Introduction
It is widely recognized that exposure to mold toxins, also known as mycotoxins, can have significant detrimental effects on human health. This study focuses on a group of fifteen individuals who, following exposure to mold toxins, developed attention deficit disorder (ADD) and experienced a noticeable slowing of reaction time. These cognitive deficits were meticulously documented through detailed patient histories and, importantly, objective measurements using the Test of Variables of Attention (TOVA). The TOVA is a validated tool that provides a quantitative assessment of attention span and reaction time. Our findings reveal that subjects exposed to mold exhibited statistically significant reductions in attention span and increases in reaction time compared to control groups. Intriguingly, after undergoing ten sessions of hyperbaric oxygen treatment (HBOT), significant improvements were observed in both attention span and reaction time. This preliminary research suggests that hyperbaric oxygen therapy holds considerable promise as a treatment modality for patients suffering from the cognitive consequences of mold toxin exposure, warranting further, more in-depth investigation and careful attention in future studies.
Exposure to toxic substances, including mold and mycotoxins, can profoundly disrupt brain function in both children and adults. Mycotoxins are toxic secondary metabolites produced by fungi, predominantly molds, and are known to be harmful to both animals and humans [1]. Notably, the adverse effects of mycotoxin exposure can persist for years even after the source of exposure has been eliminated [2].
The impact of toxin exposure, including mold, can lead to substantial and long-lasting impairment of cognitive function, often resulting in temporary or even permanent disability. Common symptoms reported by affected individuals include short-term memory deficits, episodes of disorientation, balance and coordination problems, difficulties with multitasking, and diminished attention span and slowed reaction times. Sick Building Syndrome (SBS), a condition often linked to mold and mycotoxin exposure, encompasses a range of symptoms that are frequently observed in individuals inhabiting “sick” buildings. These symptoms, while widely reported, are not fully understood and can include headaches, poor concentration, fatigue, memory loss, dry skin, and itchy eyes [3, 4]. SBS affects both adults and younger populations.
Several types of opportunistic molds are known to produce toxins, including Stachybotrys chartarum, Aspergillus species (A. fumigatus, A. flavus, A. niger, A. versicolor, etc.), Cladosporium, Alternaria, Penicillium, Trichoderma, and Fusarium graminearum, among others [5]. These molds thrive in environments characterized by moisture and dampness, and their proliferation can lead to mycotoxicoses, a broad term encompassing all diseases caused by toxic molds [5].
A recent study investigating the health complaints of 209 patients with confirmed exposure to mixed mold infestations concluded that exposure to these molds and their associated mycotoxins in water-damaged buildings results in a multitude of health issues, particularly affecting the central nervous system and the pulmonary system [6]. Patients commonly exhibit a range of pathological signs, including headaches, gastrointestinal and neuromuscular abnormalities, and various other symptoms [7].
Objective diagnostic techniques, such as brainstem auditory evoked response (BAER) tests, have indicated neurological abnormalities in patients exposed to toxic opportunistic molds through indoor air contamination [5]. Clinical studies involving children with a history of mold exposure, utilizing neurophysiologic tests like electroencephalograms (EEGs), brainstem evoked potentials (BAEPs), visual evoked potentials (VEPs), and somatosensory evoked potentials (SSEPs), have yielded abnormal results. These findings underscore significant neurological deficits and highlight the considerable extent to which toxic molds can neurologically and behaviorally impact children [8]. Evidence of diffuse polyneuropathy and slowed motor conduction further points to substantial neurological impairments in individuals exposed to toxic molds [8]. Myconeurotoxicity may arise from mycotoxins directly affecting the nervous system or by impacting other biological systems that subsequently compromise neurological function [9].
Impairments in attention span and reaction time are frequently observed in patients exposed to mold. Attention deficit disorder (ADD) is typically diagnosed through a comprehensive medical history combined with psychometric testing. While ADD is most often diagnosed in adolescence, it can also manifest in adults [10].
Building upon previous research demonstrating abnormal functional brain scans (SPECT) in mold-exposed patients and the subsequent improvement following hyperbaric oxygen treatment (HBOT) [11], it remained unclear whether the Test of Variables of Attention (TOVA) would also show improvement after HBOT. A prior pilot study indicated a positive trend in TOVA scores after HBOT. However, the limited sample size of that study precluded robust statistical analysis. The current study, involving 15 adult subjects, aims to provide a more statistically sound evaluation.
Materials and Methods
Subjects
Fifteen adult participants, ranging in age from 18 to 58 years, were enrolled in this study. Inclusion criteria mandated confirmed exposure to mold, mycotoxins, and related byproducts, and the development of illness as a consequence of this exposure. Subjects were recruited via referrals from practicing physicians to the corresponding author, with only those with confirmed mold exposure included in the study. All participants provided informed consent to participate in the research, and the study protocol and consent forms were approved by the UCLA IRB. While formal screening for depression or other cognitive deficits was not conducted, clinical evaluations did not reveal overt symptoms of such disorders. Potential candidates were included in the experimental group, with ages distributed to approximate a normal distribution for the sample size. Environmental testing of participants’ residences, workplaces, and schools (for student participants) confirmed the presence of mold and mycotoxins.
Exposure and immune response to mold and mold toxins were verified through specific antibody studies targeting individual molds and mycotoxins. The presence of mold antibodies, at concentrations exceeding those found in healthy blood donors [12], was used to establish adverse health effects resulting from mold exposure. Immunological evaluations confirmed elevated mold antibody levels, which were considered indicative of toxin exposure and qualified subjects for study inclusion.
The adverse effects of mold exposure were objectively assessed using functional brain scans (SPECT) [13, pulmonary function tests, and the Test of Variables of Attention (TOVA) [14]. The TOVA, a computerized test easily administered in a clinical setting, was routinely employed. Based on extensive clinical experience with over 500 mold-exposed patients, the research advisor observed that many developed clinical ADD, which was corroborated by abnormal TOVA results. TOVA tests were administered in a quiet environment with direct observation of the patient by the examiner. Tests were repeated after ten consecutive (excluding weekends) days of HBOT. All TOVA tests were conducted during morning hours to minimize variability due to diurnal effects.
TOVA measurements encompass several key variables, including response time variability (consistency), response time, commission errors (impulsivity), omission errors (inattention), post-commission response times, multiple and anticipatory responses, and an attention deficit hyperactivity disorder (ADHD) score, which is normalized against an age/gender-matched ADHD reference group. A composite score, termed the D prime score, is calculated to provide an overall assessment of the subject’s attentional performance.
The TOVA test is a simple, 21.6-minute-long computer-based task that measures a subject’s responses to visual stimuli. The test results are then compared to normative data from a large group of individuals without attention disorders. The TOVA is extensively normed for individuals aged 4 to over 80 years. It provides precise measurements of reaction times (±1 ms) and is independent of language and cultural factors.
The TOVA utilizes geometric stimuli to minimize the influence of cultural background and learning disabilities. It includes two test conditions: target infrequent and target frequent. Responding to a nontarget stimulus is classified as a commission error, indicative of impulsivity. The first half of the TOVA primarily assesses sustained attention to a monotonous task, while the second half focuses on inhibitory control.
The TOVA employs a fixed, mid-range interstimulus interval (2 seconds) and monochromatic, simple geometric configurations as visual stimuli. These design features, along with a 2.5-minute practice round, minimize practice effects, making the TOVA suitable for repeated measurements over time.
All subjects provided informed consent for the publication of their results and for hyperbaric oxygen treatment, having been fully informed about potential side effects. Statistical analysis of TOVA results was performed using a paired samples t-test via the Statistical Package for the Social Sciences (SPSS) software program.
Treatment Protocol
HBOT was administered using a portable chamber pressurized with air to 1.3 ATM. Pressure was gradually increased over approximately 15 minutes after the patient entered the chamber. 100% oxygen was delivered into the chamber, resulting in a measured concentration of 24–34% after mixing with the chamber air. Oxygen was not delivered via mask or nasal cannula, allowing patients freedom of movement within the chamber. Each treatment session lasted for 1 hour, followed by a gradual pressure reduction before the patient exited the chamber.
The treatment protocol, detailed in Table 1, represents a modified approach compared to traditional HBOT. Due to the lower pressure and oxygen concentration, this method is often referred to as “mild HBOT” (mHBOT). Treatments were administered once or twice daily, with approximately 4 hours separating treatments on the same day. All patients in this study received ten consecutive daily treatments (excluding weekends). Patients continued their existing medical treatments, and no new treatment modalities were introduced concurrently with mHBOT.
Table 1.
Portable hyperbaric oxygen chambers were used for mild hyperbaric oxygen treatment (mHBOT). The table compares conditions of mHBOT to traditional HBOT. Atmosphere absolute (ATA) of 1 ATA is atmospheric pressure at sea level. mHBOT uses 1.3 ATA compared to 2–3 ATA in traditional chambers. Pound per square inch gauge (PSIG) is pressure referenced to ambient air pressure, indicated by a pressure gauge using atmospheric pressure as a base. mHBOT uses 4.7 PSIG, much milder than 14.7–29.4 in traditional HBOT. Feet of sea water (FSW) indicates actual depth or pressure equal to that depth, used to describe hyperbaric chamber pressure. mHBOT applies less pressure. Oxygen concentration is mildly elevated from 21% in air to 24%, much less than 100% oxygen in traditional chambers.
| Sea level | Mild HBOT | Traditional HBOT |
|---|---|---|
| ATA | 1.0 | 1.3 |
| PSIG | 0 | 4.7 |
| FSW | 0 | 11 |
| Oxygen concentration | 21% | 24% |
Results
Following ten mHBOT treatment sessions, preliminary results indicated significant improvements across several TOVA metrics in the 15 study participants. These improvements were observed in attention span, reaction time, consistency of response, and the overall D prime score.
Figure 1 illustrates the effects of ten mHBOT treatments on patient inattention, reaction time, variability, and D prime score, as measured by TOVA in mold-exposed subjects.
Fig. 1.
After ten sessions of mild hyperbaric oxygen treatment (mHBOT), the 15 individuals in the study showed statistically significant improvements (indicated by *) in attention span, reaction time, consistency, and overall D prime score, as assessed by the Test of Variables of Attention (TOVA). Each subject’s post-treatment TOVA score was compared to their pre-treatment baseline. This figure represents the pooled scores of all 15 subjects before and after HBOT sessions. Higher scores signify increased attention, reduced reaction time, greater consistency, and an improved D prime score. The y-axis scale (0–100) represents deviation from standard scores exhibited by TOVA controls, where 100 indicates no abnormality.
Paired samples t-tests were used to compare pre- and post-mHBOT means for each TOVA variable. The analysis revealed a statistically significant improvement in average attention span after ten mHBOT sessions (M = 96.47, SD = 21.11) compared to pre-mHBOT levels (M = 72.67, SD = 32.35), t(14) = 3.55, p < 0.01. Similarly, statistically significant improvements were found in reaction time [t(14) = 4.41], consistency [t(14) = 4.82], and overall D prime score [t(14) = 3.58], all with p < 0.01.
Discussion
While ADD is commonly considered a condition primarily affecting children and adolescents, it can certainly manifest in adults. In adult cases following toxic exposure, ADD should be regarded as acquired or secondary. ADHD in adults is believed to share similar cognitive and psychiatric characteristics with childhood ADHD [15].
In recent years, there has been a notable increase in patients presenting with mold and mold toxin exposure. Many of these individuals report impaired cognitive function and exhibit abnormal findings on neuropsychological tests, SPECT brain scans, and TOVA tests. The TOVA test is particularly valuable as it can be repeatedly administered without significant learning effects, making it an ideal tool for monitoring patient progress before, during, and after treatment. These findings suggest that mold exposure can lead to toxic encephalopathy and ADD, conditions that may be effectively treated with mHBOT.
TOVA test results provide objective support for the presence of physiological abnormalities in patients with a history of mold exposure. Similar findings using different neurophysiological techniques have been reported by Anyanwu et al. As previously mentioned, contemporary objective neurophysiological assessments include EEG, BAEP, VEP, and SSEP. Questionnaires and EEGs were used to analyze response time abnormalities in their study. While our study focused on response time abnormalities, Anyanwu et al. observed delays in brain conduction parameters across all their patients. BAEP scans showed waveform abnormalities in 90% of their patients, and VEP scans revealed bilaterally decreased latencies. Right tibial nerve conduction was slowed, averaging 36.9 ms, and right distal sensory latencies were prolonged compared to bilateral ulnar latencies, in contrast to the absence of latencies in the control group [5]. Significantly slowed motor conductions and neurological deficits impacting children’s behavior were attributed to the extent of their toxic mold exposure.
Numerous studies support the use of hyperbaric oxygen in the treatment of mold-related infections, specifically mucormycosis [16, 17], zygomycosis [18, 19], and candidiasis [20] [21]. While the precise mechanisms of action of HBOT in promoting healing and symptom reversal are still being elucidated, HBOT is known to exert multiple beneficial effects on the body. HBOT significantly elevates oxygen concentration in all body tissues, even in areas with compromised or blocked blood flow. It stimulates the formation of new blood vessels in poorly perfused regions, enhancing blood supply to areas with arterial blockages. A rebound arterial dilation effect occurs after HBOT, resulting in increased blood vessel diameter beyond pre-treatment levels, thereby improving blood flow to compromised organs. HBOT also induces an adaptive increase in superoxide dismutase (SOD), a key endogenous antioxidant and free radical scavenger [22]. Furthermore, HBOT enhances the treatment of infections by boosting white blood cell function and potentiating the effects of germ-killing antibiotics.
The potential mechanisms underlying the effectiveness of hyperbaric oxygen in alleviating ADD symptoms remain unclear. HBOT may facilitate the repair or regeneration of injured lower motor neurons [23] and has been proposed as a promising strategy for the prevention and treatment of various neurological disorders [24].
Research in the past decade has identified stem or progenitor cells in the adult brain capable of neural regeneration [25], a process that is oxygen-dependent. Capillary density in the adult mammalian brain can be increased [26], improving nutrient delivery to regenerating tissues. HBOT has demonstrated efficacy in treating neurological injuries, even when initiated in the non-acute phase [27, 28].
The findings of this study are preliminary due to the absence of a control group and placebo arm. The implications of this small study warrant further investigation through controlled, randomized, double-blind experimental studies to rigorously evaluate the therapeutic potential of hyperbaric oxygen medicine for patients with toxic mold exposure. The challenges associated with conducting control studies with hyperbaric oxygen have been recently discussed by Clarke [29].
A recent multicenter, randomized, double-blind, controlled trial involving children with autism who received hyperbaric treatment at 1.3 ATM and 24% oxygen for 40 hourly sessions showed significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children receiving slightly pressurized room air [30]. Other studies have also provided evidence supporting hyperbaric treatment for autism [31–35].
While not a novel therapy, HBOT has only recently gained broader recognition for treating chronic degenerative conditions associated with diabetic gangrene [36], atherosclerosis [37], stroke [38], chronic vascular wound management [39], diabetic foot ulcers [36], wound healing [40], cerebral palsy [41], brain injury [42], multiple sclerosis [43], macular degeneration [44], and numerous other disorders. HBOT holds therapeutic potential in any condition where blood flow and oxygen delivery to vital organs are compromised, potentially enhancing function and healing.
Memory, reaction time, and visual motor speed assessments were conducted before, during, and after hyperbaric oxygen therapy in a teenage male patient with fetal alcohol syndrome [45]. The authors demonstrated that low-pressure hyperbaric oxygen therapy provided benefit to this patient, resulting in sustained cognitive improvements, with further gains observed after subsequent treatment courses [45].
Previous research has shown HBOT’s effectiveness in improving cerebral palsy, utilizing three-dimensional SPECT scans of cerebral hemispheres before and after mHBOT treatment [13]. The computer program used in that study allows for regional quantitative comparison of an individual’s SPECT scan against a control group of over 20 individuals. Applying the same procedure to the 15 patients in this study suffering from toxic injury due to mold exposure, baseline perfusion deficits shifted into the normal range following HBOT treatment. Quantitative analyses of this aspect of the study are currently underway, requiring careful attention to detail.
Low-pressure HBOT is a low-risk, relatively inexpensive therapy with potentially significant and measurable benefits for conditions with limited alternative treatments. In this study, 15 adults experiencing symptoms associated with mold and mycotoxin exposure demonstrated sustained cognitive improvements after a short course of low-pressure HBOT. Given these promising findings, further investigation and careful attention to these results are warranted to explore the broader implications of mHBOT for mold-related illness and cognitive impairment.
Conflict of interest statement
The authors declare no conflicts of interest.
Ethical approval
The UCLA IRB approved the consent forms and this study.
Open Access
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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