Fundamental evidence

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18 Fundamental evidence

What is functional neurology?

Functional neurology comprises the evolving body of knowledge and clinical approach concerned with the recognition, analysis, and conservative care of aberrant neurological function in the human neuraxis. The clinical application of functional neurology focuses on modulating the central integrative state of the projection systems utilised by the cortex to modulate activity throughout the neuraxis. The central integrative state of these projection systems are dependent on the processes of neural plasticity, processes which are fundamental to nervous system learning and functional change. The functional neurology approach to the management of aberrant neurological function recognises and uses the natural phenomenon of neural plasticity to evoke change in targeted functional areas of the neuraxis. This is done in order to encourage normalisation of nervous system function as far as possible. The methods utilised to evoke the neural plasticity in functional neurology tend to be conservative, non-surgical and non-pharmaceutical therapeutic interventions. Often, the functional neurologist will work in collaboration with other practitioners who do utilise pharmaceutical and surgical approaches if this is in the best interest of the patient.

Neuroplasticity

Basis for neural plasticity

Neuroplasticity refers to the processes involved in the nervous system as it adjusts its functional capacities to novel contexts (Nowak et al. 2009). The processes of neuroplasticity can be expressed at two interacting levels of nervous system function such as at the level of motor or sensory representations of body parts in the cortex which corresponds to representational or map plasticity; or at the neuronal level which can involve synaptic plasticity or changes in neuron activation levels or morphology (Boroojerdi et al. 2001). In the somatosensory cortex, some forms of plasticity can occur very rapidly, within minutes to hours (Ziemann et al. 2001). For instance, cortical neurons deafferented by peripheral nerve lesion or amputation rapidly become responsive to sensory input from adjacent functioning sites (Merzenich et al. 1983; Kolarik et al. 1994; Borsook et al. 1998). In the motor cortex, neurons can also rapidly reorganise their representative maps in response to nerve lesions or ischaemic nerve block (Ziemann et al. 1998) or during motor practice (Sadato et al. 1996; Pascual-Leone et al. 1993; Butefisch et al. 2000). It is now well documented that changes in somatocortical activation can be directly linked to both direct and indirect somatosensory input from peripheral receptors including joint receptors and muscle spindle afferent projections (Ridding et al. 2001; Kaelin-Lang et al. 2002; Tinazzi et al. 2005). Several mechanisms have been suggested to explain these plastic changes in the cortex.

Functional changes

These include changes in synaptic efficacy (Hebbian plasticity) or by reducing or modifying protein synthesis and proteinase activity in nerve cells via receptor activation of immediate early genes. These processes are controlled by the central integrative state of the neuron and are thus strongly influenced by the stimulation status of the neuron.

Synaptic efficacy and unmasking of latent horizontal connections

Synaptic connections are maintained by neurons when they are active and produce activity (action potentials) in the primary neurons. These connections modulate the neurons’ output through temporal and special summation characteristics at any given moment (Hebb 1949). Mechanisms responsible for this type of plasticity include long-term potentiation (LTP) and long-term depression (LTD) (Hess & Donoghue 1996). An intriguing example of this process has been proposed as a reason for our need to sleep and dream. The Hebbian principal of synaptic maintenance due to activation also suggests that synapses or connections between inactive neurons are being constantly degraded due to spontaneous down-regulation of molecules and substrates necessary for maintenance of synaptic function. In circuits where activity levels are high these processes are refreshed by the constant activation and expression of the genes that code for the necessary substrates. Circuits that are infrequently utilised refresh their synaptic strength during sleep and dreaming (Samvat & Osiecki 2009). During sleep, the maintenance of synaptic fitness in long-term memory circuits and circuits not frequently utilised while we are awake is stimulated by spontaneous slow (delta) wave oscillations and via fast wave stimulus during the REM component of sleep (Kavanau 2002). The activation of new and old memory circuits during REM sleep may result in what we perceive as dreams (Massimini et al. 2007).

It seems that many synaptic connections that are maintained in the system have a moderate to low efficacy for individually inducing a large enough change in a neuron’s membrane potential to result in the generation of an action potential. Some of these pre-existing but semi-dormant projection fibres have been referred to as horizontal fibres. Should the firing characteristics of other more primary firing inputs to the neuron change, say through functional dysfunction, trauma or stroke, the effect of these synapses on the system become ‘unmasked’ and may change their effects on the system drastically (Durian-Smith & Gilbert 1994). The effects may be either beneficial or harmful to the individual depending on a complex set of circumstances including the functional area of the brain involved and the increase or decrease in inhibitory influences on the system. For example, in the case of a stroke, survivors typically experience an acute increase in perilesional excitability due, for the most part, to increases in excitatory neurotransmitters, followed by chronic changes that include changes in intracortical and interhemispheric inhibitory imbalances that manifest in a variety of physical symptoms that could facilitate or hinder recovery, depending on the functional systems involved (Kreisel 2006).

Immediate early gene activation of protein synthesis

It is now commonly accepted that the brain controls mental, physiological, and behavioural processes and that brain function is controlled by gene activation. It is also accepted that social, developmental, and environmental factors can alter gene expression and that alteration in this gene expression induces change in brain function (Kandel 1998). This process is accomplished by special transmission proteins called immediate early genes (IEG) which are activated by a variety of second-messenger systems in the neuron in response to membrane stimulus (Chen & Tonegawa 1997; Kaczmarek & Chaudhuri 1997). Two types of IEG responses have been recognised and include type 1 IEG responses which are specific for the genes in the nucleus of the neuron and type 2 IEG responses which are specific for mitochondrial genes (Pleasure 1992). These genes are activated by a complex interaction involving receptor stimulation and the biochemical status of the neuron.

Redirection, reorganisation or rerouting of nerve transmission

This type of plasticity includes creation of new anatomical connections (sprouting of axons and dendrites) or elimination of existing connections or by altering synapses morphologically (Sanes & Donoghue 1997). A typical example of this type of plastic change is recovery after ischemic strokes. Mechanisms of plasticity result in reorganisation of the nervous system in such a way as to allow other parts of the CNS to take over some of the functions that were impaired from the ablative loss of neural tissue. For example, injury to cortical areas elicits a sequence of self-repair mechanisms, including redirection of tasks to other cortical areas. This reorganisation may include functional circuits far removed from the original site of injury. This injury-induced reorganisation may include enlargement of the cortical areas representative of the new circuits involved, and it may provide the neural substrate for adaptation and recovery of motor behaviour after injury (Frost et al. 2003). This type of reorganisation seems to occur spontaneously in response to injury, and training can facilitate the shift of processing from damaged parts of the CNS to more functionally intact areas. Focused rehabilitation that facilitates expression of neural plasticity is presently the most effective form of reorganisation stimulus but additional methods are under investigation and include stimulation of the cerebral cortex utilising both direct current in the form of transcranial direct current stimulation (tDCS) (Plautz et al. 2003; Schlaug & Renga 2008) and magnetic currents in the form of transcranial direct magnetic stimulation (TMS) (Khedr et al. 2005; Kim et al. 2006).

Afferent modulation of cortical function

The development and maintenance of functional projection systems of the neuraxis is dependent on the central integrative state of the neurons supporting the projection fibres of the system. This is dependent to a large degree on the afferent input and efferent output transmitted by the system. Changes in cortical activation can result from changes or attenuation of afferent information arriving in the cortex from peripheral or subcortical structures. The changes resulting from attenuation of the afferent input that are manifested both morphologically and functionally in the cortex seem to also occur at all levels within the projection system involved (Merzenich et al. 1984). For instance changes in cortical somatotopic maps in cats also show acute and chronic changes at the level of the spinal cord, dorsal columns and the thalamus following nerve transsection (Dostrovsky et al. 1976; Millar et al. 1976). Similar findings have also been found in monkeys (Merzenich et al.1981, 1983, 1984).

There is extensive evidence that alterations in motor activities which involve both afferent and efferent projection systems can induce structural and functional plasticity within the cortex, basal ganglia, cerebellum, and spinal cord in humans (Classen et al. 1998; Kelly et al. 2003; De Zeeuw & Yeo 2005; Graybiel 2005). Novel movement performance induces changes in cortical synaptic number, strength, and topography of cortical maps in the projection systems and neural assemblies involved in the performance of the movements (Montfils et al. 2005). Peripheral sensory stimulation has also been shown to induce long-lasting modulation of cortical activation and cortical motor output (Ridding et al. 2001). Cortical representation of cranial nerves has also been shown to modulate with alterations in afferent input. Hamdy et al. (1998) reported an increase in excitation levels in the pharynx cortical representation maps following short-term (10 min) stimulation of the pharynx. These changes lasted 30 minutes following the cessation of the initial stimulus. In a similar study, Ridding et al. (2000) showed that repetitive mixed nerve stimulation of the ulnar nerve increased the excitability of the cortical projections to the hand muscles of the same hand lasting at least 15 minutes longer than the stimulus. The rapid development of these plastic changes suggests that the mechanism involves unmasking or disinhibition of pre-existing weak (horizontal) projections (Boroojerdi et al. 2001).

Spinal and extremity manipulations have been postulated to exert their effects through a wide variety of anatomical, mechanical, and physiological parameters which result in modulation of mechano-receptive afferentation including somatosensory receptors, proprioception, and pain modulators. We will now look at some of the evidence that supports the effects of joint manipulation on various aspects of the neuraxis, starting with the local effects, then expanding to include segmental and suprasegmental modulatory actions that may help to explain the more wide-ranging effects we can detect following manipulation.

Korr (1975) proposed that effects of spinal manipulation on receptors in the paraspinal tissues were mediated by group I and II proprioceptive afferents. He proposed that spinal manipulation increases joint mobility by producing a barrage of impulses in muscle spindle afferents and smaller-diameter afferents, ultimately silencing facilitated gamma motor neurons. Group III and IV afferents have also been implicated as contributing to the effects of manipulation on the paraspinal structures. Studies on the spines of rats, rabbits, and cats have helped us understand the mechanical and chemical stimuli that can excite the receptive endings of sensory paraspinal neurons. The majority of afferents, including those with receptive fields in or near the facet joint capsule, responded in a graded fashion to the direction of a non-noxious load applied to the joint (Pickar & McLain 1995). Several studies have also demonstrated the effects of the manipulation on structures in the intervertebral foramina. Substantial evidence demonstrates that the dorsal roots (DRs) and dorsal root ganglia (DRG) are more susceptible to the effects of mechanical compression than are the axons of peripheral nerves (Rydevik 1992). Compressive loads as low as 10 mg applied rapidly to the DRs slightly increases the discharge of group I, II, III, and IV afferents (Howe et al. 1977). Clearly, the idea that a herniated disc could directly compress the DRs or DRG is a realistic and plausible scenario. A second scenario outlining the mechanism of involvement of a herniated intervertebral disc affecting nerve root function suggests that its effects are mediated indirectly by the release of neuroactive and immune-stimulating chemicals (McCarron et al. 1987). This mechanism would help explain the common observation that, even in the absence of compression, herniated discs are accompanied by neurological and immunological (inflammatory) findings.

Central facilitation (also called central sensitisation) refers to the increased excitability or enhanced responsiveness of dorsal horn neurons to an afferent input. Central facilitation can be manifested by increased spontaneous central neural activity, by enhanced discharge of central neurons to an afferent input, or by a change in the receptive field properties of central neurons (Cook et al. 1987). We currently know that the phenomenon of central facilitation increases the receptive field of central neurons and allows innocuous mechanical stimuli access to central pain pathways. In other words, subthreshold mechanical stimuli may initiate pain, because central neurons have become sensitised and they are responding to inappropriate stimuli (Woolfe 1994).

Substantial evidence demonstrates that spinal manipulation evokes paraspinal muscle reflexes and alters motor neuron excitability. Posterior to anterior spinal manipulative treatments applied to the cervical, thoracic, lumbar, and sacroiliac regions increased paraspinal EMG activity in a pattern related to the region of the spine that was manipulated. The EMG response latencies occur within 50 to 200 ms after initiation of the manipulative thrust (Suter et al. 1994; Herzog et al. 1999). The effects of spinal manipulation on somatomotor activity may be quite complex, producing both excitatory and inhibitory effects. Changes in muscle spindle input produced by spinal manipulation could also contribute to the inhibition of somatosomatic reflexes. Using magnetic stimulation, Zhu et al. (1993, 2000) stimulated lumbar paraspinal muscles and recorded the evoked cerebral potentials. Stimulation of paraspinal muscle spindles using vibration reduced the magnitude of the cerebral potentials. Similarly, muscle spasm in human patients reduced the magnitude of the paraspinal muscle-evoked cerebral potentials. Spinal manipulation reversed these effects, improving muscle spasm and restoring the magnitude of the evoked cerebral potentials, suggesting that increased sensory input from paraspinal muscle spindles during muscle spasm may contribute to the reduced magnitude of the evoked cerebral potentials.

Spinal manipulation of dysfunctional joints may modify transmission in neuronal circuitries, not only at a spinal level as indicated by the above research, but at a cortical level, and possibly also deeper brain structures such as the basal ganglia. In 1997, Carrick, utilising manipulation of the upper cervical spine which is known to increase the frequency of firing of multimodal neurons in areas of the thalamus and brainstem that project to the visual striate cortex, demonstrated that asymmetrically altering the afferent input to the thalamus resulted in an asymmetrical effect on the size of the blind spot in each eye. The blind spot was found to decrease on the side of increased afferent stimulus (side of the adjustment). This was attributed to an increase in brain function on the contralateral side due to changes in thalamocortical activation that occurred due to multimodal sensory integration in the thalamus. Haavik-Taylor and Murphy (2007) utilised somatosensory evoked responses to investigate cortical changes following cervical manipulation. They found that spinal manipulation of dysfunctional cervical joints can lead to transient cortical plastic changes, as demonstrated by attenuation of cortical somatosensory evoked responses. They further concluded that cervical spine manipulation may alter cortical somatosensory processing and sensorimotor integration. Unpublished data in my own lab have shown normalisation of quantitative electroencephalography (qEEG) findings in a variety of patients following cervical and extremity manipulation, suggesting cortical modulatory effects.

Several theories have been postulated (Holt et al. 2006) to suggest possible mechanisms of cortical modulation resulting from changes in afferent stimulation following manipulation. A summary of these theories includes the following ten possibilities.

1. Cervical manipulations excite spinoreticular pathways or collaterals of dorsal column and spinocerebellar pathways. Spinoreticular fibres originate at all levels of the cord but particularly in the upper cervical segments. They synapse on many areas of the pontomedullary reticular formation (PMRF).

2. Cervical manipulations cause modulation of vestibulosympathetic pathways. This may involve the same pathways as above or could reflect modulation of vestibular neurons at the level of the vestibular nuclei.

3. Cervical manipulations cause vestibulocerebellar activation of the nucleus tractus solitarius (NTS), dorsal motor nucleus of vagus, and nucleus ambiguous.

4. Manipulations may result in brain hemisphere influences causing descending excitation of the pontomedullary reticular formation (PMRF). The PMRF will exert tonic inhibitory control of the IML.

5. Lumbosacral manipulations may result in sympathetic modulation due to direct innervation of the RVLM via dorsal column nuclei or spinoreticular fibres that ascend within the ventrolateral funiculus of the cord.

6. Spinal manipulation may alter the expression of segmental somatosympathetic reflexes by reducing small-diameter afferent input and enhancing large-diameter afferent input. This may influence sympathetic innervation of primary and secondary organs of the immune system.

7. Spinal manipulations may alter the expression of suprasegmental somatosympathetic reflexes by reducing afferent inputs on second-order ascending spinoreticular neurons. This may influence sympathetic innervation of immune system organs at a more global level.

8. Spinal manipulations may alter central integration of brainstem centres involved in descending modulation of somatosympathetic reflexes. This may occur via spinoreticular projections or interactions between somatic and vestibular inputs in the reticular formation. Both somatic (high threshold) and vestibular inputs have been shown to increase output from the rostral ventrolateral medulla (RVLM), which provides tonic excitatory influences on the intramedial lateral (IML) cell column of the spinal cord. Proprioceptive (low threshold) inputs from the cervical spine have been shown to have an antagonistic effect on vestibular inputs to the RVLM. Neurons in the brainstem reticular formation also mediate tonic descending inhibition of segmental somatosympathetic reflexes. Segmental somatosympathetic reflexes appear to be most influential in the absence of descending inhibitory influences from the brainstem.

9. Spinal manipulations may alter central integration in the hypothalamus via spinoreticular and spinohypothalamic projections and the influence of spinal afferents on vestibular and midline cerebellar function. Direct connections have been found to exist between vestibular and cerebellar nuclei and the hypothalamus, nucleus tractus solitaries, and parabrachial nuclei. The latter two nuclei project to the hypothalamus, in addition to visceral and limbic areas of the medial temporal and insular regions of the cortex.

10. Spinal manipulations may influence brain asymmetry by enhancing summation of multimodal neurons in the CNS, monoaminergic neurons in the brainstem or basal forebrain regions, cerebral blood flow via autonomic influences, or by influencing the hypothalamic-mediated isoprenoid pathway.

The concept of cortical hemisphericity

The concept of cortical hemispheric asymmetry or cortical lateralisation involves the assumption that the two hemispheres of the brain control different asymmetric aspects of a diverse array of functions and that the hemispheres can function at two different levels of activation. The level at which each hemisphere functions is dependent on the central integrative state of each hemisphere, which is determined to a large extent by the afferent stimulation it receives from the periphery, the local integration of pericortical neurons as well as the degree of inhibition received from the contralateral hemisphere and the state of the nutrient and oxygen supply. Afferent stimulation is gated through the brainstem and thalamus, both of which are asymmetric structures themselves, and indirectly modulated by their respective ipsilateral cortices (Savic et al. 1994). Imbalances may develop between the activation of one hemisphere and the other with a number of different aetiological pathways including aberrant patterns of activation or arousal (Obrut 1994), acute or chronic ablative lesions (Leipert 2000; Murase 2004; Kreisel 2006), asymmetric afferentation excesses or deficits (Merzenich et al. 1983), inter- or intrahemispheric transmission imbalances (Brown et al. 1994; Bastings 2002), circulation deficits, asymmetric neurotransmitter concentrations (Xu et al. 2005; Hachinski et al. 1992) or asymmetric metabolic dysfunction. Often, a combination of these factors contributes to the state of asymmetry between the hemispheres. At some point of asymmetrical dysfunction a critical level of imbalance of activity or arousal levels between one cortical hemisphere and the other can result in a functional disconnect syndrome (Stroka et al. 1973; Leisman & Ashkenazi 1980). The critical level at which this functional disconnect first becomes symptomatic seems to vary between individuals. The morphological and functional changes result from neuroplastic processes, as described above. Neuroplastic changes may be maladaptive in cases of asymmetric cortical stimulation or inhibition levels resulting in a chronic state of disequilibrium in lateralised cortical systems. For example, in stroke survivors, ablative injury to areas of cortex may result not only in disruption of functional activities related to the site of the injury but also in a lack of inhibitory projections to the contralateral hemisphere. This sets into motion the chronic state of overexcitation in the contralateral hemisphere (Leipert et al. 2000; Murase et al. 2004). The chronic disinhibition of the contralesional cortical area may result in a vicious cycle in which the lesioned area experiences a chronic overinhibition due to the overexcitation of the contralesional site which in turn inhibits the lesioned site to an even greater degree. This same cycle may develop from any of the aetiologies listed above.

Asymmetries in cortical function based on fMRI, BOLD, PET, and qEEG studies have been found in a number of different symptomatologies and conditions including attention deficit disorder and attention deficit hyperactivity disorder (Melillo & Leisman 2004), autism (Leisman & Melillo 2009), and depression (Henriques & Davidson 1991).

Hemispheric asymmetries have also been shown to exist under normal physiological conditions such as in the control of movement, for example, the dynamic dominance hypothesis of movement control in which the left hemisphere is proposed to have a greater contribution to dynamic control and the right hemisphere a greater contribution to positional control involved in movements of the limbs (Sainburg 2002, 2005). Blood (2008) has proposed that motor and postural control exhibit opposite hemispheric dominance and may be involved with the development and maintenance of dystonias.

Hemispheric asymmetries have also been shown to exist with respect to cortical control of cardiovascular function. The research suggests that asymmetries in brain function can influence the heart through ipsilateral pathways. It is quite clear from the literature in this area that stimulation or inhibition at various levels on the right side of the neuraxis results in greater changes in heart rate, while increased sympathetic tone on the left side of the neuraxis results in a lowered ventricular fibrillation threshold. This occurs because parasympathetic mechanisms are dominant in the atria, while sympathetic mechanisms are dominant in the ventricles (Lane et al. 1992, 1995).

Neurotransmitter asymmetries in the cortex have also been discovered. Quite consistent results have been reported in a number of studies that have suggested that noradrenergic innervation, the biological substrate of arousal, shows a clear right hemispheric asymmetry (Pearlson & Robinson 1981; Neveu et al. 1991; Hachinski et al. 1992). Several studies have also shown strong indications that the neurotransmitter serotonin shows a right hemispheric dominance (Tekes et al. 1988; Demeter et al. 1989; Arato et al. 1991), which may occur from birth as an inborn feature of cortical function (Frecska et al. 1990).

Cortical asymmetries have also been documented with respect to hormonal regulation (Wittling 1998). Cortisol secretion has been associated with the right hemisphere with predominance of control demonstrated in this hemisphere during emotionally related situations (Wittling & Roschmann 1993; Wittling & Schweiger 1993). Various studies have shown that right hemispheric chemical dominance was associated with up-regulation of the hypothalamic-mediated isoprenoid pathway and was more prevalent among individuals with various metabolic and immune disorders including a high body mass index, various lung diseases including asthma and chronic bronchitis, increased levels of lipid peroxidation products, decreased free radical scavenging enzymes, inflammatory bowel disease, systemic lupus erythematosus (SLE), osteoarthritis, and spondylosis. Left hemispheric chemical dominance was associated with a down-regulated isoprenoid pathway and was more prevalent among individuals with low body mass index, osteoporosis, and bulimia.

A number of studies have indicated that cortical asymmetries may exist when different emotional states are activated. The left frontal cortex appears to be activated during the expression or experience of positive emotional states, whereas the right frontal cortex seems to be activated during the expression or experience of negative emotional states (Davidson 1984; Davidson & Tomarken 1989; Leventhal & Tomarken 1986; Silberman & Weingartner 1986). The severity of symptoms in depression has been linked to the activation levels in the left frontal cortex (Robinson et al. 1984). Those patients with left frontal cortex lesions with sparing of the right frontal cortex showed the most severe depressive symptoms.

Cortical asymmetry has also been shown to be important in immune regulatory functions. Natural killer cell activity was significantly increased in human females with extreme left frontal cortical activation when compared to females with extreme right frontal cortical activation (Kang et al. 1991). The level of hemispheric activation in these women was determined by electroencephalographic (EEG) determinants of regional alpha power density. This measurement has been shown to be inversely related to emotional or cognitive brain activation (Davidson 1988). A variety of animal studies have also provided direct evidence of the relationship between cerebral asymmetry and immune system function (Barneoud et al. 1987; Neveu 1988). Partial ablation of the left frontoparietal cortex in mice, which results functionally in relative right cortical activation, resulted in decreased immune responses and partial right cortical ablation, which would result functionally in a left cortical activation, showed no change or a reduced immune response (Renoux et al. 1983; Neveu et al. 1986). Other studies have shown that the development of the lymphoid organs including the spleen and thymus occurs with left cortical lesions, whereas increased development of the spleen and thymus occurs with right cortical lesions, and activation of T cells is significantly diminished in lesions involving the left cortex and elevated with lesions of the right cortex (Renoux et al. 1983; Biziere et al. 1985; Renoux & Biziere 1986; Barneoud et al. 1988). These findings indicate that T-cell-mediated immunity is modulated asymmetrically by both hemispheres, with each hemisphere acting in opposition to the other. Increased activity of the left cortex seems to enhance the responsiveness of a variety of T-cell-dependent immune parameters, whereas increased right cortical activity seems to be immunosuppressive. B-cell activity was found not to be affected by cortical activation asymmetry (Neveu et al. 1988; LaHoste et al. 1989). It appears from the findings of the above studies that changes in hemispheric activation because of either ablation of cortical areas or modulation in physiological activation levels result in changes in immunological response activity. Both hemispheres seem to be active in the modulation of immune response, with the left hemisphere enhancing cellular immune responses and the right inhibiting those responses. Some evidence does suggest that the involvement of the right hemisphere may not act directly on immune components but may modulate the activity of the left hemisphere, which does act directly to regulate immune function (Renoux et al. 1983).

It seems clear that a great deal of research has documented that the brain often works in an asymmetric fashion in order to produce accurate and efficient processing and integration of information. It also appears clear that if these asymmetric processes become unbalanced they can result in unwanted thoughts, actions, and behaviours. The recognition and correction of these cortical asymmetries in clinical practice offers the great hope of reducing the afflictions experienced by humankind as a result of these dysfunctional states.

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