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Year : 2016  |  Volume : 2  |  Issue : 1  |  Page : 43-47

Role of event-related potentials in evaluation of cognitive function in subclinical hypothyroid patients

1 Department of Physiology, Maulana Azad Medical College, New Delhi, India
2 Department of Pathology, Maulana Azad Medical College, New Delhi, India
3 Department of Medicine, Maulana Azad Medical College, New Delhi, India
4 Department of Neurology, GB Pant Institute of Medical Education & Research, New Delhi, India

Date of Web Publication25-Jan-2016

Correspondence Address:
Rashmi Mahaur
Department of Physiology, Maulana Azad Medical College, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2394-7438.174838

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Context: Hypothyroidism has been associated with neurocognitive deficit, but status of cognitive function in subclinical hypothyroidism is unclear. Also, cognitive impairment found in these patients has been associated with aging. Aims: The purpose of this study was to evaluate cognitive function in hypothyroid and subclinical hypothyroid patients using objective methods and to correlate it with age, thyroid stimulating hormone (TSH) level, and education status of patients. Settings and Design: It was a cross-sectional study conducted on 90 female participants aged 30-50 years. Thirty patients diagnose with subclinical hypothyroidism (group 1) were compared with 30 age- and sex-matched hypothyroid patients (group 2) and euthyroid controls (group 3). Subjects and Methods: Cognitive function was evaluated using three parameters such as mini mental scale examination (MMSE), event-related potentials - P300latency and amplitude, auditory and visual reaction time. Statistical Analysis Used: SPSS version 17 was used for statistical analysis. The data were also analyzed for variables related to age, TSH, and education level. Results: Significant delay in P300latency and prolonged reaction time was found in both subclinical hypothyroid and hypothyroid group compared to controls (P < 0.001). P300amplitude and MMSE score showed no significant difference in all groups. In hypothyroid patients, P300latency at Fz, Pz was positively correlated with age while nonsignificant correlation was observed in subclinical hypothyroid patients. TSH and education level of patients showed no significant correlation with cognitive function tests. Conclusions: Delayed P300latency and prolonged reaction time in both subclinical hypothyroid and hypothyroid patients shows that cognitive function is affected adversely. Event-related potentials may be more sensitive than clinical evaluation by MMSE, for early diagnosis of mild cognitive impairment in subclinical hypothyroidism.

Keywords: Cognitive, hypothyroidism, impairment, mini mental scale examination, P300latency, reaction time, subclinical

How to cite this article:
Mahaur R, Mahajan AS, Jain AK, Singh T, Dhanwal DK, Gupta M. Role of event-related potentials in evaluation of cognitive function in subclinical hypothyroid patients. MAMC J Med Sci 2016;2:43-7

How to cite this URL:
Mahaur R, Mahajan AS, Jain AK, Singh T, Dhanwal DK, Gupta M. Role of event-related potentials in evaluation of cognitive function in subclinical hypothyroid patients. MAMC J Med Sci [serial online] 2016 [cited 2021 Sep 23];2:43-7. Available from: https://www.mamcjms.in/text.asp?2016/2/1/43/174838

  Introduction Top

Subclinical hypothyroidism is a condition of mild thyroid failure characterized by increased level of serum TSH and normal serum free T4 and T3 concentrations in contrast to hypothyroidism that is a thyroid derangement with decreased serum concentrations of free T4 or T3.[1] It occurs in 4–20% of adult population with higher prevalence in women and advancing age.[2]

Low thyroid function is known to have adverse effects on developing brain. Hypothyroidism in middle-aged and elderly are associated with decreased cognitive functioning, especially memory, visuospatial organization, attention, and reaction time.[3] However, occurrence of cognitive decline in subclinical hypothyroidism is not established. Although some studies have reported cognitive decline in subclinical hypothyroidism, others found no cognitive impairment.[4],[5] These apparently conflicting findings could be related to the difference in severity of the disease and age of patients included in different studies, also lack of uniformity in type of cognitive tests administered.

In both subclinical hypothyroidism and clinical hypothyroidism, cognitive changes have been observed in elderly; hence, it is necessary to see if the changes are age-related or otherwise.

The objective of this study was to evaluate cognitive functions in both hypothyroid and subclinical hypothyroid patients and also assess effect of age, serum TSH level, and education status on cognitive functions in these patients.

  Subjects and Methods Top

The study was a cross-sectional, case–control type performed on a total sample of 90 participants; women aged 30–50 years. Patients with subclinical hypothyroidism (TSH >5 mIU/L, normal FT4 and FT3) were included in group 1, patients with primary hypothyroidism (TSH >5 mIU/L, FT4 <12 pmol/L) were included in group 2, and euthyroid controls were included in group 3. Each group comprised of 30 participants. The patients were recruited from medical outpatient department while euthyroid controls (volunteers) with comparable education were enrolled from hospital staff. Informed consent was taken, and the study was approved by the Institutional Ethical Committee.

A questionnaire for information regarding symptoms, medical history, demographic features, medications, personal history, and any family history of thyroid disease was completed for both patients and controls. Education level of patients was noted. Patients presenting with history suggestive of diabetes, stroke, obesity, cardiovascular disease, hypertension, smoking, liver disease, neurological disorder, psychiatric disorder, or other endocrine disorder were excluded from the study. Patients with history of use of drugs such as sulfonylurea, lithium, amiodarone, ethionamide, iodine, phenylbutazone, alcohol, and other drugs likely to affect thyroid gland were excluded. Pregnant and postmenopausal females were also excluded. A complete clinical examination was performed in all patients before investigations.

Thyroid function tests included serum TSH, free T4, free T3, and anti-thyroid peroxidase (TPO) done by electrochemiluminescence method, using Cobas e 411 kits and measured by ELECSYS 2010 manufactured by Roche/Hitachi, Germany, 2004.

Cognitive function tests included P300 measured by Galileo NT software of EB Neuro machine made in Florence, Italy, 2002, as per the guidelines of International Federation of Clinical Neurophysiologists.[6]

Protocol for P300 testing

During the procedure, patient was asked to comfortably sit in a chair with backrest, Ag/AgCl disc electrodes were placed on scalp at Fz, Cz, and Pz (active electrodes) position using the 10–20 international system. Reference electrodes A1 and A2 were placed on each earlobe and one in the center of forehead for grounding. All electrodes were plugged in the junction box. Impedance between skin and electrode was monitored and kept below 5 Kilo ohms. Auditory stimuli were given using standard oddball acoustic paradigm. A total of 200 stimuli were randomly presented to patient, of which 40 (20%) were rare or target stimuli and rest 80% were frequent stimuli. Acoustic stimuli were of 80 dB, each linear tone with a starting condensation phase with a plateau phase of 100 ms, rise/fall of 10 ms, and a rate of once every 1 s. The signals were in phase at the two ears. The Galileo NT settings were selected so as to filter the evoked responses to the frequent and the rare stimuli with a band pass of 0.1–20 Hz and averaged simultaneously for 40 responses. Recordings were taken, P300 wave was identified as the largest positive peak occurring for all electrode sites after the N100-P200-N200 complex with latency more than 250 ms. Then, latency and amplitude of the waveform were measured. Latency was calculated from the point of stimulation.

Reaction time is a simple test to measure global attention and speed of processing.[7]

Protocol for reaction time

Reaction time by auditory and visual method was measured using Recorders & Medicare System Pvt Ltd (RMS) Reaction time machine made in Chandigarh, 2007. The subject was made to sit across evaluator in a noise free room. She was familiarized with equipment and procedure prior to test. Then, the subject was presented with auditory stimulus and response time was noted (measured in milliseconds by instrument). Thereafter, visual stimulus was given and response time was noted. The procedure was repeated, and best responses for both auditory and visual reaction time were taken as final reading.

Protocol for mini mental scale examination

A Hindi adaptation of mini mental scale examination (MMSE) was used for clinical scoring of cognitive functions.[8] The test included simple questions and problems in Hindi representing different cognitive domains such as orientation to time, orientation to place, registration of three words, attention and calculation, recall of three words, language, and visual construction. A score of 24–30 indicates no cognitive impairment; 18–23 suggest mild cognitive impairment, and 0–17 is observed in severe cognitive impairment.

The data were analyzed using the SPSS (SPSS version 17, IBM) statistical software version 17.0. One-way analysis of variance followed by multiple comparisons Tukey's test was used to compare mean across the three groups. Welch test followed by Dunnetts T3 multiple comparisons were performed when homogeneity of variance condition violated. This condition was tested by Levene's test. Unpaired Student's t-test was used to compare variables measured only in two groups. Krushal–Wallis followed by Mann–Whiteny U-test was applied to compare distribution across three groups. Pearson's correlation was used to assess the strength of correlation of age, TSH, and education level with all cognitive function tests for each group. P < 0.05 was considered statistically significant.

  Results Top

The baseline characteristics of all subjects are shown in [Table 1]. The hypothyroid patients (39.47 ± 6.89 years) although in same range were found significantly older compared to subclinical hypothyroid patients (34.63 ± 4.80 years). Also, hypothyroid patients had a higher body mass index compared to euthyroid controls but not subclinical hypothyroid patients. The education status of all groups was comparable.
Table 1: Baseline characteristics measured in Groups 1, 2, and 3

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[Table 2] shows the thyroid profile of subjects. Differences were observed in all groups. Hypothyroid patients had the highest TSH and anti TPO levels and lowest free T3 and T4 levels. Although free T3, T4 levels in subclinical hypothyroid patients were within normal range, they were still significantly different from euthyroid group. In thyroid profile serum TSH, free T3, free T4 among study groups (1 and 2) and control group 3 was significantly different. Anti TPO was measured only in study groups 1 and 2, and significant difference was observed.
Table 2: Thyroid status (TSH, FT3, FT4, and anti TPO) of Group 1, 2, and 3

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The cognitive function tests are shown in [Table 3]. P300 latencies at Fz, Cz, and Pz electrodes in both subclinical hypothyroid and hypothyroid groups were significantly delayed compared to euthyroid controls. However, P300 latencies between subclinical hypothyroid group and hypothyroid group were comparable. No significant difference was observed in P300 amplitudes at Fz, Cz, and Pz in all the three groups. The mean auditory and visual reaction time were significantly prolonged in subclinical hypothyroid as well as hypothyroid group compared to controls with P < 0.001. Although both auditory and visual reaction times were more prolonged in hypothyroid patients compared to subclinical hypothyroid patients, this difference was not statistically significant. MMSE scores were within normal range for both the patient groups.
Table 3: Comparison of cognitive function tests in the three groups

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The P300 latency at Fz and Pz in hypothyroid patients showed significant positive correlation with age [Table 4]. Similar correlation was seen in euthyroid controls while nonsignificant negative correlation was seen in subclinical hypothyroid patients. TSH level and education status showed no significant correlation with cognitive functions in any group.
Table 4: Correlation of age with P300 latency in Group 1, 2 and 3

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  Discussion Top

In this study, patients with hypothyroidism and subclinical hypothyroidism had significant delay in P300 wave latency and increased auditory and visual reaction time compared to euthyroid controls. Event-related study particularly delayed P300 latency has been associated with cognitive impairment by several studies.[9]

In support of our study, Tütüncü et al. and Sahay et al. observed similar findings of delayed P300 latency in both subclinical hypothyroid and hypothyroid patients as compared to controls.[10],[11] Jensovsky et al. studied patients belonging to older age (52 ± 12.5 years) with subclinical hypothyroidism, and also found P300 wave latency was delayed compared to controls.[12]

On the contrary, some studies have found no difference in P300 wave study in subclinical hypothyroid patients compared to euthyroid controls. In two different studies by Mahmoud et al. and Sharma et al., significant delay in P300 latency in hypothyroid patients was found but not in subclinical hypothyroid patients.[13],[14] Guldiken et al. studied event-related brain potentials in subclinical hypothyroid patients and compared with normal subjects, found no significant difference in the amplitude or latencies of P300.[15]

In our study, cognitive deficit in both subclinical hypothyroid and hypothyroid groups was found comparable. A possible explanation can be high mean TSH of 12.04±10.09 mIU/L in subclinical hypothyroid group i.e. severe subclinical hypothyroidism (TSH>10 mIU/L), while in other similar studies TSH was <10 mIU/L.[16]

Cognitive decline due to aging is associated with increase in P300 latency and decrease in amplitude,[9] similar age-related changes in hypothyroid patients and controls were found in our study. However, cognitive decline in subclinical patients showed negative correlation with age although association was not found significant.

Reaction time by both auditory and visual stimuli was prolonged in subclinical hypothyroid and hypothyroid patients compared to controls. del Ser Quijano et al. recorded findings of MMSE, test of global cognitive performance and reaction time for attention.[17] They found that subclinical hypothyroid patients had a prolonged reaction time as compared to controls which improved significantly after hormonal treatment. Therefore, our results show that cognitive impairment can be picked up earlier by objective measurement of P300 and reaction time compared to clinical evaluation by MMSE.

Cognitive functions tests of our patient groups showed no significant correlation with TSH level. Similarly, Mahmoud et al. and Khedr et al. also found no significant correlation between TSH and cognitive function.[13],[18] However, in the study by Sharma et al., P300 latency and TSH were positively correlated in hypothyroid patients.[14] Bégin et al. proposed that the inconsistent relationship between TSH and cognitive function suggests that circulating TSH may not be sufficiently sensitive or direct marker of thyroid hormone sufficiency for brain function.[3]

  Conclusion Top

Cognitive impairment was found both in subclinical hypothyroid and primary hypothyroid patients compared to euthyroid controls, both by event-related potential study (P300) and reaction time measurements. The P300 latency was related to age in hypothyroid patients but not in subclinical hypothyroid patients and was not related to education status. Objective evaluation of cognitive impairment in thyroid disorders is more suitable for early diagnosis.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012;379:1142-54.  Back to cited text no. 1
LeFevre ML. U.S. Preventive services task force. Screening for thyroid dysfunction: U.S. Preventive services task force recommendation statement. Ann Intern Med 2015;162:641-50.  Back to cited text no. 2
Bégin ME, Langlois MF, Lorrain D, Cunnane SC. Thyroid function and cognition during aging. Curr Gerontol Geriatr Res; volume 2008, Article ID 474868, doi:10.1155/2008/474868.  Back to cited text no. 3
Samuels MH. Cognitive function in subclinical hypothyroidism. J Clin Endocrinol Metab 2010;95:3611-3.  Back to cited text no. 4
Ritchie M, Yeap BB. Thyroid hormone: Influences on mood and cognition in adults. Maturitas 2015;81:266-75.  Back to cited text no. 5
Nuwer MR, Lehmann D, Lopes da Silva F, Matsuoka S, Sutherling W, Vibert JF. IFCN guidelines for topographic and frequency analysis of EEGs and EPs. Report of an IFCN committee. International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol 1994;91:1-5.  Back to cited text no. 6
Jakobsen LH, Sorensen JM, Rask IK, Jensen BS, Kondrup J. Validation of reaction time as a measure of cognitive function and quality of life in healthy subjects and patients. Nutrition 2011;27:561-70.  Back to cited text no. 7
Ganguly M, Ratcliff G, Chandra V, Sharma S, Gibly J, Pandav R, et al. A Hindi version of the MMSE: The development of a cognitive screening instrument for population of a largely illiterate rural elderly population in India. Int J Geriatr Psychiatry 1995;10:367-77.  Back to cited text no. 8
Polich J. Updating P300: An integrative theory of P3a and P3b. Clin Neurophysiol 2007;118:2128-48.  Back to cited text no. 9
Tütüncü NB, Karatas M, Sözay S. Prolonged P300 latency in thyroid failure: A paradox. P300 latency recovers later in mild hypothyroidism than in severe hypothyroidism. Thyroid 2004;14:622-7.  Back to cited text no. 10
Sahay R, Reddy R, Pallagolu S. Assessment of cognitive function in hypothyroidism using P300 evoked potentials. Endocr Abstr 2012;29:1619.  Back to cited text no. 11
Jensovsky J, Ruzicka E, Spackova N, Hejdukova B. Changes of event related potential and cognitive processes in patients with subclinical hypothyroidism after thyroxine treatment. Endocr Regul 2002;36:115-22.  Back to cited text no. 12
Mahmoud A, Sadek H, Shereen F, Moustafa A, Ginina AM, Kisk NA, et al. Screening for cognitive dysfunction in patients with hypothyroidism. Egypt J Neurol Psychiatry Neurosurg 2008;45:175-84.  Back to cited text no. 13
Sharma K, Behera JK, Sood S, Rajput R, Satpal, Praveen P. Study of cognitive functions in newly diagnosed cases of subclinical and clinical hypothyroidism. J Nat Sci Biol Med 2014;5:63-6.  Back to cited text no. 14
Guldiken B, Guldiken S, Taskarin B, Peynirchi H, Turgut N, Turgul N, et al. Evaluation of cognitive functions in subclinical hypothyroidism by event related potentials. Arch Neuropsychiatry 2008;45:69-71.  Back to cited text no. 15
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-38.  Back to cited text no. 16
del Ser Quijano T, Delgado C, Martínez Espinosa S, Vázquez C. Cognitive deficiency in mild hypothyroidism. Neurologia 2000;15:193-8.  Back to cited text no. 17
Khedr EM, El Toony LF, Tarkhan MN, Abdella G. Peripheral and central nervous system alterations in hypothyroidism: Electrophysiological findings. Neuropsychobiology 2000;41:88-94.  Back to cited text no. 18


  [Table 1], [Table 2], [Table 3], [Table 4]

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