Hypoglycemia-Associated EEG Changes Following Antecedent Hypoglycemia in Type 1 Diabetes Mellitus

Abstract

Background:

Recurrent hypoglycemia has been shown to blunt hypoglycemia symptom scores and counterregulatory hormonal responses during subsequent hypoglycemia. We therefore studied whether hypoglycemia-associated electroencephalogram (EEG) changes are affected by an antecedent episode of hypoglycemia.

Methods:

Twenty-four patients with type 1 diabetes mellitus (10 with normal hypoglycemia awareness, 14 with hypoglycemia unawareness) were studied on 2 consecutive days by hyperinsulinemic glucose clamp at hypoglycemia (2.0–2.5 mmol/L) during a 1-h period. EEG was recorded, cognitive function assessed, and hypoglycemia symptom scores and counterregulatory hormonal responses were obtained.

Results:

Twenty-one patients completed the study. Hypoglycemia-associated EEG changes were identified on both days with no differences in power or frequency distribution in the theta, alpha, or the combined theta–alpha band during hypoglycemia on the 2 days. Similar degree of cognitive dysfunction was also present during hypoglycemia on both days. When comparing the aware and unaware group, there were no differences in the hypoglycemia-associated EEG changes. There were very subtle differences in cognitive function between the two groups on day 2. The symptom response was higher in the aware group on both days, while only subtle differences were seen in the counterregulatory hormonal response.

Conclusion:

Antecedent hypoglycemia does not affect hypoglycemia-associated EEG changes in patients with type 1 diabetes mellitus.

Introduction

Recurrent hypoglycemia blunts symptomatic and sympathoadrenal responses during subsequent hypoglycemia.¹ In diabetes mellitus, this increases the risk of further episodes and a vicious cycle commences, eventually leading to hypoglycemia-associated autonomic failure (HAAF) characterized by impaired hypoglycemia awareness and a blunted counterregulatory hormonal response during hypoglycemia.² The effect of recurrent hypoglycemia on the brain function is, however, controversial. Thus, studies investigating cognitive function have reported effects of acute recurrent hypoglycemia varying from negative,³ over none,⁴ to positive.⁵

The electroencephalogram (EEG) provides information on the cerebral metabolic function. During hypoglycemia, the EEG is characterized by increased activity in the low-frequency bands, most pronounced in the theta band.⁶ We have previously demonstrated the absence of differences in the hypoglycemia-associated EEG changes between patients with type 1 diabetes mellitus and normal hypoglycemia awareness and unawareness during a single episode of insulin-induced hypoglycemia.⁷ The acute effect of antecedent hypoglycemia on hypoglycemia-associated EEG changes is, however, not known. We therefore assessed the acute effect of hypoglycemia on hypoglycemia-associated EEG changes on two consecutive days.

Research Design and Methods

The study is a part of a clinically controlled study investigating the response to hypoglycemia in patients with type 1 diabetes mellitus.⁷ The protocol was registered at clinicaltrials.gov (No. NCT01337362) and approved by the Regional Committee on Biomedical Research Ethics, Copenhagen, Denmark. Written informed consent was obtained from all participants.

Twenty-four patients with type 1 diabetes mellitus were recruited from the diabetes mellitus outpatient clinics at Nordsjaellands Hospital and Steno Diabetes Center. Inclusion criteria were type 1 diabetes mellitus >5 years, age >18 years, and being either hypoglycemia aware or unaware. Hypoglycemia awareness status was classified by three methods: the Pedersen-Bjergaard method,⁸ the Gold score,⁹ and the Clark method.¹⁰ Exclusion criteria included pregnancy or breastfeeding, any brain disorder or cardiovascular disease, use of antiepileptic drugs, beta blocking agents, or neuroleptic agents, use of benzodiazepines within the last month, and alcohol or drug abuse.

Participants underwent a hyperinsulinemic hypoglycemic clamp on two consecutive days. They were tested during 1-h periods: at normoglycemia (5.0–6.0 mmol/L) and at hypoglycemia (2.0–2.5 mmol/L). A 1-h recovery period (5.0–6.0 mmol/L) then followed. Insulin (Actrapid^®; Novo Nordisk, Ballerup, Denmark) was infused intravenously at a continuous rate of 1.0 mU/kg/min, while 20% glucose was infused at a variable rate to keep plasma glucose at the target. After the clamp on day 1, the participants slept at home and returned fasting the next morning for an identical glucose clamp on day 2. The participants wore a continuous glucose monitor (CGM) (Guardian^® REAL-Time with Enlite™ sensor, Medtronics, Minneapolis, MN) for 5 days before the hypoglycemic clamp to assure that there were no glucose measurements below 3.5 mmol/L within 24 h of the beginning of day 1. If hypoglycemia occurred between day 1 and 2, the study was still continued on day 2.

At each glucose level on both days, the same test battery was carried out, including standardized recording of the EEG, assessment of cognitive function, filling in a hypoglycemia symptom questionnaire (the Danish modification of the Edinburgh Hypoglycemia Scale¹¹), and measurement of the counterregulatory hormonal response. The test battery has previously been reported in detail.⁷

Recording of the EEG

Digital EEG was measured continuously (Cadwell, Kennewick, Washington) with electrodes placed according to the international 10–20 system using Electro-Caps. In addition, at each glycemic level, two 5-min recordings were made under standardized conditions. Results from the bipolar P3–C3 montages and the monopolar C3-channel with A1A2 as a reference were reported.

Quantitative EEG (qEEG) analysis was carried out focusing on frequency characteristics of the data in the theta band (4–7.75 Hz), alpha band (8–12.75 Hz), and a combined alpha–theta band (4–12.75 Hz). Average amplitude spectra were calculated and absolute amplitude and the centroid frequency (CF) were calculated for each band. The CF was defined as the center of gravity of each frequency band that subdivides the area under the spectral curve into two areas of equal size. qEEG analysis was performed on both the two full 5-min recordings and on 4–10-s pooled segments of artifact-free recordings from within the 5-min recordings.

An additional EEG analysis was also performed on the entire normoglycemic and hypoglycemic periods, where a multiscale entropy approach was used and measures of sample entropy (SampEn) were obtained. SampEn measures the likelihood that EEG patterns repeat over time and is robust to variations in amplitude, frequency, and differences in data length. For this analysis SampEn was obtained for a tau of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22, the pattern size (m) was 4 and the distance (r) in the SampEn was set to 0.2 times the standard deviation.¹²

Results

Ten patients were characterized as having normal hypoglycemia awareness and 14 patients as being hypoglycemia unaware according to all 3 methods for classification of hypoglycemia awareness. Three patients did not complete the study and had to be excluded from further analyses; two (one aware, one unaware) due to problems with blood sampling on day 2 and one (aware) in whom EEG recording failed due to electrical interference. The characteristics of the remaining 21 patients are listed in Table 1. There were no episodes of hypoglycemia (plasma glucose below 3.5 mmol/L) between day 1 and 2.

Table 1.

Baseline Characteristics of the Completing 21 Participants

Variable	Overall group	Aware	Unaware	P _{(Aware–Unaware)}
N (% males)	21 (57)	8 (63)	13 (54)	1
Age, years	54 (2.7)	48 (5.2)	58 (2.6)	0.09
Duration of diabetes mellitus, years	28 (2.5)	22 (4.0)	32 (2.9)	0.06
HbA_1c,%	7.8 (0.2)	7.9 (0.4)	7.8 (0.3)	0.9
mmol/mol	62 (2.2)	63 (4.3)	62 (3.2)
Daily insulin dose (IU)	43 (4.6)	58 (8.2)	34 (3.7)	0.03
Diabetic renal disease (N), n%	3 (14)	2 (25)	1 (8)	0.1
Autonomic neuropathy (N), n%	4 (19)	2 (25)	2 (15)	0.5
Peripheral neuropathy (N), n%	6 (29)	2 (25)	4 (31)	0.7
SH episodes, lifetime (N), n%				0.003
0 (n%)	3 (14)	3 (38)	—
1–5 (n%)	6 (29)	4 (50)	2 (15)
6–10 (n%)	2 (9.5)	1 (12)	1 (8)
11–20 (n%)	2 (9.5)	—	2 (15)
>21 (n%)	8 (38)	—	8 (62)

Variables are mean (SEM) or number (percentages) as appropriate.

SH, severe hypoglycemia; SEM, standard error of mean.

The glucose clamp

The mean glucose concentration during hypoglycemia was 2.4 (0.05) mmol/L (mean [standard error of mean]) on both days, while nadir was 2.1 (0.05) mmol/L on day 1 and 2.1 (0.04) on day 2. Plasma glucose concentrations and glucose infusion rates (GIRs) did not differ between day 1 and 2 (Supplementary Fig. S1; Supplementary Data are available online at www.liebertpub.com/dia). The aware group was studied at a slightly higher glucose concentration during hypoglycemia (aware: 2.5 mmol/L both days, unaware: 2.3 mmol/L both days, P = 0.02 and P = 0.003, respectively) despite a lower GIR (aware GIR 0.009 [0.002] mmol/kg/h on both days, unaware GIR day 1: 0.016 [0.001] mmol/kg/h and day 2: 0.015 [0.002], P = 0.01 both days).

EEG analysis

The qEEG analysis of the 5-min EEG at rest identified hypoglycemia-associated EEG changes on both days (Fig. 1). Amplitudes increased in theta and alpha–theta bands and CF in the alpha–theta band decreased on day 1 (Table 2). On day 2 there were increases in theta, alpha, and alpha–theta amplitudes as well as a decrease in CF in both the alpha and alpha–theta band.

FIG. 1.

Electroencephalogram (EEG) amplitude spectra showing the amplitude of the EEG signals in the different bands during normoglycemia and hypoglycemia before (A) and after (B) an episode of recent antecedent hypoglycemia in a group of patients with type 1 diabetes mellitus (N = 21). The theta and the alpha bands are marked within the black vertical lines. The dashed line is the mean amplitude during normoglycemia, and the solid line is the mean amplitude during hypoglycemia. Error bars depict SEM. *Difference in amplitude between the two glycemic levels (P < 0.05). SEM, standard error of mean.

Table 2.

qEEG Analysis on 5-min Electroencephalogram Recordings Under Standardized Conditions of the Absolute Amplitude and Centroid Frequency

	Day 1 Norm	Day 1 Hypo	P	Day 2 Norm	Day 2 Hypo	P
log (AA theta)	1.44 (0.11)	1.74 (0.11)	<0.001	1.45 (0.10)	1.75 (0.11)	<0.001
log (AA alpha)	2.10 (0.14)	2.13 (0.11)	0.6	1.95 (0.14)	2.09 (0.11)	0.01
log (AA alpha–theta)	2.57 (0.13)	2.70 (0.11)	0.005	2.48 (0.12)	2.68 (0.10)	<0.001
CF theta (Hz)	5.97 (0.03)	5.96 (0.03)	0.8	5.94 (0.03)	5.97 (0.03)	0.1
CF alpha (Hz)	10.10 (0.07)	10.07 (0.05)	0.4	10.11 (0.05)	10.03 (0.04)	0.01
CF alpha–theta (Hz)	8.63 (0.10)	8.38 (0.09)	<0.001	8.48 (0.09)	8.32 (0.09)	0.048

AA, absolute amplitude; CF, centroid frequency; Norm, normoglycemia; Hypo, hypoglycemia; qEEG, quantitative EEG. Variables are mean (SEM).

The hypoglycemia-associated EEG changes did not differ between day 1 and 2 as there were no significant differences in either band-specific amplitude or CF during hypoglycemia between the 2 days. However, for the absolute amplitude for the alpha band and CF alpha, differences between normoglycemia and hypoglycemia were only significant on day 2. For the absolute amplitude, this was due to numerical lower amplitude during normoglycemia on day 2 compared with day 1.

Hypoglycemia-associated EEG changes were present in both awareness groups on both days (Supplementary Table S1) but did not differ between the two groups or experimental days.

qEEG analysis of the artifact-free EEG segments showed similar results as the crude analysis indicating a robust change toward a slower frequency (Supplementary Table S2).

The multiscale entropy approach analysis also showed that SampEn was higher during hypoglycemia on both day 1 and 2 (P < 0.05 for Tau 8–22 on both days), but there were no differences in the changes between day 1 and 2 (P > 0.2).

Cognitive function

Cognitive performance estimated by Stroop tests¹³ and Trail Making Test B¹⁴ declined during hypoglycemia on both days (Fig. 2) in the total group as well as in each awareness group (Supplementary Table S3). There was no difference during hypoglycemia between the 2 days.

FIG. 2.

Cognitive assessment during hypoglycemia before and after an episode of recent antecedent hypoglycemia in a group of patients with type 1 diabetes mellitus (N = 21). Cognitive function was assessed during normoglycemia (Normo) and hypoglycemia (Hypo). (A) Results from the Trail Making Test B, where the white bars represent normoglycemia and the hatched bars represent hypoglycemia. (B) Results from the Stroop Tests where the white bars represent normoglycemia day 1, bars with vertical lines represent hypoglycemia day 1, black bars represent normoglycemia day 2 and checkered bars represent hypoglycemia day 2. Error bars depict SEM. *Difference between levels during hypoglycemia and normoglycemia (P < 0.05). #Difference between day 1 and 2 (P < 0.05).

There were also no differences between the two awareness groups during hypoglycemia on day 1. On day 2, the aware group performed better during hypoglycemia in the Stroop Word test (P = 0.02).

Hypoglycemia symptom scores

The total symptom score increased during hypoglycemia on both days. Absolute scores were lower on day 2 during normo- and hypoglycemia (P = 0.006). When analyzing autonomous, neuroglycopenic, and other symptom scores separately, they were all lower during hypoglycemia on day 2 although only significant for neuroglycopenic and other symptoms (Table 3).

Table 3.

Hypoglycemia Symptom Scores on Day 1 and Day 2

	Day 1 Norm	Day 1 Hypo	P	Day 2 Norm	Day 2 Hypo	P	P (Day 1–Day 2)
Total score	25 (1.3)	41 (5.2)	<0.001	22 (0.9)	36 (4.6)	<0.001	0.006
Autonomous symptom score	5.9 (0.5)	11 (1.5)	0.001	5.6 (0.4)	9.7 (1.4)	<0.001	0.1
Neuroglycopenic score	12 (0.9)	21 (2.8)	<0.001	10.0 (0.4)	18 (2.5)	<0.001	0.01
Other symptoms	6.9 (0.4)	9.8 (1.2)	0.008	6.3 (0.3)	8.4 (0.9)	0.001	0.043

Hypoglycemia symptom scores were measured twice at each glycemic level. Each symptom was ranked on a scale from 1 to 7. Norm and Hypo represent the symptom scores during normoglycemia and hypoglycemia and are based on each participant's highest symptom score during each glycemic level. The symptoms were grouped into three categories. Autonomous symptoms, which included sweating, palpitations, hunger, and tremor with a possible score from 4 to 28 points. Neuroglycopenic symptoms, which included confusion, dizziness, slurred speech, double vision, difficulty in concentration, impaired vision, tired, circumoral paraesthesia, and weakness with a possible score from 9 to 63 points and Other symptoms, which included cold sensation, anxiety, warm sensation, nausea, and drowsiness with a possible score from 5 to 35 points. Variables are described as mean (SEM).

As expected, symptom scores were blunted in the hypoglycemia-unaware group (Supplementary Table S4). The unaware group scored a maximum of 31 points on day 1 and 25 points on day 2 (P = 0.045), whereas the aware group scored a maximum of 58 points on day 1 and 53 points on day 2 (P = 0.058). The differences between the two groups were significant on both days (day 1 P = 0.001, day 2 P < 0.001).

Hormonal counterregulatory response

On both days, the counterregulatory hormonal responses increased during hypoglycemia (Supplementary Fig. S2). For glucagon, adrenalin, and cortisol there were no differences in concentrations during hypoglycemia, while the concentration of growth hormone was lower during hypoglycemia on day 2 (P = 0.002).

Growth hormone response to hypoglycemia was blunted on day 2 in the aware group (P = 0.01) (Supplementary Table S4), and tended to be so in the unaware group (P = 0.06). Although adrenalin and cortisol concentrations were numerically lower during hypoglycemia on day 2 in the aware group, the difference was not significant (adrenalin P = 0.6, cortisol P = 0.09). The aware group had a higher maximum adrenalin response than the unaware group on day 1 (P = 0.02) but not on day 2 (P = 0.3). The increase in cortisol levels during hypoglycemia was also higher in the aware group, although it was only a trend on day 2 (day 1 P = 0.046, day 2 P = 0.07).

Discussion

This study shows that hypoglycemia-associated EEG changes are not affected by a recent single episode of hypoglycemia, either in hypoglycemia-aware or in hypoglycemia-unaware patients with type 1 diabetes mellitus. This indicates that there is no immediate adaptation to hypoglycemia in the brain's response to hypoglycemia as measured by EEG in relation to acute hypoglycemia in patients with type 1 diabetes mellitus.

The hypoglycemia-associated EEG changes were accompanied by cognitive impairment during hypoglycemia. The impairment was present in both the aware group and the unaware group on both days. This finding contrasts a previous study that only reported a significant cognitive dysfunction during hypoglycemia in patients with normal awareness but not in patients with impaired hypoglycemia awareness, but the authors also reported that there was no significant hypoglycemia awareness interaction for the trail making B test.¹⁵ There was no overall robust difference in the cognitive performance during hypoglycemia between the 2 days. This finding is in concordance with some of the previous studies that could also not detect an effect of antecedent hypoglycemia in healthy subjects^4,16 or in persons with type 1 diabetes mellitus.^17,18 Others have, however, reported that cognitive function was better preserved during repeated hypoglycemia than during a single episode of hypoglycemia in healthy subjects⁵ and persons with type 1 diabetes mellitus.¹⁹

In our study, two episodes of hypoglycemia 24 h apart were induced to blunt sympathoadrenal response to hypoglycemia on the second day to assess whether this also would affect hypoglycemia-associated EEG changes. This was based on previous studies showing that an episode of hypoglycemia within the previous 24 h reduces the adrenalin and hypoglycemia symptom responses during the following episode of hypoglycemia in healthy subjects and in patients with type 1 diabetes mellitus.^3,16,20,21 In contrast to these studies, we only found a modest effect of antecedent hypoglycemia 24 h prior. One explanation may be that the participants in our study differ from the participants in previous studies. They are older and have a longer duration of diabetes mellitus and thereby a priori a greater lifetime exposure to hypoglycemia and in turn more pronounced HAAF that would be less modifiable by a further single episode. Such patients may perhaps require a more prolonged or more severe hypoglycemic event to modify their responses.

The major consequence of HAAF is an increased risk of severe hypoglycemia.² Great efforts have therefore been made to develop an alarm that can sense low glucose levels and warn the patients in due time. Hypoglycemia-associated EEG changes are suggested as a biosensor for hypoglycemia detection.²² Our observations that neither acute nor chronic recurrent hypoglycemia causes adaptation in the EEG⁷ lend support to the suggestion that continuous EEG monitoring potentially constitutes a method for a hypoglycemia alarm. Especially it is of note that hypoglycemia-unaware patients who are at the greatest risk of developing severe hypoglycemia have preserved EEG reactions to hypoglycemia.

The strength of our study is that the setup allowed each participant to be his/her own control at the same glucose level during hypoglycemia on the 2 days. Moreover, CGM was applied to avoid any symptomatic and asymptomatic hypoglycemia 5 days before the study and between the study days, which could potentially blunt the symptomatic and hormonal responses.^3,16,20,21 Finally, EEG analyses were performed both on the complete EEG recording during the normoglycemic and hypoglycemic period and on 5-min EEG recordings recorded during standardized conditions as well as on artifact-free segments within the 5-min recordings. All three analyses identified hypoglycemia-associated EEG changes with no difference between day 1 and 2.

There are also limitations to the study. First, hypoglycemia was induced by a hyperinsulinemic glucose clamp technique, where a variable glucose infusion controlled the plasma glucose level. This approach secured tight control of plasma glucose concentrations at similar levels on day 1 and 2 but may not necessarily mirror clinical hypoglycemia with respect to rate of glucose fall and glucose nadir. Second, only results from the C3–P3 electrodes are reported for the sake of simplicity. This area was chosen because hypoglycemia-associated EEG changes are most abundant in this area.²³ However, if antecedent hypoglycemia led to a universal adaptation in metabolism in the cortex, it would also have been present in the C3–P3 area. Finally, the hypoglycemia-unaware group tended to be older and have a longer duration of diabetes compared with the aware group. Since age and duration of diabetes are associated with hypoglycemia unawareness, this was to be expected. Age and duration of diabetes have, however, been shown not to affect hypoglycemia-associated EEG changes,²⁴ but we cannot exclude that the difference between the two groups could have masked an effect of awareness status on hypoglycemia-associated cognitive dysfunction.

In conclusion, antecedent hypoglycemia does not change hypoglycemia-associated EEG changes in patients with type 1 diabetes mellitus. These changes are present in both hypoglycemia-aware and hypoglycemia-unaware patients with no difference between the two groups. The cognitive function was also affected during hypoglycemia on both days with only subtle differences between hypoglycemia-aware and hypoglycemia-unaware patients during hypoglycemia after antecedent hypoglycemia.

Footnotes

Acknowledgments

The authors thank the participants and research nurses Pernille Banck-Petersen, Tove Larsen, and Charlotte Hansen, Department of Cardiology, Nephrology, and Endocrinology, Nordsjaellands Hospital Hillerød for skillful technical assistance. Funding: The study was funded by research grants from the University of Southern Denmark, the Danish PhD School of Endocrinology, the Research Foundation at Nordsjaellands Hospital, HypoSafe A/S, the Fog Foundation, the Augustinus Foundation, the Tvergaard Foundation, the Olga Bryde Nielsen Foundation, and the Helen Rude's Foundation.

Author Contribution

A.S.S. contributed to the conceptual design, recruited participants, conducted the study, researched the data, performed the data analysis, and wrote the manuscript. C.B.J., T.W.K., U.P.B., L.S.R., and B.T. contributed to the conceptual design, data analysis, and wrote the manuscript. C.S.F. contributed in performing the study. L.H., J.F., J.J.H., J.S.M., and M.N.N. contributed with data analysis. L.T. contributed to recruitment and enrollment of participants from the Steno Diabetes Center. All authors have contributed significantly to the writing, reviewing, and editing of the manuscript.

Author Disclosure Statement

Duality of interests: A.S.S. has received research grants from HypoSafe and lecturing fees from Sanofi-Aventis. L.S.R. is an employee at HypoSafe and C.B.J. is a part-time employee in HypoSafe. No other potential conflicts of interest relevant to this article were reported.

References

Graveling

, Frier

: Impaired awareness of hypoglycaemia: a review. Diabetes Metab, 2010; 36 Suppl 3:S64–S74.

Cryer

: Mechanisms of hypoglycemia-associated autonomic failure in diabetes. NEJM, 2013; 369:362–372.

Dagogo-Jack

, Craft

, Cryer

: Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest, 1993; 91:819–828.

Hvidberg

, Fanelli

, Hershey

, et al.: Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans. Diabetes, 1996; 45:1030–1036.

Fruehwald-Schultes

, Born

, Kern

, et al.: Adaptation of cognitive function to hypoglycemia in healthy men. Diabetes Care, 2000; 23:1059–1066.

Baskaran

, Milev

, McIntyre

: A review of electroencephalographic changes in diabetes mellitus in relation to major depressive disorder. Neuropsychiatr Dis Treat, 2013; 9:143–150.

Sejling

, Kjær

, Pedersen-Bjergaard

, et al.: Hypoglycemia-associated changes in the electroencephalogram in patients with type 1 diabetes and normal hypoglycemia awareness or unawareness. Diabetes, 2015; 64:1760–1769.

Pedersen-Bjergaard

, Pramming

, Thorsteinsson

: Recall of severe hypoglycaemia and self-estimated state of awareness in type 1 diabetes. Diabetes Metab Res Rev, 2003; 19:232–240.

Gold

, MacLeod

, Frier

: Frequency of severe hypoglycemia in patients with type 1 diabetes and impaired awareness of hypoglycemia. Diabetes Care, 1994; 17:697–703.

10.

Clarke

, Cox

, Gonder-Frederick

, et al.: Reduced awareness of hypoglycemia in adults with IDDM: a prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care, 1995; 18:517–522.

11.

Hepburn

, Deary

, Frier

, et al.: Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care, 1991; 14:949–957.

12.

Fabris

, Sparacino

, Sejling

, et al.: Hypoglycemia-related electroencephalogram changes assessed by multiscale entropy. Diabetes Technol Ther, 2014; 16: 688–694.

13.

Golden

: A group version of the Stroop Color and Word Test. J Pers Assess, 1975; 39:386–388.

14.

Bowie

, Harvey

: Administration and interpretation of the trail making test. Nat Protoc, 2006; 1:2277–2281.

15.

Zammitt

, Warren

, Deary

, Frier

: Delayed recovery of cognitive function following hypoglycemia in adults with type 1 diabetes: effect of impaired awareness of hypoglycemia. Diabetes, 2008; 57:732–736.

16.

Robinson

, Parkin

, Macdonald

, Tattersall

: Antecedent hypoglycaemia in non-diabetic subjects reduces the adrenaline response for 6 days but does not affect the catecholamine response to other stimuli. Clin Sci (Lond), 1995; 89:359–366.

17.

George

, Marques

, Harris

, et al.: Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM. Diabetes Care, 1997; 20:1293–1298.

18.

Leelarathna

, Little

, Walkinshaw

, et al.: Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes: hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial. Diabetes Care, 2013; 36:4063–4070.

19.

Fanelli

, Paramore

, Hershey

, et al.: Impact of nocturnal hypoglycemia on hypoglycemic cognitive dysfunction in type 1 diabetes. Diabetes, 1998; 47:1920–1927.

20.

Heller

, Cryer

: Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes, 1991; 40:223–226.

21.

Arbelaez

, Powers

, Videen

, et al.: Attenuation of counterregulatory responses to recurrent hypoglycemia by active thalamic inhibition: a mechanism for hypoglycemia-associated autonomic failure. Diabetes, 2008; 57:470–475.

22.

Juhl

, Højlund

, Elsborg

, et al.: Automated detection of hypoglycemia-induced EEG changes recorded by subcutaneous electrodes in subjects with type 1 diabetes-The brain as a biosensor. Diabet Res Clin Pract, 2010; 88:22–28.

23.

Tribl

, Howorka

, Heger

, et al.: EEG topography during insulin-induced hypoglycemia in patients with insulin-dependent diabetes mellitus. Eur Neurol, 1996; 36:303–309.

24.

Remvig

, Elsborg

, Sejling

, et al.: Hypoglycemia-related electroencephalogram changes are independent of gender, age, duration of diabetes, and awareness status in type 1 diabetes. J Diabet Sci Technol, 2012; 6:1337–1344.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.04 MB

0.00 MB

0.02 MB

0.07 MB

0.03 MB