On the physiology of cognitive decline in type 1 diabetes.

OBJECTIVES: Type 1 diabetes mellitus (T1DM) may be associated with cognitive impairment and notably a decline in psychomotor speed, information processing speed and attention. The mechanism for this decline is uncertain. Previous studies by our group and others have demonstrated a decline in EEG-power and event-related potential amplitude in T1DM. The objectives of the present study were to explore whether 1) the association between event-related potential (N100) amplitude and psychomotor speed is different between T1DM and healthy subjects, and 2) the decline in N100 amplitude depends on duration of diabetes. METHODS: Patients with T1DM (N = 204) and healthy control subjects (N = 358) were included in a cross-sectional study. Event-related brain potentials were recorded with auditory reaction tasks. Psychomotor speed was evaluated with the Grooved Pegboard test in a subset of the patients (N = 70) and the healthy control subjects (N = 89). RESULTS: Patients with T1DM had a decrease in the N100 amplitude that correlated with a decline in psychomotor speed, longer duration of diabetes and increasing age. In healthy controls, the N100 amplitude did not decrease with age and the association between psychomotor speed and N100 amplitude was absent. CONCLUSION: The association between psychomotor speed and N100 amplitude is likely to be a specific trait for T1DM since it was not found in healthy controls and was dependent on diabetes duration. Our findings indicate that the pathogenesis of cognitive decline in T1DM may involve a disease-related factor with a long-term influence on the N100 amplitude.

Mechanism of visual network dysfunction in relapsing-remitting multiple sclerosis and its relation to cognition.

OBJECTIVE: To investigate if changes in brain network function and connectivity contribute to the abnormalities in visual event related potentials (ERP) in relapsing-remitting multiple sclerosis (RRMS), and explore their relation to a decrease in cognitive performance. METHODS: We evaluated 72 patients with RRMS and 89 healthy control subjects in a cross-sectional study. Visual ERP were generated using illusory and non-illusory stimuli and recorded using 21 EEG scalp electrodes. The measured activity was modelled using Dynamic Causal Modelling. The model network consisted of 4 symmetric nodes including the primary visual cortex (V1/V2) and the Lateral Occipital Complex. Patients and controls were tested with a neuropsychological test battery consisting of 18 cognitive tests covering six cognitive domains. RESULTS: We found reduced cortical connectivity in bottom-up and interhemispheric connections to the right lateral occipital complex in patients (p < 0.001). Furthermore, interhemispherical connections were related to cognitive dysfunction in several domains (attention, executive function, visual perception and organization, processing speed and global cognition) for patients (p < 0.05). No relation was seen between cortical network connectivity and cognitive function in the healthy control subjects. CONCLUSION: Changes in the functional connectivity to higher cortical regions provide a neurobiological explanation for the changes of the visual ERP in RRMS. SIGNIFICANCE: This study suggests that changes in connectivity to higher cortical regions partly explain visual network dysfunction in RRMS where a lower interhemispheric connectivity may contribute to impaired cognitive function.

Cognitive function did not improve after initiation of natalizumab treatment in relapsing-remitting multiple sclerosis. A prospective one-year dual control group study.

BACKGROUND: Cognitive impairment in multiple sclerosis (MS) is common and has severe implications. Natalizumab (NZ) has documented effects on relapse rate and radiological disease activity in relapsing-remitting MS (RRMS) but studies regarding its specific effects on cognitive functioning are few. Previous studies have reported improvement, however, often lacking relevant control groups. The objective of the present study was to evaluate the cognitive effects of NZ treatment, compared to patients on stable first-line treatment and healthy control subjects. METHODS: MS patients starting NZ (MS-NZ), MS controls with stable interferon beta therapy (MS-C) and healthy control subjects (HC) were evaluated twice with one year interval, using a cognitive test battery covering six cognitive domains. The effects of NZ on levels of self-reported depression, fatigue, daytime sleepiness and perceived health were also examined. RESULTS: MS patients (MS-NZ and MS-C) had significantly lower baseline cognitive performance compared to HC (global score, p=0.002), but there were no significant differences between MS-NZ and MS-C. At follow-up, both MS-NZ and MS-C had improved significantly in four and five cognitive domains, respectively, and in global score (p=0.013 and p<0.001, respectively). HC improved significantly in three cognitive domains but not in global score. A regression analysis including baseline cognitive z-score and z-score change showed that participants with lower baseline scores had a significantly greater improvement, compared to those with better initial performance (p=0.021). There were no significant changes in depression, fatigue, daytime sleepiness or perceived health in MS-NZ or MS-C. CONCLUSIONS: Initiation of NZ therapy did not result in true cognitive improvement over one year. Presumably, the increased test performance in both MS groups was artificial and due to retest effects that were stronger in patients with lower baseline performance. Adequate control groups are essential when evaluating cognitive functioning in intervention trials among RRMS patients.

Cortical plasticity in patients with median nerve lesions studied with MEG.

We have previously shown age- and time-dependent effects on brain activity in the primary somatosensory cortex (SI), in a functional magnetic resonance imaging (fMRI) study of patients with median nerve injury. Whereas fMRI measures the hemodynamic changes in response to increased neural activity, magnetoencephalography (MEG) offers a more concise way of examining the evoked response, with superior temporal resolution. We therefore wanted to combine these imaging techniques to gain additional knowledge of the plasticity processes in response to median nerve injury. Nine patients with median nerve trauma at the wrist were examined with MEG. The N1 and P1 responses at stimulation of the injured median nerve at the wrist were lower in amplitude compared to the healthy side (p < .04). Ulnar nerve stimulation of the injured hand resulted in larger N1 amplitude (p < .04). The amplitude and latency of the response did not correlate with the sensory discrimination ability. There was no correlation between N1 amplitude and size of cortical activation in fMRI. There was no significant difference in N1 latency between the injured and healthy median nerve. N1 latency correlated positively with age in both the median and ulnar nerve, and in both the injured and the healthy hand (p < .02 or p < .001). It is concluded that conduction failure in the injured segment of the median nerve decreases the amplitude of the MEG response. Disinhibition of neighboring cortical areas may explain the increased MEG response amplitude to ulnar nerve stimulation. This can be interpreted as a sign of brain plasticity.

Inter-hemispheric plasticity in patients with median nerve injury.

Peripheral nerve injuries result in reorganization within the contralateral hemisphere. Furthermore, recent animal and human studies have suggested that the plastic changes in response to peripheral nerve injury also include several areas of the ipsilateral hemisphere. The objective of this study was to map the inter-hemispheric plasticity in response to median nerve injury, to investigate normal differences in contra- and ipsilateral activation, and to study the impact of event-related or blocked functional magnetic resonance imaging (fMRI) design on ipsilateral activation. Four patients with median nerve injury at the wrist (injured and epineurally sutured >2 years earlier) and ten healthy volunteers were included. 3T fMRI was used to map the hemodynamic response to brain activity during tactile stimulation of the fingers, and a laterality index (LI) was calculated. Stimulation of Digits II-III of the injured hand resulted in a reduction in contralateral activation in the somatosensory area SI. Patients had a lower LI (0.21±0.15) compared to healthy controls (0.60±0.26) indicating greater ipsilateral activation of the primary somatosensory cortex. The spatial dispersion of the coordinates for areas SI and SII was larger in the ipsilateral than in the contralateral hemisphere in the healthy controls, and was increased in the contralateral hemisphere of the patients compared to the healthy controls. There was no difference in LI between the event-related and blocked paradigms. In conclusion, patients with median nerve injury have increased ipsilateral SI area activation, and spatially more dispersed contralateral SI activation during tactile stimulation of their injured hand. In normal subjects ipsilateral activation has larger spatial distribution than the contralateral. Previous findings in patients performed with the blocked fMRI paradigm were confirmed. The increase in ipsilateral SI activation may be due to an interhemispheric disinhibition associated with changes in the afferent signal inflow to the contralateral primary somatosensory cortex.

Event related potential and response time give evidence for a physiological reserve in cognitive functioning in relapsing-remitting multiple sclerosis.

Cognitive dysfunction is common in multiple sclerosis (MS). Different factors may moderate the degree of cognitive deficit. The aim of the present study was to distinguish different mechanisms for cognitive reserve in relapsing-remitting MS (RRMS). The effects of clinical variables (physical disability, depression), premorbid intelligence (years of education, vocabulary knowledge), visual event-related potential measures (P300) and response time (RT) were studied in RRMS patients (n=71) and healthy subjects (n=89). Patients with high P300 amplitude and short RT had better cognitive performance. This effect was significantly weaker in controls. High P300 and short RT may be physiological markers of a cognitive reserve in RRMS. In contrast, the association between cognitive scores and premorbid intelligence was similar in patients and in control subjects. The effects of physiological reserve and clinical variables were studied in a hierarchical linear regression model of cognitive performance in RRMS. P300 amplitude and RT explained a considerable amount of variance in global cognitive performance (34%, p<0.001). The effects of P300 and RT were not moderated by premorbid intelligence. Physical disability and depression added significantly to explained variance, and the final model accounted for 44% (p<0.001) of the variation. We conclude that physiological reserve is the strongest moderator of cognitive impairment in RRMS.

P300 amplitude and response speed relate to preserved cognitive function in relapsing-remitting multiple sclerosis.

OBJECTIVE: To explore if cognitive impairment in relapsing-remitting multiple sclerosis (RRMS) is associated with abnormal neural function and if there is evidence of neural compensatory mechanisms. METHODS: Seventy-two RRMS patients and 89 healthy control subjects were included in a cross-sectional study. Event-related brain potential (P300) and response time (RT) were recorded with visual and auditory choice reaction tasks. Cognitive function was evaluated with an 18 item test battery. RESULTS: Patients had a decrease in cognitive function (p<0.001 for global score) and increased visual P300 amplitude frontally. P300 amplitude was normal in other brain areas and RT was normal. P300 latency was normal except for an increase in auditory latency occipitally. Cognitive performance correlated positively with parietal P300 amplitude in patients but not in controls. Cognition had stronger correlation (negative) with RT in patients than in controls. CONCLUSIONS: Patients with low P300 amplitude and long RT were more often cognitively impaired. This indicates that general factors such as signal amplitude and speed are limiting for cognitive function in RRMS patients. The increase in frontal P300 amplitude may be a compensatory effect. SIGNIFICANCE: Our findings suggest that high amplitude and fast speed may be protective against cognitive impairment.

A mechanistic model of mismatch negativity in the ageing brain.

OBJECTIVE: We investigated the neurophysiological mechanisms underpinning the generation of the mismatch negativity (MMN) in the ageing brain. METHODS: We used dynamic causal modelling (DCM) to study connectivity models for healthy young and old subjects. MMN was elicited with an auditory odd-ball paradigm in two groups of healthy subjects with mean age 74 (n=30) and 26 (n=26). DCM was implemented using up to five cortical nodes. We tested models with different hierarchical complexities. RESULTS: We showed that the network generating MMN consisted of 5 nodes that could modulate all intra- and inter-nodal connections. The inversion of this model showed that old subjects had increased input from rSTG to the rIFG (p<0.01) together with increased inhibition of pyramidal cells (p<0.05). Furthermore, there was reduced modulation of activity within rIFG (p<0.02) on stimulus change. CONCLUSION: The age related change in MMN is due to a decline in frontal-based control mechanisms, with alterations in connectivity between temporal and frontal regions together with a dysregulation of the excitatory-inhibitory balance in the rIFG. SIGNIFICANCE: This study provides for the first time a neurobiological explanation for the age related changes of the MMN in the ageing brain.

Cognitive impairment has a strong relation to nonsomatic symptoms of depression in relapsing-remitting multiple sclerosis.

It is unclear how cognitive impairment in multiple sclerosis (MS) is influenced by physical disability, fatigue, and depression. Our aim was to identify the strongest clinical predictors for cognitive impairment in relapsing-remitting MS (RRMS) patients. The clinical risk factors included in the analysis were physical disability (EDSS), fatigue (FSS), the somatic and nonsomatic components of depression (BDI), disease progression rate [Multiple Sclerosis Severity Score (MSSS)], and psychotropic medication. Cognitive impairment had a prevalence of 30.5% in patients affecting preferentially attention, executive functions, processing speed and visual perception/organization. MSSS was not associated with cognitive impairment, depression, or fatigue. In regression models, cognitive performance was best predicted by the nonsomatic symptoms of depression alone or in combination with physical disability. Exclusion of patients with any psychotropic medication did not influence the results. Our results underscore the importance of evaluating depressive symptoms when suspecting cognitive impairment in patients with RRMS.

Attenuation of long-range temporal correlations in the amplitude dynamics of alpha and beta neuronal oscillations in patients with schizophrenia.

Although schizophrenia was previously associated with affected spatial neuronal synchronization, surprisingly little is known about the temporal dynamics of neuronal oscillations in this disease. However, given that the coordination of neuronal processes in time represents an essential aspect of practically all cognitive operations, it might be strongly affected in patients with schizophrenia. In the present study we aimed at quantifying long-range temporal correlations (LRTC) in patients (18 with schizophrenia; 3 with schizoaffective disorder) and 28 healthy control subjects matched for age and gender. Ongoing neuronal oscillations were recorded with multi-channel EEG at rest condition. LRTC in the range 5-50s were analyzed with Detrended Fluctuation Analysis. The amplitude of neuronal oscillations in alpha and beta frequency ranges did not differ between patients and control subjects. However, LRTC were strongly attenuated in patients with schizophrenia in both alpha and beta frequency ranges. Moreover, the cross-frequency correlation between LRTC belonging to alpha and beta oscillations was stronger for patients than healthy controls, indicating that similar neurophysiological processes affect neuronal dynamics in both frequency ranges. We believe that the attenuation of LRTC is most likely due to the increased variability in neuronal activity, which was previously hypothesized to underlie an excessive switching between the neuronal states in patients with schizophrenia. Attenuated LRTC might allow for more random associations between neuronal activations, which in turn might relate to the occurrence of thought disorders in schizophrenia.

Decreased cortical connectivity and information flow in type 1 diabetes.

OBJECTIVE: To investigate the effect of type 1 diabetes on EEG connectivity and information flow and study the relationship between these parameters and electrophysiological, neuropsychological and clinical variables. METHODS: Connectivity was assessed using several measures (phase coherence, phase lag index, synchronization likelihood and phase slope index) on 119 patients and 61 healthy controls over several frequency bands (between 0.5 and 45 Hz). Data was further correlated to EEG power, event related potentials, neuropsychological function and demographic variables. RESULTS: Multivariate test on the connectivity data showed a difference between patients and controls both with mastoid reference (p<0.01) and current source density estimates (p<0.04). Connectivity and information flow correlated with EEG power but not with event related potentials or neuropsychological function. CONCLUSIONS: Connectivity and information flow are decreased in diabetes. These variables assess other functions of the brain than captured by the present cognitive tests. Several tests need to be performed in order to monitor the effect of diabetes on brain function. SIGNIFICANCE: The decrease in connectivity and cortical information flow are EEG abnormalities that add to the previously described EEG and ERP abnormalities described for type 1 diabetes.

Effect of valproate, lamotrigine and levetiracetam on excitability and firing properties of CA1 neurons in rat brain slices.

The purpose of this study was to analyze the rapid effects of the antiepileptic drugs valproate, lamotrigine, and levetiracetam on excitability and firing properties of hippocampal neurons. The drug effects on resting potential, action potential, and repetitive firing properties were studied in whole-cell current-clamp recordings of CA1 neurons in rat brain slices. Lamotrigine changed action potential rising slope by -24 ± 38 V/s (mean ± SD), peak amplitude by -6.8 ± 5.0 mV, and maximum firing frequency by -60 ± 13%. Lamotrigine thereto increased the voltage threshold by 4.3 ± 4.2 mV and augmented the action potential attenuation during repetitive firing. All effects were significant (P < 0.01 to P < 0.0002) compared to control cells. Valproate and levetiracetam showed no significant effects on these parameters. None of the tested drugs had a significant effect on the resting potential. The lamotrigine effects are consistent with sodium channel blocking which may explain or contribute to the antiepileptic mode of action. Valproate and levetiracetam did not show these effects and the mechanism of their antiepileptic action need to be different. These findings (valproate) differ in some respects from findings reported in cultured or dissociated neurons. In a slice where the neurons have largely preserved connections, drug effects are likely to be more similar to the therapeutic action in the brain.

Effects of intensified metabolic control on CNS function in type 2 diabetes.

The mild cognitive decline associated with type 2 diabetes (T2DM) has been suggested to be reversible with improved glycemic control. In order to characterise this cognitive decline and study the effects of improved glycemic control we have studied patients with T2DM (N=28) and healthy control subjects (N=21). One group of patients with diabetes (N=15) were given a 2-month treatment of intensified glycemic control, whereas the other group (N=13) maintained their regular treatment. Cognitive function in four different domains, auditory event-related potentials (ERPs) and resting EEG power spectrum were studied in the two groups of patients and in healthy control subjects before and after the 2-month trial period. There were significant differences at baseline (p<0.02) between patients with T2DM and controls. Patients had lower scores in two cognitive domains: verbal fluency (p<0.01) and visuospatial ability (p<0.03). T2DM also affected ERP with a decrease in N100 amplitude (p<0.04) and an increase in P300 latency (p<0.03). Furthermore, resting EEG activity in the beta band (13-30Hz) was reduced (p<0.04). The change between 1st and 2nd investigation was significantly different in the three groups of patients/subjects (p<0.03). Patients receiving intensified treatment for glycemic control had an improvement of cognitive ability in visuospatial ability (p<0.02) and semantic memory performance (p<0.04) together with increased resting EEG activity in the alpha band (8-13Hz, p<0.02) and connectivity in the theta (4-8Hz, p<0.03) and alpha bands (p<0.03) over central and lateral regions. Furthermore, there was an increase in the connectivity in the beta band (p<0.04) over the central regions of the scalp. In conclusion, subjects with T2DM had a similar type of cognitive function impairment and EEG/ERP abnormality as previously demonstrated for subjects with type 1 diabetes (T1DM). Intensified therapy showed cognitive improvement not shown for regular treatment, suggesting that the negative effect of T2DM on cognition is reversible by means of improved glycemic control. Furthermore, there was an improvement in electro-physiological measures, suggesting increased availability of compensatory mechanisms in subjects with intensified treatment.

Age- and time-dependent effects on functional outcome and cortical activation pattern in patients with median nerve injury: a functional magnetic resonance imaging study.

OBJECT: The authors conducted a study to determine age- and time-dependent effects on the functional outcome after median nerve injury and repair and how such effects are related to changes in the pattern of cortical activation in response to tactile stimulation of the injured hand. METHODS: The authors studied 11 patients with complete unilateral median nerve injury at the wrist repaired with epineural suture. In addition, 8 patients who were reported on in a previous study were included in the statistical analysis. In the entire study cohort, the mean age at injury was 23.3 +/- 13.4 years (range 7-57 years) and the time after injury ranged from 1 to 11 years. Sensory perception was measured with the static 2-point discrimination test and monofilaments. Functional MR imaging was conducted during tactile stimulation (brush strokes) of Digits II-III and IV-V of both hands, respectively. RESULTS: Tactile sensation was diminished in the median territory in all patients. The strongest predictor of 2-point discrimination was age at injury (p < 0.0048), and when this was accounted for in the regression analysis, the other age- and time-dependent predictors had no effect. The activation ratios (injured/healthy hand) for Digit II-III and Digit IV-V stimulation were positively correlated (rho 0.59, p < 0.011). The activation ratio for Digit II-III stimulation correlated weakly with time after injury (p < 0.041). The activation ratio of Digits IV-V correlated weakly with both age at injury (p < 0.048) and time after injury (p < 0.033), but no predictor reached significance in the regression model. The mean ratio of ipsi- and contralateral hemisphere activation after stimulation of the injured hand was 0.55, which was not significantly different from the corresponding ratio of the healthy hand (0.66). CONCLUSIONS: Following a median nerve injury (1-11 years after injury) there may be an initial increase in the volume of the cortical representation, which subsequently declines during the restoration phase. These dynamic changes may involve both median and ulnar nerve cortical representation, because both showed negative correlation with time after injury. These findings are in agreement with animal studies showing that cortical plasticity is an important mechanism for functional recovery after peripheral nerve injury and repair.

Cognitive impairment correlates to low auditory event-related potential amplitudes in type 1 diabetes.

Type 1 diabetes may be associated with a mild decline in cognitive function and mostly in mental speed. In order to study the pathophysiology of this, we have investigated auditory event-related potentials (AERP) and their relation to cognitive function in diabetes patients. AERP was recorded in patients with type 1 diabetes (n=119) and in a healthy control group (n=61). AERP was obtained with an odd-ball and a two-stimulus paradigm. Cognitive function was evaluated in 10 domains in the patients. Patients had normal N100 latency, but a highly significant decrease in auditory N100 amplitude (p<10(-6)), which correlated with a decrease in psychomotor speed but not with function in other domains. Psychomotor speed also correlated with P300 amplitude, although P300 amplitude was only slightly decreased in the patients. Even stronger correlations were found with the parietal N100-P300 peak-to-peak amplitude, which correlated both to psychomotor speed (rho=0.61, p<10(-7)) and processing speed (p<0.005). P300 latency was increased in patients, and this correlated to low global cognitive score and older age. We conclude that the decline in psychomotor speed in type 1 diabetes is associated with a highly significant decrease in the auditory N100 peak amplitude. This association and the relatively small abnormality in P300 latency is quite different from those generally found in dementia, and suggest that the underlying defect is located in the brain stem or the white matter. Presumably small conduction defects in ascending fibers can distort the firing synchrony necessary for signal generation in the cortex.

Robustly estimating the flow direction of information in complex physical systems.

We propose a new measure (phase-slope index) to estimate the direction of information flux in multivariate time series. This measure (a) is insensitive to mixtures of independent sources, (b) gives meaningful results even if the phase spectrum is not linear, and (c) properly weights contributions from different frequencies. These properties are shown in extended simulations and contrasted to Granger causality which yields highly significant false detections for mixtures of independent sources. An application to electroencephalography data (eyes-closed condition) reveals a clear front-to-back information flow.

Predictors of cognitive impairment in type 1 diabetes.

A decline in cognitive function has been reported in type 1 diabetes, but its relation to different disease factors such as hypoglycemic events and peripheral neuropathy is controversial. The objective of the present study was to identify factors that are important for cognitive impairment in type 1 diabetes. A cross-sectional study was performed in adult patients (N=150) with type 1 diabetes (duration 26.6+/-11.4 years). Function in different cognitive domains was evaluated by the same trained examiner, in order to eliminate inter-rater variability. Peripheral nerve function was tested quantitatively. Predictors of cognitive impairment were identified using multiple regression analysis. The major finding was that long diabetes duration and young age of diabetes onset were the strongest predictors of low scores in psychomotor speed, memory, processing speed, attention, working memory, verbal ability, general intelligence, executive functions and a low global score. The number of previous hypoglycemic events had no defined effect upon cognitive functioning. Other significant predictors were low compound muscle action potential (CMAP) (for visual perception-organization), old age (for visual-spatial ability), short stature, high BMI and hypertension. Presence of retinopathy and long-term metabolic control correlated with nerve conduction defects, but not with cognitive impairment. Although a history of hypoglycemic events was not a predictor of cognitive impairment, we cannot exclude the possibility that the influence of young age of diabetes onset depends on the effect of hypoglycemic events early in life. The clinical relationships of cognitive impairment differ from those of peripheral neuropathy, indicating a different pathogenesis. The influence of diabetes duration, BMI, height, age and CMAP may suggest that loss of the neuroprotective effects of insulin or insulin-like growth factors plays a role.

The human EEG--physiological and clinical studies.

The present review summarizes the research in EEG performed by our group during the last 5 years. Our studies have been focussed on two areas: studies of variability and correlations in the oscillations during resting conditions of normal subjects, and the abnormalities related to type 1 diabetes. Recordings in normal subjects showed that also under standardized conditions with regular cycles of closed and open eyes, there is a temporal variability of the spectral components in EEG that necessitates samples>124 s in order to achieve estimates of alpha power with a coefficient of variation<0.1 in all recording channels (brain regions). The temporal variability in alpha and beta power demonstrates long-range temporal correlations, i.e., periods of large power (alpha or beta) are more likely to be followed by large power, and vice versa. The long-range temporal correlations were reproducible, especially during the closed-eyes condition, stronger in males than females, and not age dependent. In patients with type 1 diabetes, the alpha and beta power components were both decreased with similar nadirs in the posterior temporal regions, and the slow spectral components were increased in the frontal regions. The cognitive function was presently not studied but in a group of adolescents with diabetes we found a correlation between the presence of slow activity and the number of hypoglycaemic episodes. The loss of alpha and beta power was highly correlated which initiated a study of the normal alpha-beta correlation. A significant 1:2 phase synchronization was present between alpha and beta oscillations with a phase lag of about pi/2 in all electrode derivations. The strong frequency relationship between the resting beta and alpha oscillations suggested that they are generated by a common mechanism.

C-Peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy.

OBJECTIVE: C-peptide replacement in animals results in amelioration of diabetes-induced functional and structural abnormalities in peripheral nerves. The present study was undertaken to examine whether C-peptide administration to patients with type 1 diabetes and peripheral neuropathy improves sensory nerve function. RESEARCH DESIGN AND METHODS: This was an exploratory, double-blinded, randomized, and placebo-controlled study with three study groups that was carried out at five centers in Sweden. C-peptide was given as a replacement dose (1.5 mg/day, divided into four subcutaneous doses) or a dose three times higher (4.5 mg/day) during 6 months. Neurological examination and neurophysiological measurements were performed before and after 6 months of treatment with C-peptide or placebo. RESULTS: The age of the 139 patients who completed the protocol was 44.2 +/- 0.6 (mean +/- SE) years and their duration of diabetes was 30.6 +/- 0.8 years. Clinical neurological impairment (NIA) (score >7 points) of the lower extremities was present in 86% of the patients at baseline. Sensory nerve conduction velocity (SCV) was 2.6 +/- 0.08 SD below body height-corrected normal values at baseline and improved similarly within the two C-peptide groups (P < 0.007). The number of patients responding with a SCV peak potential improvement >1.0 m/s was greater in C-peptide-treated patients than in those receiving placebo (P < 0.03). In the least severely affected patients (SCV < 2.5 SD below normal at baseline, n = 70) SCV improved by 1.0 m/s (P < 0.014 vs. placebo). NIA score and vibration perception both improved within the C-peptide-treated groups (P < 0.011 and P < 0.002). A1C levels (7.6 +/- 0.1% at baseline) decreased slightly but similarly in C-peptide-and placebo-treated patients during the study. CONCLUSIONS: C-peptide treatment for 6 months improves sensory nerve function in early-stage type 1 diabetic neuropathy.

Long-range temporal correlations in alpha and beta oscillations: effect of arousal level and test-retest reliability.

OBJECTIVE: The aim of the present study was to evaluate test-retest reliability and condition sensitivity of long-range temporal correlations in the amplitude dynamics of electroencephalographic alpha and beta oscillations. METHODS: Twelve normal subjects were measured two times with a test-retest interval of several days. Open- and closed-eyes conditions were used, representing different levels of arousal. The amplitude of the alpha and beta oscillations was extracted with bandpass filtering and the Hilbert transform. The long-range temporal correlations were quantified with detrended fluctuation analysis. RESULTS: The amplitude dynamics of the alpha and beta oscillations demonstrated power-law long-range temporal correlations lasting for tens of seconds. These correlations were degraded in the open- compared to the closed-eyes condition. Test-retest statistics demonstrated that the long-range temporal correlations had significant reliability, which was greatest in the closed-eyes condition. CONCLUSIONS: The presence of long-range temporal correlations indicates that the amplitude of neuronal oscillations at a given time is dependent on the amplitude at times as remote in the past as tens of seconds. The reliability of long-range temporal correlations suggests that the mechanisms generating the amplitude fluctuations are not perturbed over several days. The systematic changes in the scaling exponents at different levels of arousal indicate that these changes occur on many time scales (5-80 s) as a result of modifications in the intrinsic dynamics of the neuronal oscillations. SIGNIFICANCE: This study demonstrates that the dynamics of spontaneous neuronal oscillations possess long-range temporal correlations with properties suitable for functional and clinical studies.