**2. Biomarkers of AD**

A biomarker in medicine is conceptualized as a measurable detector of a physiological, anatomic, or biochemical alternation that can distinct normal biologic processes from pathological. Biomarker should be able to provide reliable diagnosis, follow the development of disease, and measure responses to a therapeutic intervention. The development of a new biomarker for any clinical condition is based on the ability to accurately detect specific pathophysiology against the gold or reference standard. This creates problem specifically to AD because there is no in vivo gold standard. Currently, the final diagnosis of AD requires both the presence of amnestic symptoms and postmortem histopathological confirmation. Premortem diagnosis of AD is only "probable" or "possible" based on symptoms characteristic of Alzheimer's type of dementia and neuroimaging findings.

The growing body of evidences evolves AD research field toward the concept of disease pathogenesis as a continuum of long-term phases in which clinical symptomatology and underlying pathophysiological process have different temporal development rates [45]. The existing findings indicate that the onset of the first symptoms marked the already irreversible stage of the disease [44]. Therefore, only detection of preclinical phase, before the occurrence of the first symptoms, but with present neuropathological changes characteristic of AD, would provide a major opportunity for therapeutic intervention in possible still reversible stage of disease. The main problem of AD research lies in the fact that is not yet found a solid link between the specific biomarker occurrence in presymptomatic individuals and the subsequent appearance of clinical symptoms [44, 45]. Although major advances in brain imaging, neurochemistry, and genetic research that highly accelerated the field, there still remains a need for the establishment of accurate biomarkers of preclinical AD, which will differentiate subjects without the risk of progression to dementia from those at risk for developing symptomatic AD. Today, five stateof-the-art diagnostic measures of AD are proposed for diagnostic criteria [46, 47]. Three of these are neuroimaging measures, and the other two are the laboratory indicators related to cerebrospinal fluid (CSF) proteins. Laboratory measures of AD include a reduced level of amyloid-beta 42 or an increase in p-tau concentration in the CSF. Imaging measures include tracers that allow detection of fibrillary amyloid-beta deposits in the cortex by positron emission tomography (PET) and detectors, also known as injury or topographical biomarkers, of a medial temporal lobe atrophy and reduced glucose metabolism in temporoparietal regions, as determined by magnetic resonance imaging (MRI) and fluorodeoxyglucose (FDG) PET, respectively. However, proposed biomarkers have limited efficiency in detecting preclinical changes associated with the disease [45–50] and are invasive for subjects because there are risks associated with lumbar puncture (CSF), exposure to radiation (PET/CT), or claustrophobic time-consuming scanning (MRI). Moreover, the classification results of proposed biomarkers are based on the difference between group means of measured variables that generally cannot provide a clear boundary between normal and pathological responses. The underlying reason for the limited discriminatory accuracy of proposed biomarkers lies in the high individual heterogeneity and variability of neural responses, cerebral anatomy, and metabolism [51], especially in the elderly population. Consequently, there is an urgent need for additional, noninvasive, more accurate tool that can be used to differentiate presymptomatic and symptomatic AD from normal aging.

by which the neural system rapidly adjusts its response to subsequent stimuli, a neural feature with an essential impact in everyday life [58, 60]. This fast inhibition or enhancement of the neural response provoked by the external stimuli refers to different gating mechanisms: by gating-out neural system selectively suppresses its responses to irrelevant or redundant stimuli and by gating-in reinforcing responses on task-relevant or novel stimuli [59, 60]. Gating-out has been proposed as a mechanism of habituating to redundant stimuli that protect working memory overload by preventing irrelevant information from recurrent sensory processing, while at the same time, gating-in processing enables recognition of relevant envi-

Topological Biomarker of Alzheimer's Disease http://dx.doi.org/10.5772/intechopen.76633 175

Sensory gating deficits have been associated with several clinical conditions. Patients with schizophrenia [62–64], Alzheimer's disease [60, 64, 65], bipolar disorder [66], post-traumatic stress disorder [67], Parkinson's disease [68], or Huntington's disease [69] show alerted sensory gating dynamics compared to controls. Abnormality in extracranially measured auditory gating responses is recognized as one of the best established marks for schizophrenia [70, 71]. In addition, alerted sensory gating has been associated with impaired performance on tasks measuring sustained attention [72], inhibition of distractors [73], or performance on

Multiple neurotransmitters are found to be involved in sensory gating processing, including the cholinergic, dopaminergic, GABAergic, glutamatergic, noradrenergic, and serotonergic systems [74]. Pharmacological studies have emphasized the particular importance of the cholinergic system in regulating the decreased response to repeated stimuli (gating-out) through stimulation of the α-7 nicotinic receptor [75] and the muscarinic M1 receptor [76]. More recently, a marker of the gene for the α-7 nicotinic receptor has been strongly linked to sensory gating abnormalities [75]. Notably, α7-containing receptors are also known for fast

Sensory gating is typically assessed using a paired stimulus or oddball paradigm during an electrophysiological recording. In a paired-click paradigm, the event-related potential (ERP) component P50 or its magnetic counterpart M50, elicited about 50 ms after stimulus presentation, is measured during the presentation of two identical stimuli (S1 and S2) with an interstimulus interval (ISI) of 500 ms [72, 78]. The habituation of the response to the redundant second stimulus, expressed as the ratio between responses amplitudes (S2/S1), indicates the strength of gating-out inhibition [79]. Auditory oddball paradigm is characterized by the varying occurrence probability of a deviant (novel) stimulus between a series of repeated standard stimuli and therefore evokes both gating mechanisms, habituation of redundant information (standard stimuli) and pre-attentive memory-based comparison processes

desensitization in the presence of agonist and high Ca2+ permeability [77].

ronment inputs that are essential for survival [59–61].

*2.2.1. Clinical correlates of sensory gating*

neurocognitive tasks [64].

*2.2.2. Neurochemistry of sensory gating*

*2.2.3. Assessment of sensory gating*

(deviant stimuli) [60, 64].

#### **2.1. Topological biomarker of AD**

Besides high sensitivity and specificity, ideal AD biomarker should be individual, robust, and must be able to follow the evolution of the pathophysiological process of AD from early preclinical changes to symptomatic aggravation of the disease. A promising, but so far underutilized line of biomarker research is the alternation of basic neural network topography as a consequence of AD pathology [52]. An efficient way to start topographic search for AD biomarker is studying the most fundamental, still focal neural mechanisms that occur very early in the processing stream of simple sensory inputs. Dominantly cholinergic modulation of a sensory gating processing [53, 54] indicates that sensory gating network would likely be alerted in AD pathophysiology because the leading neurochemical feature of AD is a deterioration of the cholinergic signal transmission by selective impact on the plasticity of nicotinic (nAChr) and muscarinic (mAChr) synaptic receptors [55]. On a large scale, this synaptic dysfunction is likely to cause subtle alterations in sensory gating processing years before meeting criteria for symptomatic AD [56, 57].

#### **2.2. Sensory gating**

Sensory gating is a fundamental process of sensory processing, arising within the first 50 ms of exposure to a stimulus, much earlier than conscious perception. It is a phenomenon by which the neural system rapidly adjusts its response to subsequent stimuli, a neural feature with an essential impact in everyday life [58, 60]. This fast inhibition or enhancement of the neural response provoked by the external stimuli refers to different gating mechanisms: by gating-out neural system selectively suppresses its responses to irrelevant or redundant stimuli and by gating-in reinforcing responses on task-relevant or novel stimuli [59, 60]. Gating-out has been proposed as a mechanism of habituating to redundant stimuli that protect working memory overload by preventing irrelevant information from recurrent sensory processing, while at the same time, gating-in processing enables recognition of relevant environment inputs that are essential for survival [59–61].

#### *2.2.1. Clinical correlates of sensory gating*

symptoms, but with present neuropathological changes characteristic of AD, would provide a major opportunity for therapeutic intervention in possible still reversible stage of disease. The main problem of AD research lies in the fact that is not yet found a solid link between the specific biomarker occurrence in presymptomatic individuals and the subsequent appearance of clinical symptoms [44, 45]. Although major advances in brain imaging, neurochemistry, and genetic research that highly accelerated the field, there still remains a need for the establishment of accurate biomarkers of preclinical AD, which will differentiate subjects without the risk of progression to dementia from those at risk for developing symptomatic AD. Today, five stateof-the-art diagnostic measures of AD are proposed for diagnostic criteria [46, 47]. Three of these are neuroimaging measures, and the other two are the laboratory indicators related to cerebrospinal fluid (CSF) proteins. Laboratory measures of AD include a reduced level of amyloid-beta 42 or an increase in p-tau concentration in the CSF. Imaging measures include tracers that allow detection of fibrillary amyloid-beta deposits in the cortex by positron emission tomography (PET) and detectors, also known as injury or topographical biomarkers, of a medial temporal lobe atrophy and reduced glucose metabolism in temporoparietal regions, as determined by magnetic resonance imaging (MRI) and fluorodeoxyglucose (FDG) PET, respectively. However, proposed biomarkers have limited efficiency in detecting preclinical changes associated with the disease [45–50] and are invasive for subjects because there are risks associated with lumbar puncture (CSF), exposure to radiation (PET/CT), or claustrophobic time-consuming scanning (MRI). Moreover, the classification results of proposed biomarkers are based on the difference between group means of measured variables that generally cannot provide a clear boundary between normal and pathological responses. The underlying reason for the limited discriminatory accuracy of proposed biomarkers lies in the high individual heterogeneity and variability of neural responses, cerebral anatomy, and metabolism [51], especially in the elderly population. Consequently, there is an urgent need for additional, noninvasive, more accurate tool that

can be used to differentiate presymptomatic and symptomatic AD from normal aging.

in sensory gating processing years before meeting criteria for symptomatic AD [56, 57].

Sensory gating is a fundamental process of sensory processing, arising within the first 50 ms of exposure to a stimulus, much earlier than conscious perception. It is a phenomenon

Besides high sensitivity and specificity, ideal AD biomarker should be individual, robust, and must be able to follow the evolution of the pathophysiological process of AD from early preclinical changes to symptomatic aggravation of the disease. A promising, but so far underutilized line of biomarker research is the alternation of basic neural network topography as a consequence of AD pathology [52]. An efficient way to start topographic search for AD biomarker is studying the most fundamental, still focal neural mechanisms that occur very early in the processing stream of simple sensory inputs. Dominantly cholinergic modulation of a sensory gating processing [53, 54] indicates that sensory gating network would likely be alerted in AD pathophysiology because the leading neurochemical feature of AD is a deterioration of the cholinergic signal transmission by selective impact on the plasticity of nicotinic (nAChr) and muscarinic (mAChr) synaptic receptors [55]. On a large scale, this synaptic dysfunction is likely to cause subtle alterations

**2.1. Topological biomarker of AD**

174 Biomarker - Indicator of Abnormal Physiological Process

**2.2. Sensory gating**

Sensory gating deficits have been associated with several clinical conditions. Patients with schizophrenia [62–64], Alzheimer's disease [60, 64, 65], bipolar disorder [66], post-traumatic stress disorder [67], Parkinson's disease [68], or Huntington's disease [69] show alerted sensory gating dynamics compared to controls. Abnormality in extracranially measured auditory gating responses is recognized as one of the best established marks for schizophrenia [70, 71]. In addition, alerted sensory gating has been associated with impaired performance on tasks measuring sustained attention [72], inhibition of distractors [73], or performance on neurocognitive tasks [64].

#### *2.2.2. Neurochemistry of sensory gating*

Multiple neurotransmitters are found to be involved in sensory gating processing, including the cholinergic, dopaminergic, GABAergic, glutamatergic, noradrenergic, and serotonergic systems [74]. Pharmacological studies have emphasized the particular importance of the cholinergic system in regulating the decreased response to repeated stimuli (gating-out) through stimulation of the α-7 nicotinic receptor [75] and the muscarinic M1 receptor [76]. More recently, a marker of the gene for the α-7 nicotinic receptor has been strongly linked to sensory gating abnormalities [75]. Notably, α7-containing receptors are also known for fast desensitization in the presence of agonist and high Ca2+ permeability [77].

#### *2.2.3. Assessment of sensory gating*

Sensory gating is typically assessed using a paired stimulus or oddball paradigm during an electrophysiological recording. In a paired-click paradigm, the event-related potential (ERP) component P50 or its magnetic counterpart M50, elicited about 50 ms after stimulus presentation, is measured during the presentation of two identical stimuli (S1 and S2) with an interstimulus interval (ISI) of 500 ms [72, 78]. The habituation of the response to the redundant second stimulus, expressed as the ratio between responses amplitudes (S2/S1), indicates the strength of gating-out inhibition [79]. Auditory oddball paradigm is characterized by the varying occurrence probability of a deviant (novel) stimulus between a series of repeated standard stimuli and therefore evokes both gating mechanisms, habituation of redundant information (standard stimuli) and pre-attentive memory-based comparison processes (deviant stimuli) [60, 64].

#### *2.2.4. Neuroimaging of sensory gating*

Notably, there is a problem in noninvasively studying the gating function in vivo. Only functional neuroimaging technique with millisecond temporal resolution can capture the sensory gating dynamics, which occurs within the first 100 ms after stimulus input. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), and near-infrared spectroscopy (NIRS) are neuroimaging techniques that provide indirect look at the brain at work. These techniques provide measures of metabolic and vascular signals that are associated with neuronal activity, which are assumed to be linearly correlated, although reliable functional relations are not yet established. The temporal resolution of these functional techniques is rather low, on a minute scale, compared to underlying neural activity, which extends from 1 to 3 ms of action potential firing to a few tens of milliseconds of synchronous synaptic activity of thousands of postsynaptic neurons.

mapping of elementary sensory gating processing that rises within first 100 ms after stimulus presentation. Moreover, the sources of MEG signals, primarily cortical intracellular postsynaptic currents, make MEG the first choice technique for the noninvasive study of synaptic function in real time. Consequently, MEG has an advantage in the neuroimaging search for

Topological Biomarker of Alzheimer's Disease http://dx.doi.org/10.5772/intechopen.76633 177

In line with the hierarchical model of neural processing [85], sensory gating responses have been long conceptualized to originate in the primary sensory areas [86, 87], due to the very early appearance in a sensory process stream. However, a report of the gating response presence after bilateral damage of the primary auditory areas [88] suggested a contribution from at least one source related to arousal level or state [89]. Efforts to delineate the neuroanatomy of the sensory gating network long have yielded inconsistent findings [90–93]. The recent works, relied on advanced MEG-based multi-dipole source localization, finally provide a reliable set of neural generators [60, 64, 94–96]. Moreover, our novel results revealed possible explanations concerning the problem of inconsistent reports regarding auditory gating network topology, suggesting that paired-click and oddball paradigms, which are often used to challenge sensory gating effects, evoke different gating generator topologies, even though

early neurodegenerative biomarkers associated with synaptic alterations.

*2.2.6. Auditory sensory gating networks evoked by oddball and paired-click paradigm*

Using the oddball paradigm, which evokes both gating-in and gating-out mechanisms, we have demonstrated that auditory gating network comprises a medial prefrontal (mPFC) generator along with the anticipated generators in the bilateral primary auditory cortices [60, 64, 96], as shown in panel A) of **Figure 1**. Our finding suggests the existence of a novel, very fast sensory processing stream (i.e., sensory gating loop), which links executive PFC to primary auditory cortex within the first 50 ms after stimulus presentation, alongside well-affirmed but slower limbic (dorsal) and somatic (ventral) sensory processing pathways [60, 96]. The existence of additional fast sensory processing stream, sensory gating loop, is anatomically supported by dense bidirectional connections between medial PFC and superior temporal cortices found in both primate and human anatomical studies [97, 98]. The mPFC possesses extensive cortico-cortical connections, including extensive local projections to and from other prefrontal regions, as well as with motor, limbic, and sensory cortices [99]. These structural properties of the connecting pathways provide the ability for localized primary auditory generators and PFC regions to work together as a large-scale neural network via fast sensory gating loop.

Our novel research provides evidence that passive paired-click and oddball paradigms activate a different prefrontal generator within the auditory gating network [60, 96]. Spatiotemporal source localization of auditory gating responses evoked by the passive paired-click paradigm revealed a different gating topology consisting of a dorsolateral PFC (dlPFC) source in addition to the sources in the bilateral primary auditory cortices [78, 96], as shown in panel B) of **Figure 1**. This result implies the existence of early rerouting within prefrontal cortex by shifting prefrontal gating activation from dorsolateral to medial prefrontal region, depending on a paradigm [60, 96], suggesting that mPFC and dlPFC regions serve different functions involved during the early sensory processing. A passive paired-click paradigm characterized

*2.2.5. Cortical network underlying sensory gating*

they are both passive for the subjects [96].

Unlike other functional neuroimaging techniques, electroencephalography (EEG) and magnetoencephalography (MEG) provide a critical opportunity to directly and noninvasively study the brain activity [80, 81]. Neurons in the human cortex generally process their information by means of electromagnetic signals and thus enable the direct recording of their activity. EEG and MEG are electrophysiological techniques that are both sensitive to the electrochemical currents within and between the brain cells. With sub-millisecond temporal resolution, these techniques can easily capture the dynamics of spontaneous and evoked neural responses. MEG and EEG provide a complimentary information about the underlying electromagnetic brain activity. MEG measures the magnetic field generated by the primary intracellular ionic currents through postsynaptic dendrites, while EEG measures the voltage scalp distribution generated by the secondary extracellular ionic flow, both produced by the normal brain activity [80, 81].

Though EEG can capture both radial and tangential components of a produced extracellular electrical field [80, 81], there was a widely accepted assumption that MEG detects only sources that are tangential to the scalp surface. However, recently, it was shown that source orientation is not a significant factor in limiting MEG sensitivity. Using both numerical simulation and empirical measurements, it has been demonstrated that source depth and spatial extent of activated assembly on convoluted cortical surface are the main factors that compromise the sensitivity of MEG to neural activity in the human cortex [82]. Although both techniques have high temporal resolution, MEG outperforms EEG in spatiotemporal localization of neural substrate underlying extracranially captured electromagnetic activity. Using modern signal analysis methods the centimeter spatial resolution of EEG approach that of conventional fMRI [83]. On the other hand, MEG technique has an excellent, millimeter spatial accuracy [82, 84]. Moreover, MEG can detect low-amplitude dipole current source in the deep tissue of dislocate cortex, which is simultaneously active with several times higher-magnitude dipole sources in the superficial regions of primary sensory areas [60], demonstrating a high spatial resolution of synchronously active sources within a neural network. Therefore, MEG can be used in two basic ways. The first, similar to the ordinary EEG recordings, utilizes studies of rhythmic brain activity, evoked neural processing, and clinical diagnostics to detect the presence or signs of abnormality in spontaneous or evoked brain activity. The second and more ambitious use of MEG is in the estimation of the location, strength, and time courses of neuronal current sources of spontaneous and evoked magnetic signals recorded outside the head. In conclusion, MEG is a unique method that enables the noninvasive spatiotemporal mapping of elementary sensory gating processing that rises within first 100 ms after stimulus presentation. Moreover, the sources of MEG signals, primarily cortical intracellular postsynaptic currents, make MEG the first choice technique for the noninvasive study of synaptic function in real time. Consequently, MEG has an advantage in the neuroimaging search for early neurodegenerative biomarkers associated with synaptic alterations.

#### *2.2.5. Cortical network underlying sensory gating*

*2.2.4. Neuroimaging of sensory gating*

176 Biomarker - Indicator of Abnormal Physiological Process

Notably, there is a problem in noninvasively studying the gating function in vivo. Only functional neuroimaging technique with millisecond temporal resolution can capture the sensory gating dynamics, which occurs within the first 100 ms after stimulus input. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), and near-infrared spectroscopy (NIRS) are neuroimaging techniques that provide indirect look at the brain at work. These techniques provide measures of metabolic and vascular signals that are associated with neuronal activity, which are assumed to be linearly correlated, although reliable functional relations are not yet established. The temporal resolution of these functional techniques is rather low, on a minute scale, compared to underlying neural activity, which extends from 1 to 3 ms of action potential firing to a few tens of milliseconds of synchronous synaptic activity of thousands of postsynaptic neurons. Unlike other functional neuroimaging techniques, electroencephalography (EEG) and magnetoencephalography (MEG) provide a critical opportunity to directly and noninvasively study the brain activity [80, 81]. Neurons in the human cortex generally process their information by means of electromagnetic signals and thus enable the direct recording of their activity. EEG and MEG are electrophysiological techniques that are both sensitive to the electrochemical currents within and between the brain cells. With sub-millisecond temporal resolution, these techniques can easily capture the dynamics of spontaneous and evoked neural responses. MEG and EEG provide a complimentary information about the underlying electromagnetic brain activity. MEG measures the magnetic field generated by the primary intracellular ionic currents through postsynaptic dendrites, while EEG measures the voltage scalp distribution generated by the secondary extracellular ionic flow, both produced by the normal brain activity [80, 81]. Though EEG can capture both radial and tangential components of a produced extracellular electrical field [80, 81], there was a widely accepted assumption that MEG detects only sources that are tangential to the scalp surface. However, recently, it was shown that source orientation is not a significant factor in limiting MEG sensitivity. Using both numerical simulation and empirical measurements, it has been demonstrated that source depth and spatial extent of activated assembly on convoluted cortical surface are the main factors that compromise the sensitivity of MEG to neural activity in the human cortex [82]. Although both techniques have high temporal resolution, MEG outperforms EEG in spatiotemporal localization of neural substrate underlying extracranially captured electromagnetic activity. Using modern signal analysis methods the centimeter spatial resolution of EEG approach that of conventional fMRI [83]. On the other hand, MEG technique has an excellent, millimeter spatial accuracy [82, 84]. Moreover, MEG can detect low-amplitude dipole current source in the deep tissue of dislocate cortex, which is simultaneously active with several times higher-magnitude dipole sources in the superficial regions of primary sensory areas [60], demonstrating a high spatial resolution of synchronously active sources within a neural network. Therefore, MEG can be used in two basic ways. The first, similar to the ordinary EEG recordings, utilizes studies of rhythmic brain activity, evoked neural processing, and clinical diagnostics to detect the presence or signs of abnormality in spontaneous or evoked brain activity. The second and more ambitious use of MEG is in the estimation of the location, strength, and time courses of neuronal current sources of spontaneous and evoked magnetic signals recorded outside the head. In conclusion, MEG is a unique method that enables the noninvasive spatiotemporal

In line with the hierarchical model of neural processing [85], sensory gating responses have been long conceptualized to originate in the primary sensory areas [86, 87], due to the very early appearance in a sensory process stream. However, a report of the gating response presence after bilateral damage of the primary auditory areas [88] suggested a contribution from at least one source related to arousal level or state [89]. Efforts to delineate the neuroanatomy of the sensory gating network long have yielded inconsistent findings [90–93]. The recent works, relied on advanced MEG-based multi-dipole source localization, finally provide a reliable set of neural generators [60, 64, 94–96]. Moreover, our novel results revealed possible explanations concerning the problem of inconsistent reports regarding auditory gating network topology, suggesting that paired-click and oddball paradigms, which are often used to challenge sensory gating effects, evoke different gating generator topologies, even though they are both passive for the subjects [96].

#### *2.2.6. Auditory sensory gating networks evoked by oddball and paired-click paradigm*

Using the oddball paradigm, which evokes both gating-in and gating-out mechanisms, we have demonstrated that auditory gating network comprises a medial prefrontal (mPFC) generator along with the anticipated generators in the bilateral primary auditory cortices [60, 64, 96], as shown in panel A) of **Figure 1**. Our finding suggests the existence of a novel, very fast sensory processing stream (i.e., sensory gating loop), which links executive PFC to primary auditory cortex within the first 50 ms after stimulus presentation, alongside well-affirmed but slower limbic (dorsal) and somatic (ventral) sensory processing pathways [60, 96]. The existence of additional fast sensory processing stream, sensory gating loop, is anatomically supported by dense bidirectional connections between medial PFC and superior temporal cortices found in both primate and human anatomical studies [97, 98]. The mPFC possesses extensive cortico-cortical connections, including extensive local projections to and from other prefrontal regions, as well as with motor, limbic, and sensory cortices [99]. These structural properties of the connecting pathways provide the ability for localized primary auditory generators and PFC regions to work together as a large-scale neural network via fast sensory gating loop.

Our novel research provides evidence that passive paired-click and oddball paradigms activate a different prefrontal generator within the auditory gating network [60, 96]. Spatiotemporal source localization of auditory gating responses evoked by the passive paired-click paradigm revealed a different gating topology consisting of a dorsolateral PFC (dlPFC) source in addition to the sources in the bilateral primary auditory cortices [78, 96], as shown in panel B) of **Figure 1**. This result implies the existence of early rerouting within prefrontal cortex by shifting prefrontal gating activation from dorsolateral to medial prefrontal region, depending on a paradigm [60, 96], suggesting that mPFC and dlPFC regions serve different functions involved during the early sensory processing. A passive paired-click paradigm characterized

**Figure 1.** Auditory sensory gating network evoked by the oddball paradigm (panel A) and paired-click paradigm (panel B). The best-fitting source locations are superimposed on volumetric MRI head data to achieve a spatial (3D) rendering of the auditory gating topology. In addition to anticipated bilateral generators in primary auditory areas (blue and green dots), both paradigms evoke a prefrontal gating generator (red dot). While oddball tones provoke medial PFC activation, the tones of a paired-click paradigm activate dorsolateral PFC areas.

Taking advantage of the differences in the evoked gating networks between individuals whose PFC generator was activated (Type 1 in **Figure 2**) and cognitively impaired individuals whose PFC gating generator was not activated (Type 2 in **Figure 2**) by the tones of an oddball paradigm, we have carried out a differential analysis of the functional roles for each generator. Our results show that cortical gating dynamics of STG generators evoked by both the standard and deviant tones demonstrated highly increased strength of both gating components in all subjects lacking PFC generator activity [60]. This result is of extreme clinical importance because the prevalent view of the gating-related pathologies assumes that the larger amplitude of the extracranial gating response to the standard tone (i.e., redundant stimuli) reflects impaired gating out processing of neural substrate in primary auditory areas only (i.e., STG generators) [61–63, 66–69]. Our novel results provide strong evidence of sustained inhibitory activity of the PFC generator that suppresses or modulates the activity of the STG generators as an underlying mechanism of both gating phenomena. Consequently, impaired activity of a PFC gating generator could be a primary cause of impaired extracranially measured sensory gating responses, found in numerous neurological and psychological clinical conditions.

STG gating response (Mb1 and Mb2) are significantly increased when PF source activation is absent.

**Figure 2.** Estimated cortical dynamics of auditory gating network generators evoked by the oddball paradigm. Cortical dynamics of medial prefrontal (PF) and STG gating generators for both tones (standard and deviant) are shown for eight representative subjects (four of each network type). Gating network type 1 comprised bilateral STG and the PF source, while network type 2 was characterized by the absence of PF activation. The time courses of the STG activity were individually averaged across hemispheres and displayed for 30–200 ms time window to include M100, the most prominent STG response, for the amplitude comparison with earlier Mb1 and Mb2 components. Both components of

Topological Biomarker of Alzheimer's Disease http://dx.doi.org/10.5772/intechopen.76633 179

**3. Link between impaired sensory gating and AD pathology**

The initial symptoms of AD include subtle decline of the ability to learn new information along with diverse amnestic disorders without present brain injuries. Clinically indicated AD signs are pointing to the existence of functional impairment of synapses that are involved in converting and forming new declarative memory [32]. Whereas longer retention of sensory memory traces derive more successful memory encoding [101], sensory gating process, conceptualized

by the constant repetition of both short- and long-term patterns (S1–500 ms; S2–8 s) could result in long-term repetition suppression produced by the dlPFC. On the contrary, an oddball paradigm, characterized by the varying occurrence probability of a novel stimulus between a series of repeated stimuli, could put the neural network into a state of perceptual expectation (gating-in) while simultaneously suppressing redundant stimuli (gating-out). This phenomenon could be interpreted as the bottom-up, stimulus-driven initiation of attention during the very early sensory processing [100] executed by the mPFC region.

#### *2.2.7. Functional mechanisms underlying auditory sensory gating*

In addition to the spatial localization of auditory gating networks, we have disclosed the functional relation within network generators providing strong evidence of a modulatory role for the mPFC generator on bilateral superior temporal gyri (STG) sources dynamics during gating processing (**Figure 2**). This result discloses the long-sought mechanism underlying the auditory gating effect [60]. We demonstrated the complex form of estimated cortical morphology of the neural responses produced by the gating generators. In particular, gating response of STG generators is found to be composed of two consecutive cortical subcomponent, Mb1 peaking at 35–53 ms and Mb2 peaking at 75–95 ms post-stimulus, for both oddball paradigm tones [60]. We also provide the first estimates of cortical gating response produced by the mPFC generator, which has an analogous tandem form [60], as shown in **Figure 2**.

**Figure 2.** Estimated cortical dynamics of auditory gating network generators evoked by the oddball paradigm. Cortical dynamics of medial prefrontal (PF) and STG gating generators for both tones (standard and deviant) are shown for eight representative subjects (four of each network type). Gating network type 1 comprised bilateral STG and the PF source, while network type 2 was characterized by the absence of PF activation. The time courses of the STG activity were individually averaged across hemispheres and displayed for 30–200 ms time window to include M100, the most prominent STG response, for the amplitude comparison with earlier Mb1 and Mb2 components. Both components of STG gating response (Mb1 and Mb2) are significantly increased when PF source activation is absent.

Taking advantage of the differences in the evoked gating networks between individuals whose PFC generator was activated (Type 1 in **Figure 2**) and cognitively impaired individuals whose PFC gating generator was not activated (Type 2 in **Figure 2**) by the tones of an oddball paradigm, we have carried out a differential analysis of the functional roles for each generator. Our results show that cortical gating dynamics of STG generators evoked by both the standard and deviant tones demonstrated highly increased strength of both gating components in all subjects lacking PFC generator activity [60]. This result is of extreme clinical importance because the prevalent view of the gating-related pathologies assumes that the larger amplitude of the extracranial gating response to the standard tone (i.e., redundant stimuli) reflects impaired gating out processing of neural substrate in primary auditory areas only (i.e., STG generators) [61–63, 66–69]. Our novel results provide strong evidence of sustained inhibitory activity of the PFC generator that suppresses or modulates the activity of the STG generators as an underlying mechanism of both gating phenomena. Consequently, impaired activity of a PFC gating generator could be a primary cause of impaired extracranially measured sensory gating responses, found in numerous neurological and psychological clinical conditions.
