Pathological amygdala activation during working memory performance: Evidence for a pathophysiological trait marker in bipolar affective disorder

Recent evidence suggests that deficits of working memory may be a promising neurocognitive endophenotype of bipolar affective disorder. However, little is known about the neurobiological correlates of these deficits. The aim of this study was to determine possible pathophysiological trait markers of bipolar disorder in neural circuits involved in working memory. Functional magnetic resonance imaging was performed in 18 euthymic bipolar patients and 18 matched healthy volunteers using two circuit‐specific experimental tasks established by prior systematic neuroimaging studies of working memory. Both euthymic bipolar patients and healthy controls showed working memory‐related brain activations that were highly consistent with findings from previous comparable neuroimaging studies in healthy subjects. While these patterns of brain activation were completely preserved in the bipolar patients, only the patients exhibited activation of the right amygdala during the articulatory rehearsal task. In the same task, functional activation in right frontal and intraparietal cortex and in the right cerebellum was significantly enhanced in the patients. These findings indicate that the right amygdala is pathologically activated in euthymic bipolar patients during performance of a circuit‐specific working memory task (articulatory rehearsal). This pathophysiological abnormality appears to be a trait marker in bipolar disorders that can be observed even in the euthymic state and that seems to be largely independent of task performance and medication. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Supersensitivity to light: possible trait marker for manic-depressive illness

Exposure to light during the night reduces plasma melatonin levels. A previous study showed that, in response to light, nighttime plasma melatonin levels fell twice as much in a group of acutely ill manic-depressive patients as in a group of normal subjects. The present study compares 11 euthymic manic-depressive patients not taking medications with 24 age- and sex-matched normal subjects. Melatonin levels in these patients also fell twice as much as the levels of the normal subjects, suggesting that supersensitivity to light may be a trait marker for bipolar affective disorder.     

H-reflex studies in a family with possibly X-linked neuronal Charcot-Marie-Tooth disease

The neuronal type of Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy, type II) was found to be present in ten of thirty-two members of one family.Motor nerve conduction velocities in this type of the disease may be normal in persons who are only mildly affected. Hoffmann-reflex investigation was effective in discriminating between affected and non-affected subjects. The mode of inheritance seemed to be X-linked, but this remained doubtful, because the outcome of the Hoffmann-reflex investigations was abnormal in one clinically non-affected boy.Xg(a)-typing gave no information as to linkage with the gene-locus of CMT. Close linkage between the loci for deutan anomaly and for CMT appeared to be very unlikely.     

Analgesia to painful stimuli in affective illness.

Patients with bipolar and unipolar affective illness (N = 76) were compared with 48 control subjects on a psychophysical pain rating procedure using both threshold and signal detection analysis. Affectively ill patients were more analgesic than controls, and depressed men were significantly more analgesic than depressed women or control subjects. Bipolar men showed a different pattern of analgesia than unipolar patients. Pain appreciation in depressed patients may be related to endogenous opiate-like substances; this could be assessed in narcotic antagonist studies of pain-tolerant depressed subjects.     

Thyroid function and affective illness: a reappraisal

It has been generally accepted that increased thyroid function facilitates treatment response in depression. Recent data show that response to several antidepressant treatments, particularly lithium and carbamazepine, are associated with decreased thyroid hormone levels. An alternative hypothesis that decreased thyroid indices are related to antidepressant response is proposed and clinical and research implications are discussed.     

Focal cortical dysplasia possibly related to a probable prenatal ischemic injury

Focal cortical dysplasias are a frequent etiology of partial seizure disorders refractory to medical treatment. We report the case of a patient with focal cortical dysplasia, confirmed by surgery, in association with ischemic cerebral lesions that possibly occurred during the intra-uterine development. This observation reinforces the hypothesis of a possible factor of causality between prenatal ischemia and anomalies of cortical development.     

A risk factor strategy for investigating affective illness

A "risk factor" approach to affective illness is outlined. Characteristics which are correlated with vulnerability to depression (or mania) should be sought and attempts made to either modify them or elucidate a pathophysiologic link between the characteristic and the illness. Genetic factors, biochemical factors, life events, demographic variables, and behavioral factors may be examined under the assumption that affective illness is multifactorially determined. Identification of these risk factors by a prospective epidemiologic study in a geographically delimited area is discussed; the risk factor model is compared with the high-risk model.     

Epileptic encephalopathy in children possibly related to immune-mediated pathogenesis

Severe epilepsy in the paediatric population negatively influences neurological and cognitive development. Different etiological factors could be responsible of these severe epilepsies, and an early diagnosis could change, in some cases, the neurological and cognitive development. Immune mechanisms have been reported in epilepsy. Epilepsy has been associated with systemic lupus erythematosus, with the presence of anti-phospholipid antibodies (aPL), anti-cardiolipin antibodies, anti-nuclear antibodies, Β2-glycoprotein antibodies, and anti-glutamic acid decarboxylase (anti-GAD) antibodies. CNS inflammation and markers of adaptive immunity have been, also, associated with some epileptic syndromes, such as West syndrome, temporal lobe epilepsy, febrile seizures, tonic–clonic seizures, and tuberous sclerosis. Inflammation and blood–brain barrier (BBB) disruption could be one of the mechanisms responsible for seizure recurrence. Recently clinical entities, characterized by severe epilepsy with a febrile, acute or sub-acute onset, sometimes associated with status epilepticus, followed by drug-resistant, partial epilepsy have been described. Some of these publications also suggested acronyms for the condition described: Acute Encephalitis with Refractory, Repetitive Partial Seizures (AERRPS) reported by Japanese authors, Devastating Epileptic Encephalopathy in School-aged Children (DESC) reported by French authors. Among children with acquired symptomatic severe epilepsy, we identified a group of previously normal children who had developed severe partial epilepsy after an acute/sub-acute illness resembling encephalitis. The etiological factors for those patients seems to remain unknown, and a possible immune-mediating or inflammatory process as pathogenesis of the disease could be hypothesized. More studies need to be addressed to finally define this peculiar epileptic entity.     

Prolactin and growth hormone response to levodopa in affective illness

Prolactin (PRL) and growth hormone (GH) response to L-Dopa have been studied in 51 affectively ill women (26 unipolar and 25 bipolar) before and after amitriptyline treatment and in 14 normal female controls. There was no difference in GH response to L-dopa in all groups studied except for bipolar postmenopausal women, who showed a blunted GH response to L-Dopa compared to bipolar premenopausal women. After amitriptyline treatment, no difference in GH response was found in all groups studied. Basal PRL levels were significantly lower in unipolar premenopausal and bipolar premenopausal patients in comparison to their controls. PRL response to L-Dopa was significantly less inhibited in postmenopausal controls than in premenopausal controls and in bipolar premenopausal patients compared to premenopausal controls. These data provide further evidence of hypothalamo-pituitary dysfunction in subgroups of affective disorders and emphasize the importance of considering the menopausal status in neuroendocrine studies of psychiatric disorders.     

Evidence for a locus on chromosome 1 that influences vulnerability to alcoholism and affective disorder

OBJECTIVE: Depression (major depression or depressive syndrome) is more prevalent in alcoholic than in nonalcoholic subjects in families with multiple members with alcoholism studied as part of the Collaborative Study on the Genetics of Alcoholism (National Institute on Alcohol Abuse and Alcoholism). First-degree relatives of probands with comorbid alcoholism and depression have a higher prevalence of both disorders than relatives of probands with alcoholism alone, and both groups have a higher prevalence than the relatives of comparison subjects selected without regard to psychopathology. Data from the collaborative study were used to test three phenotypes (comorbid alcoholism and depression, alcoholism or depression, and depression) for genetic linkage. METHOD: Genome-wide sibling-pair linkage analyses were performed with the phenotypes comorbid alcoholism and depression, alcoholism or depression, and depression (major depression or depressive syndrome). Analyses were performed in two data sets (initial and replication data sets) from subject groups ascertained with identical criteria, as well as in the combined data set. RESULTS: Peak lod scores on chromosome 1 (near 120 centimorgan) for the alcoholism or depression phenotype were 5.12, 1.52, and 4.66 in the initial, replication, and combined data sets, respectively. The corresponding lod scores on chromosome 2 were 2.79, 0.20, and 3.26; on chromosome 6, they were 3.39, 0.00, and 0.92; and on chromosome 16, they were 3.13, 0.00, and 2.06. Lod scores on chromosome 2 for the comorbid alcoholism and depression phenotype in the three data sets were 0.00, 4.12, and 2.16, respectively. CONCLUSIONS: The results suggest that a gene or genes on chromosome 1 may predispose some individuals to alcoholism and others to depression (which may be alcohol induced). Loci on other chromosomes may also be of interest.     

Genes related to phospholipid metabolism as risk factors related to bipolar affective disorder

The studies of genetic epidemiology provides consistent evidence of genetic factors having a major role on the risk for the bipolar affective disorder, although, vulnerability genes have not yet been identified in unequivocal form. The authors show that phospholipids play an important role in the cellular signalling processes, besides this, some studies with mood-stabilisers neurochemistry suggest that these drugs act in the phospholipase regulated signalling views. They conclude that analysis of gene variants that code enzymes of the phospholipids metabolism as potential susceptibility genes can extend the knowledge concerning the risk factors and the physiopatological mechanisms underling this mood disturbance.     

A hypothesis of thyroid-catecholamine-receptor interaction. Its relevance to affective illness

Recent prospective studies suggest that thyroid state plays a role in affective disorders. A lack of thyroid hormones can lower the threshold for depression; an excess can contribute to a state of tense dysphoria. Thyroid function in some persons also appears to influence the course of affective disorders. Adequate mobilization of thyroid hormones favors recovery from depression; excess mobilization increases the risk of mania in vulnerable individuals. Although other mechanisms may be involved, evidence suggests that the modulation by thyroid hormones of the beta-adrenergic receptor response to catecholamines may contribute to these effects. Norepinephrine stimulates such receptors; thyroid hormones increase their ability to receive stimulation. The plausibility of such interactions between catecholamines and thyroid hormones occurring in the CNS is strengthened by their common origin in the amino acid tyrosine and by their synergism in many metabolic processes.     

Glycine: a possible role in lithium's action and affective illness

In addition to its incorporation into proteins, glycine functions as both a regulator of one-carbon metabolism and as an inhibitory neurotransmitter. Clinical recognition of the hyperglycinemias and reported elevations of erythrocyte glycine concentrations in patients with bipolar disorders have implicated this amino acid in the etiopathology of some neuropsychiatric disorders. Moreover, chronic lithium administration, an almost specific intervention for the treatment and prophylaxis of bipolar disorders, has been shown to induce elevations in brain and erythrocyte glycine levels. In view of glycine's complex metabolic interrelationships and neurotransmitter function, additional research exploring its possible role in either affective illness or lithium's action is indicated.     

Myelin mosaicism and brain plasticity in heterozygous females of a canine X-linked trait

The shaking (sh)pup, an animal model of Pelizaeus-Merzbacher disease, is characterized by severe central nervous system dysmyelination in affected males, and myelin mosaicism in some female heterozygotes as a result of X-linked inactivation. Heterozygous females develop a tremor of varying severity that usually disappears at 4 to 6 weeks, whereas male hemizygotes have severe, generalized tremor that persists throughout life. We have used these two myelin-deficient models to study the potential for recovery with time as reflected by brainstem auditory evoked responses (BAERs). At set time points, the state of myelination in the trapezoid body was studied microscopically. Sequential BAERs demonstrated consistently prolonged interpeak latencies during the period of gross tremor in heterozygotes, with the trend continuing to a lesser extent after tremor cessation. The random nature of X-linked inactivation resulted in variable myelin mosaicism that was reflected in variations in BAER changes within animals in the same litter. In most heterozygotes, the tremor resolved with time, the BAE returned to near normal, and myelin mosaicism was lost. In contrast, in the affected males, the severity of tremor and lack of recovery was demonstrated by consistent abnormalities in BAER waves at all times studied, and severe and persistent myelin deficiency in the trapezoid body. These findings show that despite the normal tightly programmed temporal development of myelin in the brain in the heterozygous mosaic state, sufficient plasticity persists during the neonatal period for late-stage myelination to occur.     

Motor activity and affective illness. The relationship of amplitude and temporal distribution to changes in affective state

We measured motor activity with a self-contained monitoring device worn on the wrists of affectively ill patients and volunteer normal control subjects. Decreases in the daytime motor activity level were observed in depressed patients, compared with their improved (euthymic) or manic mood states. Moreover, affectively ill patients, even during euthymic periods, showed lower daytime motor activity levels than the control group housed in the same ward. These data provide objective evidence for decreases in motor activity that occur concomitantly with the depressive phase of illness in patients with affective disorder, and fluctuate in patients in euthymic or manic phases.