Central auditory functions in post-COVID-19 adults; a case control study

Background This study aimed to evaluate the central auditory abilities in post-coronavirus disease 2019 (COVID-19) adults by using Central Auditory Tests (CATs). This study included a complaining group (GI), a non-complaining group (GII), and a control healthy group (GIII). All subjects were evaluated using CATs Results Results demonstrated statistically significant differences across groups as regards Speech Perception in Noise Test (SPIN), Duration Pattern Sequence Test (DPT), Gap in Noise Test (GIN), and Memory Test (ANOVA, p -value ≤ 0.05). The post-hoc test revealed that, except for recognition memory, both study groups showed statistically significant differences from the control group. Also, significant differences were detected between both GI and GII groups regarding SPIN −10 signal-to-noise ratio (S/N), DPT, GIN threshold, memory for content, and memory for sequence Conclusions COVID-19 led to central auditory processing disorders (c)APD.


Background
In December 2019, the coronavirus emerged and began its rapid spread across numerous countries [1].Many studies have discussed otological, rhinological, and laryngeal issues related to COVID-19 disease [2][3][4][5].However, little research highlighted the central auditory processing deficit post-Covid infection.The term "post-COVID conditions" included a wide range of physical and mental health consequences experienced by some patients when they presented four weeks or more after COVID-19 disease, according to the United States Centers for Disease Control and Prevention [6].Fatigue and "brain fog" are among the most commonly reported post-COVID-19 symptoms [7].The term "brain fog" was used to describe difficulty concentrating, memory problems, and sometimes confusion during the COVID-19 pandemic [8].The profile of post-COVID-19 cognitive impairment involves attention and planning difficulties, decreased information processing speed, and deficits in shortterm memory, abstraction, orientation [9], and sustained attention [10].COVID-19 disease presents some peculiar characteristics.The presence of cognitive symptoms does not have a clear temporal relation with other symptoms or their severity In patients with COVID-19 infection, cognitive symptoms may persist longer than other symptoms [11].
Accordingly, this work was designed to evaluate the central auditory abilities in post-COVID-19 adults using different Central Auditory Tests (CATs).
Normal subjects were volunteers or relatives of patients and hospital medical staff.
Fifty subjects were included in this study, with the age range of 18-45 years.Subjects were divided into three groups: The first was the complaining group (consisting of 20 post-COVID-19 complaining adults (GI)), and the second was the non-complaining group (consisting of 10 post-COVID-19 non-complaining adults (GII)).They all had at least one COVID-19 attack during the last 4 months., diagnosed by PCR.All subjects came for testing after recovery.The inclusion criteria of the study groups (GI and GII) included: (1) Age ranged from 18 to 45 years with normal peripheral hearing.( 2  All groups were matched for gender distribution with no statistically significant difference (p > 0.05).In the study group (I), females (19/20 = 95%) were more than males (1/20 = 5%).Similarly, the study group (II) also showed a greater female presence (9/10 = 90%) versus males (1/10 = 10%).The control group III mirrored the gender distribution of group I, with females constituting 95% (19 out of 20) and males 5% (1 out of 20).

Characters of COVID-19 attacks
The duration of COVID-19 attacks ranged from 7 -25 days, with the mean ± SD of 13.56 ± 4.64 days.In contrast, the time between COVID-19 acute attack/s and time of examination ranged from 6 -23 weeks with the mean ± SD of 13.80 ± 6.36 weeks.As regards the number of COVID-19 attacks, 19 subjects (63.3%) suffered from one attack of COVID-19, 10 subjects (33.3%) suffered from 2 attacks, and only one subject (3.3%) suffered from 3 attacks.

Results of the CAP Questionnaire for adults
According to the Arabic CAP Questionnaire for adults, memory problems were the most common complain, followed by lack of attention and difficulty in understanding speech in noise (Shown in Fig. 1).
As there was no statistically significant difference between right and left ears in all groups regarding all tests (paired t-test p-value > 0.05), the data from both ears were combined and averaged for subsequent statistical analysis.

Basic audiological evaluation in the two study groups and the control group
All tested groups had normal Pure Tone thresholds at all tested frequencies shown in Fig. 2, normal speech reception thresholds, and normal word discrimination.

Results of the (CATs) in all studied groups
Results of the present study revealed a statistically significant decrease in the scores of CATs in both study groups compared to the control group.ANOVA test revealed statistically significant differences among the studied groups (p ≤ 0.05) regarding SPIN-SNR zero , SPIN-SNR −10 , DPT, GIN score, GIN threshold, and memory test.The post-hoc test revealed that, with the exception of recognition memory (MR), both study groups showed statistically significant differences from the control group (lower scores in the study groups than in the control group).Also, statistically significant differences were detected between both GI (complaining) and GII (non-complaining) regarding SPIN-SNR −10 , DPT, GIN threshold, memory for content (MC) and memory for sequence (MS).

Correlations
There was a statistically significant positive correlation between [GIN score and time lag (in weeks) between acute attacks and date of examination] as shown in Fig. 3. Also, there was a statistically significant positive correlation between (SPIN-SNR −10 and O2 saturation during the acute attack) as shown in Fig. 4.However, there were no statistically significant correlations between other parameters (CATs) and duration of attacks, number of attacks, duration between attacks and testing and O 2 -saturation among the study groups.

Discussion
In the study groups, there were more females than males.This agreed with the results of Graham et al. [16] and Hugon [17], who reported that cognitive symptoms were more frequent in young females than in young males.In  contrast, this finding disagreed with that of Garg et al. [17], who reported that no difference had been observed between males and females in the likelihood of developing cognitive symptoms after COVID-19.
According to the results of the CAP questionnaire for adults in the study groups, 15 subjects (50%) complained of memory problems, ten subjects (33.3%) complained of lack of attention, nine subjects (30%) complained of difficulty in understanding speech in noise, five subjects (16.7%) complained of asking a lot to repeat speech addressed, two subjects (6.7%) complained of other medical problems, two subjects (6.7%) complained of family history of similar conditions, one subject (3.3%) complained of difficulty in sound localization, and one subject (3.3%) complained of work problems.The results of difficulty in concentration and lack of attention agreed with the results of Roger et al. [18].They reported that these symptoms were present in 19.9% of their patients after recovery.In comparison, the result of memory agreed with that of Davis et al. [19].
In this study, the SPIN test was used to assess Selective Attention (Auditory Figure Ground 2).This result agreed with that of Boboshko et al. [20].They reported that impaired speech intelligibility was one of the most frequent auditory complaints in those patients.Those authors speculated that the deterioration of speech test scores in patients after COVID-19 might occur due to auditory processing disorders (APD), memory impairment or changes in cognitive status in general.
Cognitive abilities, along with peripheral hearing and CAP, are known to influence speech intelligibility [21].The results of speech in noise tests might suggest temporal lobe affection (auditory cortex), which is responsible for selective attention [22].On the other hand, the results of this study disagreed with the results of Tufatulin et al. [3].These authors reported that no CAPD was detected in children after the new coronavirus infection.The discrepancy between the results of the current work and that study could be related to the different ages of participants in both studies.They studied children up to the age of 17 years.The retained neuroplasticity in children might play a role in the presence of a discrepancy between the two studies.The few available studies about the evaluation the central auditory abilities in post-COVID-19 adult patients include only Boboshko et al. [20] up to the knowledge of the authors of the current work.
Duration Pattern Sequence test (DP) evaluates temporal ordering, pattern recognition, auditory memory and duration discrimination [13].Post-COVID-19 patients performed worse than the controls in the DP test.Moreover, the post-COVID-19 complaining group (I) performed worse than the post-COVID-19  2).These results may be explained and supported by the results of the Douaud et al. [23] study.These authors analyzed MRIs (structural and functional brain scans before and after COVID-19 infection) of adult subjects who had normal, pre-pandemic MRIs on record at England's Biobank.Imaging studies revealed the involvement of the left parahippocampal gyrus and anterior parahippocampal gyrus.These two areas are known to play crucial roles in the memory of events (Temporal order of episodic memory) [23][24][25].
Gap In Noise test assesses temporal resolution ability.It is sensitive to cortical disorders [21].In this study, the post-COVID-19 patients performed worse than the controls regarding GIN score and GIN threshold.Moreover, the post-COVID-19 complaining group (I) performed worse than the post-COVID-19 non-complaining group (II) with regard to the GIN threshold only (Table 3).This result agreed with that of Boboshko et al. [20].The authors used the Random Gap Detection Test (RGDT) to evaluate the temporal resolution of the human auditory system in post-COVID-19 patients and reported poor results of the RGDT in many patients during the post-COVID-19 period.
As regards the Memory Test, the post-COVID-19 patients performed worse than the controls in terms of MR, MC, and MS.Moreover, the post-COVID-19 complaining group (I) performed worse than the post-COVID-19 non-complaining group (II) regarding MC and MS only (Table 4).These results agreed with the results of Graham et al. [16].The authors reported that long-term COVID-19 patients had significantly worse attention, working memory function and short-term memory.The results of the current work also agreed with the results of Ferrucci et al. [26].These authors reported that post-COVID-19 patients performed worse on verbal memory tests.Twenty percent of their post-COVID-19 patients showed long-term verbal and spatial memory dysfunctions.Moreover, Douaud et al. [23] identified consistent abnormalities in MRIs of COVID-19 adults in the left parahippocampal gyrus, which is a limbic region of the brain involved in supporting memory of events.
In order to explain the results of the post-COVID-19 non-complaining group, Woo et al. [9] reported that   [23] reported that there was a greater loss of gray matter in several areas of the COVID-19 brains in their MRIs.These areas include the left parahippocampal gyrus, cingulate cortex, insula, hippocampus, limbic cortical areas, amygdala and temporal pole.Many of the areas are related to auditory working memory, recall and language [27,28].The insula is important for understanding speech in noise, dichotic listening, temporal processing and auditory attention [29].
There are several different mechanisms involved in COVID-19-associated CNS dysfunction.These include direct viral effects (olfactory pathway or across the blood-brain barrier) and indirect mechanisms (hypoxia, activation of the immune system, inflammatory and thrombotic pathways) [30,31].COVID-19 was proven to spread through the olfactory epithelium and the ethmoid bone to the olfactory bulbs in the brain, causing olfactory disorders along with memory impairment and cognitive disabilities [32].It is reported that COVID-19 has a known neurotropism [30].
The central auditory pathways are hypothesized to be damaged by inflammation, leading to APD later [20].Inflammatory factors have been shown to not return to normal status months after recovery [33].Chronic systemic inflammation after COVID-19 infection exacerbates neurodegeneration.Thus, potentially, this would lead to long-term cognitive deficits [34].
Silent strokes or lack of oxygen also could damage the COVID-19 patient's brain.Silent strokes typically affect the brain's white matter -the wiring between brain cells that enables different parts of the brain to communicate with each other.This wiring is essential for attention, and when it is damaged, sustained attention is impaired [10].
Ferrucci et al. [26] reported that the memory impairments observed in patients with COVID-19 months after hospital discharge could be related to hypoxic factors.Long-lasting hypoxia might contribute substantially to post-infection cognitive impairments.This is because neurons are sensitive to hypoxic injury [35].
Moreover, Selective neuronal mitochondrial targeting in COVID-19 infection could affect cognitive processes.Hypoxia of brain areas may increase the reproductive capacity of the virus.In areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after the integration of the viral genome, resulting in mitochondrial dysfunction.Accordingly, neurons would become dysfunctional [8].
Furthermore, the prolonged immune response can lead to post-COVID-19 squeals.This mechanism has the potential to cross the blood-brain barrier and affect neural regions and function, including cognition [36].This mechanism or hypothesis is supported by the results of Graham et al. [16] work.These authors reported that the female: male ratio of 2.3:1 was reminiscent of autoimmune diseases.
A statistically significant positive correlation was revealed between the GIN score and the time between attacks and testing (weeks).The longer the interval between the attack and the test was, the better the GIN score was.This result agreed with the results of Davis et al. [19].Those authors reported that systemic and neurological/cognitive symptoms were the most likely to persist from disease onset to seven months.In contrast, the onset of brain fog/cognitive dysfunction occurred in the first week of symptoms.Reports of cognitive dysfunction increased over the first three months and then decreased slightly in the following months.This change might be linked to the decrease of antibody levels with time [37].
Moreover, there was a statistically significant positive correlation between the results of SPIN-SNR −10 (test of  [38] work.They reported that patients with chronic hypoxia might have the worst performance on attention tests.Also, Almeria et al. [30] reported that the need for oxygen therapy in COVID-19 patients was associated with memory, attention and executive function deficits. ) Normal middle ear function.The Exclusion criteria included: (1) Patients who had a history of hearing loss or history of any known cause of hearing loss or central auditory processing disorders (CAPD).(2) History of cognitive complaints regarding memory and attention prior to COVID-19 infection.(3) Patients with a history of past neurological and psychological illness.(4) Refusal to participate in the study.The third group was the Control group (GIII).It consisted of 20 healthy adults.They all had no complaints regarding hearing or vestibular systems.The inclusion criteria included (1) normal peripheral hearing.(2) Normal middle ear function.(3) seronegative test for antibody for COVID-19.Their exclusion criteria included: (1) seropositive antibody test for COVID-19.(2) History of cognitive complaints regarding memory and attention.(3) History of any neurological, psychological, systemic, or endocrinal diseases, and (4) Refusal to participate in the study.Equipment Sound-treated room: Transacoustic Model No RE241.Two-channel pure tone audiometer: Grasson-Stadler version 61 clinical audiometer.Immittancemetry: Interacoustic AT235H and CD player (Thomason cs96) connected to the audiometer and adjusted to deliver central speech material.

Fig. 2
Fig. 2 Line graph showing the different means of the PTA at different tested frequencies.PTA: pure tone audiometry

Fig. 3
Fig. 3 Correlation between GIN score and the time period (weeks) between date of acute attacks and date of examination (weeks) in the study groups (I & II) (N = 30).GIN: Gap In noise ability) and Monaural Separation.Post-COVID-19 patients performed statistically significantly worse than the controls at 0 dB S/N and at -10 dB S/N.The post-COVID-19 complaining group (I) performed worse than the post-COVID-19 noncomplaining group (II) regarding SPIN-SNR −10 (Table

Fig. 4
Fig. 4 Correlation between SPIN-SNR-10 and Oxygen saturation in the study (I & II) (N = 30).SPIN: Speech perception in noise, SNR: Signal to noise ratio

Results Age and gender distribution
I. Full audiological evaluation including (1) Full audiological history and for patients in the study groups (groups I and II), a detailed history of COVID-19 infection was taken.(2) Otological examination and Basic audiological evaluation.

Table 1
Oxygen saturation among complaining and noncomplaining groups t: independent sample t-test*: P value is significant at the 0.05 level.P ≤ 0.05 is significant P ≤ 0.001 is highly significant

Table 2
Comparison of Speech Perception in Noise Test (SPIN) and Duration Pattern Sequence Test (DPT) across studied groups Speech Perception in Noise Test (SPIN) and Duration Pattern sequence Test (DPT), signal to noise ratio (S/N).P1: post COVID-19 complaining versus post COVID-19 non-complaining, P2: post COVID-19 non-complaining versus control group, P3: post COVID-19 complaining versus control group * P value is significant at the 0.05 level.P ≤ 0.05 significant P ≤ 0.001 highly significant

Table 3
Comparison of Gap in Noise Test (score and threshold / msec) among studied groups Gap in Noise Test (GIN)P1: post COVID-19 complaining versus post COVID-19 non-complaining, P2: post COVID-19 non-complaining versus control group, P3: post COVID-19 complaining versus control group * P value is significant at the 0.05 level.P ≤ 0.05 significant P ≤ 0.001 highly significant

Table 4
Comparison of Auditory Memory Test among studied groups P1: post COVID-19 complaining versus post COVID-19 non-complaining, P2: post COVID-19 non-complaining versus control group, P3: post COVID-19 complaining versus control group.*:P value is significant at the 0.05 level.P ≤ 0.05 significant P ≤ 0.001 highly significant attention) and O 2 -saturation.This result can be explained by the results of Areza-Fegyveres et al. 's