Insular and occipital changes in visual snow syndrome: a BOLD fMRI and MRS study.

OBJECTIVE: To investigate the pathophysiology of visual snow (VS), through a combined functional neuroimaging and magnetic resonance spectroscopy (1 H-MRS) approach. METHODS: We applied a functional MRI block-design protocol studying the responses to a visual stimulation mimicking VS, in combination with 1 H-MRS over the right lingual gyrus, in 24 patients with VS compared to an equal number of age- and gender-matched healthy controls. RESULTS: We found reduced BOLD responses to the visual stimulus with respect to baseline in VS patients compared to controls, in the left (k = 291; P = 0.025; peak MNI coordinate [-34 12 -6]) and right (k = 100; P = 0.003; peak MNI coordinate [44 14 -2]) anterior insula. Our spectroscopy analysis revealed a significant increase in lactate concentrations in patients with respect to controls (0.66 ± 0.9 mmol/L vs. 0.07 ± 0.2 mmol/L; P < 0.001) in the right lingual gyrus. In this area, there was a significant negative correlation between lactate concentrations and BOLD responses to visual stimulation (P = 0.004; r = -0.42), which was dependent on belonging to the patient group. INTERPRETATION: As shown by our BOLD analysis, VS is characterized by a difference in bilateral insular responses to a visual stimulus mimicking VS itself, which could be due to disruptions within the salience network. Our results also suggest that patients with VS have a localized disturbance in extrastriate anaerobic metabolism, which may in turn cause a decreased metabolic reserve for the regular processing of visual stimuli.

An experimental model of Braak's pretangle proposal for the origin of Alzheimer's disease: the role of locus coeruleus in early symptom development.

BACKGROUND: The earliest brain pathology related to Alzheimer's disease (AD) is hyperphosphorylated soluble tau in the noradrenergic locus coeruleus (LC) neurons. Braak characterizes five pretangle tau stages preceding AD tangles. Pretangles begin in young humans and persist in the LC while spreading from there to other neuromodulatory neurons and, later, to the cortex. While LC pretangles appear in all by age 40, they do not necessarily result in AD prior to death. However, with age and pretangle spread, more individuals progress to AD stages. LC neurons are lost late, at Braak stages III-IV, when memory deficits appear. It is not clear if LC hyperphosphorylated tau generates the pathology and cognitive changes associated with preclinical AD. We use a rat model expressing pseudohyperphosphorylated human tau in LC to investigate the hypothesis that LC pretangles generate preclinical Alzheimer pathology. METHODS: We infused an adeno-associated viral vector carrying a human tau gene pseudophosphorylated at 14 sites common in LC pretangles into 2-3- or 14-16-month TH-Cre rats. We used odor discrimination to probe LC dysfunction, and we evaluated LC cell and fiber loss. RESULTS: Abnormal human tau was expressed in LC and exhibited somatodendritic mislocalization. In rats infused at 2-3 months old, 4 months post-infusion abnormal LC tau had transferred to the serotonergic raphe neurons. After 7 months, difficult similar odor discrimination learning was impaired. Impairment was associated with reduced LC axonal density in the olfactory cortex and upregulated ß1-adrenoceptors. LC infusions in 14-16-month-old rats resulted in more severe outcomes. By 5-6 months post-infusion, rats were impaired even in simple odor discrimination learning. LC neuron number was reduced. Human tau appeared in the microglia and cortical neurons. CONCLUSIONS: Our animal model suggests, for the first time, that Braak's hypothesis that human AD originates with pretangle stages is plausible. LC pretangle progression here generates both preclinical AD pathological changes and cognitive decline. The odor discrimination deficits are similar to human odor identification deficits seen with aging and preclinical AD. When initiated in aged rats, pretangle stages progress rapidly and cause LC cell loss. These age-related outcomes are associated with a severe learning impairment consistent with memory decline in Braak stages III-IV.

Visual-spatial neglect after right-hemisphere stroke: behavioral and electrophysiological evidence.

BACKGROUND: Visual-spatial neglect (VSN) is a neuropsychological syndrome, and right-hemisphere stroke is the most common cause. The pathogenetic mechanism of VSN remains unclear. This study aimed to investigate the behavioral and event-related potential (ERP) changes in patients with or without VSN after right-hemisphere stroke. METHODS: Eleven patients with VSN with right-hemisphere stroke (VSN group) and 11 patients with non-VSN with right-hemisphere stroke (non-VSN group) were recruited along with one control group of 11 age- and gender-matched healthy participants. The visual-spatial function was evaluated using behavioral tests, and ERP examinations were performed. RESULTS: The response times in the VSN and non-VSN groups were both prolonged compared with those of normal controls (P < 0.001). In response to either valid or invalid cues in the left side, the accuracy in the VSN group was lower than that in the non-VSN group (P < 0.001), and the accuracy in the non-VSN group was lower than that in controls (P < 0.05). The P1 latency in the VSN group was significantly longer than that in the control group (F[2, 30] = 5.494, P = 0.009), and the N1 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30] = 4.343, P = 0.022). When responding to right targets, the left-hemisphere P300 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30] = 4.255, P = 0.025). With either left or right stimuli, the bilateral-hemisphere P300 latencies in the VSN and non-VSN groups were both significantly prolonged (all P < 0.05), while the P300 latency did not differ significantly between the VSN and non-VSN groups (all P > 0.05). CONCLUSIONS: Visual-spatial attention function is impaired after right-hemisphere stroke, and clinicians should be aware of the subclinical VSN. Our findings provide neuroelectrophysiological evidence for the lateralization of VSN.

Variable sensory perception in autism.

Autism is associated with sensory and cognitive abnormalities. Individuals with autism generally show normal or superior early sensory processing abilities compared to healthy controls, but deficits in complex sensory processing. In the current opinion paper, it will be argued that sensory abnormalities impact cognition by limiting the amount of signal that can be used to interpret and interact with environment. There is a growing body of literature showing that individuals with autism exhibit greater trial-to-trial variability in behavioural and cortical sensory responses. If multiple sensory signals that are highly variable are added together to process more complex sensory stimuli, then this might destabilise later perception and impair cognition. Methods to improve sensory processing have shown improvements in more general cognition. Studies that specifically investigate differences in sensory trial-to-trial variability in autism, and the potential changes in variability before and after treatment, could ascertain if trial-to-trial variability is a good mechanism to target for treatment in autism.

Noradrenergic antagonists mitigate amphetamine-induced recovery.

Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and ß-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment.

High-Intensity Exercise as a Dishabituating Stimulus Restores Counterregulatory Responses in Recurrently Hypoglycemic Rodents.

Hypoglycemia is a major adverse effect of insulin therapy for people with type 1 diabetes (T1D). Profound defects in the normal counterregulatory response to hypoglycemia explain the frequency of hypoglycemia occurrence in T1D. Defective counterregulation results to a large extent from prior exposure to hypoglycemia per se, leading to a condition called impaired awareness of hypoglycemia (IAH), the cause of which is unknown. In the current study, we investigate the hypothesis that IAH develops through a special type of adaptive memory referred to as habituation. To test this hypothesis, we used a novel intense stimulus (high-intensity exercise) to demonstrate two classic features of a habituated response, namely dishabituation and response recovery. We demonstrate that after recurrent hypoglycemia the introduction of a novel dishabituating stimulus (a single burst of high-intensity exercise) in male Sprague-Dawley rats restores the defective hypoglycemia counterregulatory response. In addition, the rats showed an enhanced response to the novel stimulus (response recovery). We make the further observation using proteomic analysis of hypothalamic extracts that high-intensity exercise in recurrently hypoglycemic rats increases levels of a number of proteins linked with brain-derived neurotrophic factor signaling. These findings may lead to novel therapeutic approaches for individuals with T1D and IAH.

Common behavioral clusters and subcortical anatomy in stroke.

A long-held view is that stroke causes many distinct neurological syndromes due to damage of specialized cortical and subcortical centers. However, it is unknown if a syndrome-based description is helpful in characterizing behavioral deficits across a large number of patients. We studied a large prospective sample of first-time stroke patients with heterogeneous lesions at 1-2 weeks post-stroke. We measured behavior over multiple domains and lesion anatomy with structural MRI and a probabilistic atlas of white matter pathways. Multivariate methods estimated the percentage of behavioral variance explained by structural damage. A few clusters of behavioral deficits spanning multiple functions explained neurological impairment. Stroke topography was predominantly subcortical, and disconnection of white matter tracts critically contributed to behavioral deficits and their correlation. The locus of damage explained more variance for motor and language than memory or attention deficits. Our findings highlight the need for better models of white matter damage on cognition.

Gray colored glasses: is major depression partially a sensory perceptual disorder?

BACKGROUND: Major depression is a neuropsychiatric disorder that can involve profound dysregulation of mood. While depression is associated with additional abnormalities besides reduced mood, such as cognitive dysfunction, it is not well established that sensory perception is also altered in this disorder (aside from in psychotic depression). Recent studies have shown that visual processing, in as early a stage as the retina, is impaired in depression. This paper examines the hypothesis that major depression can involve alterations in sensory perception. METHODS: A Pubmed literature search investigated several lines of evidence: innervation of sensory cortex by serotonin and norepinephrine; antidepressant drugs and depression itself affecting processing of facial expressions of emotion; electroencephalography (EEG) studies of depressed persons and antidepressant drugs; involvement of the serotonergic 5HT2A receptor in both depression and hallucinogenic drug action; psychotic depression involving sensory distortions; dopamine possibly playing a role in depression; and the antidepressant effect of blocking the NMDA receptor with ketamine. RESULTS: Data from each of these lines of evidence support the hypothesis that major depression can involve sensory perceptual alterations. CONCLUSIONS: Loss of interest in one's daily activities and inability to experience pleasure, also known as anhedonia, in major depression may in part be mediated by sensory abnormalities, whereby normal sensory perceptions are no longer present to activate reward circuitry. LIMITATIONS: The data supporting the hypothesis tend to be associative, so further confirmation of the hypothesis awaits additional controlled experiments.

Synesthesia in science and technology: more than making the unseen visible.

Much of our science and technology relies on the visualization of complex data, and chemical biology, more than most fields, often deals with complex datasets. There are, however, other ways of making information available to our senses beyond the visual. Rare individuals naturally have sensory crossover, whose synesthesia permits them, for example, to see colors or shapes when hearing sounds or to sense a specific taste with a specific word. Many scientists, technologists and inventors, however, make a conscious attempt to convert one type of sensory-like input to a different sensory output. A laser light show, for example, converts sound to sight; infrared imaging converts heat to sight. Two recent examples of such intentional synesthesia are discussed in this context: sight-tasting and smell-seeing.

Relationships among 5-HTT genotype, life events and gender in the recognition of facial emotions.

Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin-transporter (5-HTTLPR) modulates neural activation during the perceptual processing of emotional facial expressions. Furthermore, behavioral research has shown that attentional bias for negative information is increased in s allele carriers. We examined the interactions among 5-HTTLPR (including SNP rs25531), life events and gender on the detection of facial emotions. We found a main effect of genotype, as well as moderating effects of childhood emotional abuse (CEA) and recent life events (RLE). S homozygous participants recognized negative facial expressions at a lower intensity than the other genotype groups. This effect was more evident in female participants and in participants who had experienced life events. The 5-HTTLPR genotype affects facial emotional perception, a process which is linked to a neurobiological response to threat and vulnerability to emotional disorders.

Risk variants in the S100B gene, associated with elevated S100B levels, are also associated with visuospatial disability of schizophrenia.

Rs9722 and rs1051169 have been reported as affecting the levels of S100B in the serum or the brain, and haplotypes containing these two SNPs have been associated with schizophrenia. The current study investigated the role of the S100B gene in an endophenotype of schizophrenia-spatial disability. 304 schizophrenia patients and 196 healthy controls were given a block design task and a mental rotation task. Results showed that the two aforementioned SNPs and related haplotypes were associated with the spatial disability of schizophrenia patients. Specifically, risk factors for the elevated S100B levels, including the A allele of rs9722, the G allele of rs1051169, and the AG haplotype, were associated with a poorer performance on both tests of spatial ability, especially the mental rotation task. These results implicate a role for S100B gene polymorphisms in the cognitive functions of schizophrenia patients and encourage further investigation into spatial disability as an endophenotype of schizophrenia.

Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease.

Olfactory dysfunction is common in subjects with Parkinson's disease. The pathophysiology of such dysfunction, however, remains poorly understood. Neurodegeneration within central regions involved in odour perception may contribute to olfactory dysfunction in Parkinson's disease. Central cholinergic deficits occur in Parkinson's disease and cholinergic neurons innervate regions, such as the limbic archicortex, involved in odour perception. We investigated the relationship between performance on an odour identification task and forebrain cholinergic denervation in Parkinson's disease subjects without dementia. Fifty-eight patients with Parkinson's disease (mean Hoehn and Yahr stage 2.5 + or - 0.5) without dementia (mean Mini-Mental State Examination, 29.0 + or - 1.4) underwent a clinical assessment, [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase brain positron emission tomography and olfactory testing with the University of Pennsylvania Smell Identification Test. The diagnosis of Parkinson's disease was confirmed by [(11)C]dihydrotetrabenazine vesicular monoamine transporter type 2 positron emission tomography. We found that odour identification test scores correlated positively with acetylcholinesterase activity in the hippocampal formation (r = 0.56, P < 0.0001), amygdala (r = 0.50, P < 0.0001) and neocortex (r = 0.46, P = 0.0003). Striatal monoaminergic activity correlated positively with odour identification scores (r = 0.30, P < 0.05). Multiple regression analysis including limbic (hippocampal and amygdala) and neocortical acetylcholinesterase activity as well as striatal monoaminergic activity, using odour identification scores as the dependent variable, demonstrated a significant regressor effect for limbic acetylcholinesterase activity (F = 10.1, P < 0.0001), borderline for striatal monoaminergic activity (F = 1.6, P = 0.13), but not significant for cortical acetylcholinesterase activity (F = 0.3, P = 0.75). Odour identification scores correlated positively with scores on cognitive measures of episodic verbal learning (r = 0.30, P < 0.05). These findings indicate that cholinergic denervation of the limbic archicortex is a more robust determinant of hyposmia than nigrostriatal dopaminergic denervation in subjects with moderately severe Parkinson's disease. Greater deficits in odour identification may identify patients with Parkinson's disease at risk for clinically significant cognitive impairment.

Assessment of NMDA receptor NR1 subunit hypofunction in mice as a model for schizophrenia.

N-methyl-D-aspartate receptors (NMDARs) play a pivotal role in excitatory neurotransmission, synaptic plasticity and brain development. Clinical and experimental evidence suggests a dysregulation of NMDAR function and glutamatergic pathways in the pathophysiology of schizophrenia. We evaluated electrophysiological and behavioral properties of NMDAR deficiency utilizing mice that express only 5-10% of the normal level of NMDAR NR1 subunit. Auditory and visual event related potentials yielded significantly increased amplitudes for the P20 and N40 components in NMDAR deficient (NR1(neo)-/-) mice suggesting decreased inhibitory tone. Compared to wild types, NR1(neo)-/- mice spent less time in social interactions and showed reduced nest building. NR1(neo)-/- mice displayed a preference for open arms of a zero maze and central zone of an open field, possibly reflecting decreased anxiety-related behavioral inhibition. However, locomotor activity did not differ between groups in either home cage environment or during behavioral testing. NR1(neo)-/- mice displayed hyperactivity only when placed in a large unfamiliar environment, suggesting that neither increased anxiety nor non-specific motor activation accounts for differential behavioral patterns. Data suggest that NMDAR NR1 deficiency causes disinhibition in sensory processing as well as reduced behavioral inhibition and impaired social interactions. The behavioral signature in NR1(neo)-/- mice supports the impact of impaired NMDAR function in a mouse model with possible relevance to negative symptoms in schizophrenia.

gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation.

BACKGROUND: This study tested the hypothesis that deficits in gamma-aminobutyric acid type A (GABA(A)) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT(2A/2C)) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABA(A) receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT(2A/2C) receptors, were studied in 23 healthy male subjects. METHODS: Subjects underwent 4 days of testing, during which they received intravenous infusions of iomazenil/placebo followed by m-CPP/placebo in a double-blind, randomized crossover design. Behavioral, cognitive, and hormonal data were collected before drug infusions and periodically for 200 min after. RESULTS: Iomazenil and m-CPP interacted in a synergistic manner to produce mild psychotic symptoms and perceptual disturbances without impairing cognition. Iomazenil and m-CPP increased anxiety in an additive fashion. Iomazenil and m-CPP interacted in a synergistic manner to increase serum cortisol. CONCLUSIONS: Gamma-aminobutyric acid-ergic deficits might increase the vulnerability to the psychotomimetic and perceptual altering effects of serotonergic agents. These data suggest that interactions between GABA(A) and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.

Apolipoprotein E-deficient mice exhibit increased vulnerability to intermittent hypoxia-induced spatial learning deficits.

Exposure to intermittent hypoxia, such as occurs in sleep-disordered breathing, is associated with oxidative stress, cognitive impairments, and increased neuronal apoptosis in brain regions involved in learning and memory. Apolipoprotein E (ApoE) has been implicated in neurodegenerative disorders, and in vitro studies suggest that one of the functions of ApoE may be to confer protection from oxidant stress-induced neuronal cell loss. Therefore, we hypothesized that ApoE-deficient (ApoE-/-) mice would display increased cognitive impairments following intermittent hypoxia. Twenty-four young adult male mice (ApoE-/-) and 24 wild-type littermates (ApoE +/+) were exposed to 14 days of normoxia (room air; n=12 per group) or intermittent hypoxia (5.7% O2 alternating with 21% O2 every 90 seconds, 12 daylight hours per day; n=12 per group). Behavioral testing consisting of a standard place-training reference memory task in the water maze revealed that ApoE+/+ and ApoE-/- mice exposed to intermittent hypoxia were found to require significantly longer times (latency) and distances (pathlength) to locate the hidden platform (P < .005), compared to mice exposed to room air. However, only intermittent hypoxia-exposed ApoE-/- mice were impaired on the final two days of training (P < .03), as well as on measures of spatial bias conducted 24 hours after completion of training (P < .02). Furthermore, increased prostaglandin E2 and malondiadehyde concentrations were present in hippocampal brain tissues following intermittent hypoxia but were significantly higher in ApoE-/- mice (P < .01). Thus, decreased ApoE function is associated with increased susceptibility to neurocognitive dysfunction in a rodent model of sleep-disordered breathing and may underlie the increased prevalence of Apolipoprotein E4 in patients with sleep-disordered breathing.

Impaired visuospatial recognition memory but normal object novelty detection and relative familiarity judgments in adult mice expressing the APPswe Alzheimer's disease mutation.

The present study examined the effects of a human APPswe mutation on object recognition memory in adult Tg2576 mice. The results showed that 14-month old Tg2576 mice were able to detect object novelty as well as control mice, even with delays of up to 24 hr. In addition, transgenic mice showed a normal recency effect and explored the most recently encountered object significantly less than an object encountered earlier in a trial. However, adult Tg2576 mice showed impairments in detecting a change in the relative positions of an array of familiar objects. The results suggest that the formation of representations involving a combination of object identity and spatial information are particularly sensitive to amyloid pathology in adult APPswe mutant mice.

Impact of repetitive transcranial magnetic stimulation of the parietal cortex on metabolic brain activity: a 14C-2DG tracing study in the cat.

Transcranial magnetic stimulation (TMS) is increasingly utilized in clinical neurology and neuroscience. However, detailed knowledge of the impact and specificity of the effects of TMS on brain activity remains unresolved. We have used 14C-labeled deoxyglucose (14C-2DG) mapping during repetitive TMS (rTMS) of the posterior and inferior parietal cortex in anesthetized cats to study, with exquisite spatial resolution, the local and distant effects of rTMS on brain activity. High-frequency rTMS decreases metabolic activity at the primary site of stimulation with respect to homologue areas in the unstimulated hemisphere. In addition, rTMS induces specific distant effects on cortical and subcortical regions known to receive substantial efferent projections from the stimulated cortex. The magnitude of this distal impact is correlated with the strength of the anatomical projections. Thus, in the anesthetized animal, the impact of rTMS is upon a distributed network of structures connected to the primary site of application.

Apolipoprotein E, B vitamins, and cognitive function in older adults.

Recognition of dated and contemporary famous faces, short-term memory, and visuospatial abilities were investigated in adults aged 75 years and older as a function of apolipoprotein E (APOE) genotype, epsilon4 or not epsilon4, and whether participants recorded normal or low levels of B vitamins. No associations between B vitamins and APOE were identified in respect to short-term memory or visuospatial skills, or for contemporary famous faces. However, in respect to the recognition of dated famous faces, deficits in persons carrying the epsilon4 allele who also recorded low vitamin B(12) values were found. The results suggest that the neurological structures and processes supporting face recognition may be vulnerable to the combined influence of the APOE epsilon4 allele and low levels of vitamin B(12). This finding was unrelated to incipient dementia up to 6 years following testing. The results are discussed with reference to the neuroanatomical reserves that epsilon4 carriers may possess.

Neuroimaging analysis of a case with left homonymous hemianopia and left hemispatial neglect.

PURPOSE: To correlate the neuro-ophthalmological observations with the magnetic resonance images (MRI) and positron emission tomographic (PET) findings in a case with left homonymous hemianopia and left hemispatial neglect. CASE: A 57-year-old woman underwent surgery for a ruptured anterior communicating artery aneurysm. After she recovered consciousness, it was found that she had left homonymous hemianopia and left hemispatial neglect. Although the hemispatial neglect slowly improved, the homonymous hemianopia persisted. MRI and measurements of cerebral glucose metabolism by 2-fluoro-2-deoxy-D-glucose(FDG)-PET were performed 1 year later. RESULTS: MRI revealed infarctions on the medial surface of the frontal lobe, on the right medial surface of the occipital lobe, and global atrophy of the right cortical hemisphere. FDG-PET disclosed severe glucose hypometabolism in the entire right hemisphere. Glucose metabolism in the right occipital cortex was 61.1% of that in the homologous region on the left side, 62.8% in the right anterior cingulate gyrus, and 93.8% in the temporal-parietal-occipital junction. CONCLUSIONS: The low glucose metabolism in the right visual cortex explains the persistent left hemianopia, and that in the right anterior cingulate gyrus and the right temporal-parietal-occipital junction may be responsible for the left hemispatial neglect. The relatively mild damage in the right temporal-parietal-occipital junction explained the recovery of the neglect symptom. Measurements of regional cerebral glucose metabolism by PET are useful for determining the cause of cerebral visual dysfunction and its prognosis after a cerebral lesion.