Huang EJ, Garcia-Verdugo JM, Yang Z, Alvarez-Buylla A: Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature [ Epub ahead of print; March 7, 2018; doi: 10.1038/nature25975 ].
This study examined the risks of myocardial infarction, stroke, peripheral artery disease, venous thromboembolism, atrial fibrillation, and heart failure in patients with migraine and in a general population comparison cohort.
Higher risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. Migraine was positively associated with myocardial infarction, ischaemic stroke, and haemorrhagic stroke, as well as venous thromboembolism and atrial fibrillation or atrial flutter. No meaningful association was found with peripheral artery disease or heart failure. The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men.
The authors concluded that migraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. They suggest that migraine may be an important risk factor for most cardiovascular diseases.
Adelborg K, Szépligeti SK, Holland-Bill L, Ehrenstein V, Horváth-Puhó E, Henderson VW, Sørensen HT: Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ. 2018 Jan 31;360:k96. doi: 10.1136/bmj.k96.