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Category: Woman's Health


Sarafem is used for treating premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome.

Active Ingredient: Fluoxetine

Sarafem (Neuro) as known as: Adepssir, Afeksin, Affectine, Affex, Alentol, Andepin, Animex-on, Anisimol, Anoxen, Ansi, Ansielix, Ansilan, Antiprestin, Anxetin, Anzolden, Aprinol, Bellzac, Biflox, Biozac, Captaton, Chertin, Clexiclor, Cloriflox, Co fluoxetine, Courage, Dagrilan, Dawnex, Depil, Depress, Deprexetin, Deprexit, Deprexone, Deprezac, Deprozan, Digassim, Dinalexin, Docfluoxetine, Dominium, Eburnate, Elizac, Equiflox, Estimul, Evorex, Exostrept, F-exina, Faboxetina, Farmaxetina, Felicium, Femox, Fibrotina, Flonital, Florak, Florexal, Flozak, Flumazenil, Flumirex, Flunirin, Flunisan, Fluocim, Fluohexal, Fluoksetin, Fluoksetyna, Fluopiram, Fluoxe-q, Fluoxebell, Fluoxelich, Fluoxemed, Fluoxetin, Fluoxetini, Fluoxgamma, Fluoxibene, Fluoxifar, Fluoxone, Fluran, Flutin, Flutinax, Flutonin, Flux, Flux hexal, Fluxadir, Fluxal, Fluxene, Fluxetin, Fluxetyl, Fluxilan, Fluxomed, Fluzac, Fluzak, Fluzyn, Fodiss, Fokeston, Foxetin, Foxtin-20, Framex, Fulsac, Gerozac, Hapilux, Indozul, Kalxetin, Lapsus, Lebensart, Lecimar, Linz, Lorien, Luramon, Magrilan, Mitilase, Modipran, Moltoben, Mutan, Nervosal, Neupax, Neuro, Nodep, Nopres, Norzac, Noxetine, Nuzak, Nycoflox, Orthon, Ovisen, Oxactin, Oxedep, Oxetin, Oxipres, Platin, Plazeron, Pms-fluoxetine, Portal, Positivum, Prizma, Proflusak, Prohexal, Prolert, Prosimed, Prozamel, Prozatan, Prozit, Psipax, Psiquial, Ranflocs, Ranflutin, Rosal, Rozax, Salipax, Sartuzin, Saurat, Selectus, Selfemra, Serol, Seromex, Serotyl, Sofluxen, Sostac, Sostac lch, Stephadilat-s, Stressless, Thiramil, Tremafarm, Trizac, Verotina, Xeredien, Xetina, Xetinax, Xetiran, Youke, Zac, Zatin, Zedprex, Zinovat

Neuro-behcet disease

Neuro-behcet disease

Behçet’s disease is recognized as a disease that cause inflammatory perivasculitis, inflammation of the tissue around a blood or lymph vessel, in practically any tissue in the body. Usually, prevalent symptoms include canker sores or ulcers in the mouth and on the genitals, and inflammation in parts of the eye. [ 1 ] In addition, patients experience severe headache and papulopustular skin lesions as well. The disease was first described in 1937 by a Turkish dermatologist, Dr. Hulusi Behçet. Behcet's disease is most prevalent in the Middle East and the Far East regions; however, it is rare in America regions. [ 2 ]

The Behcet disease with neurological involvement, Neuro-Behçet's disease (NBD), involves Central nervous system damage in 5–50% of cases. [ 3 ] The high variation in the range is due to study design, definition of neurological involvement, ethnic or geographic variation, availability of neurological expertise and investigations, and treatment protocols.

Contents Causes

Because the cause of the Behcet's disease is unknown, the cause responsible for Neuro-behcet's disease is unknown as well. Inflammation starts mainly due to immune system failure. However, no one knows what factor trigger the initiation of auto-immune disease like inflammation. Because the cause is unknown, it is impossible to eliminate or prevent the source that causes the disease. Therefore, treatments are focused on how to suppress the symptoms that hinders daily life activities. [ 4 ]


In one study of 387 Behcet's disease (BD) patients that has been done for 20 years, 13 % of men with BD developed to NBD and 5.6 % of women developed to NBD. Combining all statistical reports, approximately 9.4 % (43 of 459) BD patients advanced to NBD. In addition, men were 2.8 times more likely to experience NBD than women. This fact indicates possible gender-based pathology. [ 5 ] [ 6 ] [ 7 ] In speaking about age of NBD patients, the general range was between 20 to 40. NBD patients with age less than 10 or more than 50 were very uncommon.

Types of Neuro-Behcet's disease

There are two types of Neuro-Behcet'ss disease: Parencymal and Non-Parenchymal. The two types of Neuro-Behcet's disease rarely occur in the same person. It is suggested that the pathogenesis of the two types are probably different.[3] Statistics indicate that approximately 75 % (772 of 1031) BD patients advanced to parenchymal NBD while 17.7 % (183 of 1031) of BD patients advanced to non-parenchymal NBD. The remaining 7.3 % were not able to be categorized.


If one experiences parenchymal Neuro-Behcet's disease, meningoencephalitis. inflammation of brain, primarily occurs. The target areas of parenchymal NBD include brainstem, spinal cord, and cerebral regions. Sometimes it is hard to determine the affected area because symptoms are asymptomatic. [ 8 ]


In non-parenchymal NBD, vascular complications such as cerebral venous thrombosis primarily occurs. Other distinct characteristics include Intracranial aneurysm and extracranial aneurysm. In most cases, veins are much more likely to be affected than arteries. Venous sinus thrombosis is the most frequent vascular manifestation in NBD followed by cortical cerebral veins thrombosis. On the other hand, thrombosis and aneurysms of the large cerebral arteries are rarely reported. [ 9 ]


Peripheral nervous system involvement is rarely reported (

0.8%). In this case, Guillain-Barré syndrome, sensorimotor neuropathy, mononeuritis multiplex, autonomic neuropathy, and subclinical nerve-conduction abnormalities are observed.

Some of the syndromes are not common but recognized for the relation to NBD such as acute meningeal syndrome, tumour-like neuro-Behçet’s disease, psychiatric symptoms and optic neuropathy

Clinical characteristics

The initial signs and symptoms of NBD are usually very general. This makes NBD hard to diagnose until the patients experience a severe neurological damage. In addition, the combination of symptoms varies among patients.

Parenchymal Neuro-behcet's disease

The main symptoms is meningoencephalitis which happens in

75 % of NBD patients. Other general symptoms of Behcet's disease are also present among parenchymal NBD patients such as fever, headache, genital ulcers, genital scars, and skin lesions. When brainstem is affected, ophthalmoparesis, cranial neuropathy, and cerebellar or pyramidal dysfunction may be observed. When cerebral hemispheric involvement happens, encephalopathy, hemiparesis, hemisensory loss, seizures, and dysphasia, and mental changes include cognitive dysfunction and psychosis may be observed. As for the spinal cord involvement, pyramidal signs in the limbs, sensory level dysfunction, and, commonly, sphincter dysfunction may be observed.

Some of the symptoms are less common such as stroke (1.5 %), epilepsy (2.2-5 %), brain tumor, movement disorder, acute meningeal syndrome, and optic neuropathy.

Non-parenchymal Neuro-behcet's disease

Because Non-parenchymal NBD targets vascular structures, the symptoms arise in the same area. The main clinical characteristic is the Cerebral venous thrombosis (CVT). If one experiences CVT, a clot in one of the blood vessels in the brain blocks the blood flow and may result in stroke. This happens in the dural venous sinuses. Stroke-like symptoms such as confusion, weakness, and dizziness may be monitored. Headache tends to worsen over the period of several days.

Some of the less common symptoms include intracranial hypertension and intracranial aneurysms.


Although there is a diagnostic criterion for Behcet's disease, one for Neuro-behcet's disease does not exist. Three diagnostic tools are mainly used

Blood test

60-70 % of Japanese and Turkish patients were tested to possess HLA-B51. HLA-B serotype. These patients showed 6 times risk of getting BD. However, the same criteria is not ideal to be applied for Europeans because only 10-20 % of European patients showed to possess HLA-B51.

Cerebrospinal fluid level

Cerebrospinal fluid is a clear bodily fluid that occupies the subarachnoid space and the ventricular system around and inside the brain. It is revealed that 70-80 % of Parenchymal NBD patients show altered CSF constituents. The observed different is 1) Elevated CSF protein concentration (1 g/dL), 2) Absence of oligoclonal band, and 3) elevated CSF cell count (0–400×10⁶ cells/L) in the body.

Magnetic resonance imaging test

MRI is the most sensitive imaging technique that can be used for diagnosing NBD. As for the parenchymal NBD, medical doctors mainly monitor the upper brainstem lesion. In fact, it is possible that lesions extends to thalamus and basal ganglia. Another advantage of using MRI is the ability to perform Diffusion-weighted imaging, or [diffusion MRI]. This technique is the most sensitive tool to image an acute infarct. In the case of NBD, Diffusion MRI can determine whether the lesion were due to cerebral infarction. In other words, it can distinguish NBD from non-NBD neural disease. When only spinal cord is affected by NBD, brain looks perfectly normal when scanned by MRI. Therefore, it is necessary to scan the spinal cord as well when diagnosing possible NBD involvement. [ 10 ] As for the non-parenchymal NBD, venous sinus thrombosis can be detected.


". Despite its rarity, the patient’s ethnic background and the typical radiographic findings should prompt the clinicians to include NBD in the differential diagnosis of optic neuritis and demyelinating disease in the young. "[5]. This quote indicates that even common symptoms such as headache should be recognized as the sign for possible NBD considering the patient's ethnic background.


No definite standards of NBD treatment have been set. Therefore, it is completely up to medical doctors on how to treat NBD. However, there is a consensus among medical doctors that in cases of inflammatory parenchymal disease, "corticosteroids should be given as infusions of intravenous methylprednisolone followed by a slowly tapering course of oral steroids." It is suggested that therapy should be continued for a perioud of time even when the symptoms get suppressed because early relapse may occur. Sometimes, the medical doctors may suggest different steroid depends on the nature of the disease, severity, and the response to steroids. According to several studies, parenchymal NBD patients successfully suppress the symptoms with the prescribed steroids. As for non-parenchymal patients, there is no general consensus on how to treat the disease. The reason is that the mechanisms of cerebral venous thrombosis in BD are still poorly understood. Some doctors use anti-coagulants to prevent a clot. On the other hand, some doctors only give steroids and immunosuppressants alone. [ 11 ] [ 12 ]


Because Behcet's disease is observed on limited regions, people's attention towards Behcet's disease is low. In addition, it is hard to conduct a clinical experiment in places such U.S because there is so limited number of patients. As a result, there is limited number of research going on in the world to find out how to ultimately cure the disease. Because the cause of the disease is currently unknown, it is practically impossible for medical doctors and scientists to come up with a treatment.

  1. ^ Serdaroflu P, Yazici H, Ozdemir C, Yurdakul S, Bahar S, Aktin E (1989) Neurologic involvement in Behçet’s syndrome. A prospective study. Arch Neurol 46(3):265–269
  2. ^ Yazici H, Fresko I, Yurdakul S. (2007) Behçet’s syndrome: disease manifestations, management, and advances in treatment. Nat Clin Pract Rheumatol (3): 148–55.
  3. ^ Farah S, Al-Shubaili A, Montaser A. (1998) Behçet’s syndrome: a report of 41 patients with emphasis on neurological manifestations. J Neurol Neurosurg Psychiatry (64): 382–84.
  4. ^ Akman-Demir G, Serdaroglu P, Tasçi B, and the Neuro-Behçet Study Group (1999) Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. Brain 122:2171–2182.
  5. ^ Barros R, Santos E, Moreira B, et al. Clinical characterization and pattern of neurological involvement of Behçet’s disease in fi fteen Portuguese patients. Clin Exp Rheumatol 2007; 24
  6. ^ Ashjazadeh N, Borhani Haghighi A, Samangooie S, Moosavi H. Neuro-Behçet’s disease: a masquerader of multiple sclerosis. A prospective study of neurologic manifestations of Behçet’s disease in 96 Iranian patients. Exp Mol Pathol 2003; 74: 17–22.
  7. ^ Al-Araji A, Sharquie K, Al-Rawi Z. Prevalence and patterns of neurological involvement in Behçet’s disease: a prospective study from Iraq. J Neurol Neurosurg Psychiatry 2003; 74: 608–13.
  8. ^ Kidd D, Steuer A, Denman AM, Rudge P. Neurological complications of Behçet’s syndrome. Brain 1999; 122: 2183–94.
  9. ^ Tunc R, Saip S, Siva A, Yazici H. Cerebral venous thrombosis is associated with major vessel disease in Behçet’s syndrome. Ann Rheum Dis 2004; 63: 1693–94.
  10. ^ Turker H, Terzi M, Bayrak O, Cengiz N, Onar M, Us O. Visual evoked potentials in diff erential diagnosis of multiple sclerosis and neurobehçet’s disease. Tohoku J Exp Med 2008; 216: 109–16.
  11. ^ Akman-Demir G, Serdaroglu P, Tasçi B. Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. The Neuro-Behçet Study Group. Brain 1999; 122: 2171–82.
  12. ^ Al-Fahad S, Al-Araji A. Neuro-Behçet’s disease in Iraq: a study of 40 patients. J Neurol Sci 1999; 170: 105–11.
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Other articles

Neuro-degenerative Diseases

Fawzi Lab Neuro-degenerative Diseases ALS

Amyotrophic lateral sclerosis (ALS) is the most common form of progressive motor neuron disease with an incidence in most societies of 1-3 per 100,000. Approximately 90% of cases occur with no family history and are known as sporadic ALS while 10% are due to an inherited genetic trait and termed familial ALS. ALS is a neurodegenerative disease of both upper and lower motor neurons that is classically thought of as sparing sensory and autonomic pathways that are necessary for visual function.

Recently, ocular manifestations of disease in patients with ALS have been reported such as decreased visual acuity as well as ocular signs of disease in the c9orf72 familial ALS genetic variant.

Our research involves assessing and characterizing detailed measures of visual function in patients with ALS and comparing their visual function among patients who have different genetic variants of ALS.


This study aims to explore whether retinal imaging can be used to detect ocular changes in patients with amnestic mild cognitive impairment (aMCI), which is considered a pre-clinical state to Alzheimer’s Disease dementia (DAT).

Retinal changes have not been explored in the MCI population. Optical pathologic changes have been reported in DAT eyes. However, these histopathologic Coherence Tomography (OCT) offers high-resolution non-invasive imaging. Studies examining retinal and optic nerve thickness in aMCI patients have reported various levels of retinal and optic nerve involvement OCT. In this study we focused on aMCI patients who have a memory loss component to their disease. Patients with aMCI progress to DAT at a rate of 10-15% per year, compared to control subjects who progress at a rate of 1-2% per year.

Патент US7272559 - Noninvasive detection of neuro diseases - Google Патенты

Noninvasive detection of neuro diseases
US 7272559 B1

Noninvasive, remote methods and apparatus for detecting early phases of neuro diseases such as the non-tremor phase of Parkinson's disease, dyskinesia, dyslexia and neuroatrophy, etc. are disclosed. Five words spoken either directly into a microphone connected to a local analysis system or remotely, as by way of a telephone link to a system for analysis of time and frequency domains of speech characteristics are representative of the presence of disease. The method includes the steps of transducing a set of unmodified spoken words or numbers into electrical signals which are bandlimited and amplified. These signals are analyzed in both time and frequency domains to detect and measure the manifestation of neurological disorders in the envelope of the time representation and spectral density of the words. Detection is carried out when the subject's body is in contact with neither a sensor nor an instrument, nor subjected to any other invasive means such as providing body fluids or breath, and without the need to perform any psychomotor functions.

1. A noninvasive method of identifying and measuring a neurological manifestation in human speech of an early phase of neuro disease including:

converting a human subject's spoken words into corresponding electrical signals;

amplifying said electrical signals;

frequency band limiting, and signal conditioning the said electrical signals to produce modified signals;

determining an envelope of said modified signals;

determining a spectral density of said modified signals and providing a spectral density signal;

smoothing said spectral density signal;

determining a spectral envelope of said smoothed spectral density signal;

determining the presence of a depression in said spectral envelope;

determining an amplitude of said depression with reference to an average db level of two shoulder peaks in said spectral density signal on either side of said depression;

determining a ratio of said amplitudes of said depression and said average db level of said two shoulder peaks; and

using said ratio for identifying and measuring a neurological manifestation in the subject's spoken word, of early phases of neuro disease.

2. The method of claim 1. further including multiplying said ratio by a constant k to obtain a Parkinson Severity Index.

3. The method of claim 2. further including separating Parkinson's disease from said neuro disorders, by using different constants than those of Parkinson.

4. The method of claim 1. further including determining a compressed range for said Parkinson Severity Index by selecting a narrow bandwidth corresponding to a first format of said electrical signals.

5. The method of claim 1. further including converting said spoken words using telephony computer boards.

6. The method of claim 1. further including detecting parameters corresponding to Parkinson neuro disorders.

7. The method of claim 1. further including using said ratio and providing prediagnostic assistance to a physician for use in treating said neuro disease.

8. The method of claim 1. further including using said ratio and detecting brain cell damage.

9. The method of claim 1. further including using said ratio and detecting dykinesia.

10. The method of claim 1. further including using said ratio and detecting neuro atrophy.

11. The method of claim 1. further including using said ratio and detecting neuropathy.


This invention relates to noninvasive, remote method and apparatus for detecting early phases of neuro diseases such as the non-tremor phase of Parkinson's disease, dyskinesia, dyslexia and neuroatrophy etc. etc. from five words spoken either directly into a microphone connected to a local analysis system or remotely, as by way of a telephone link to such a system for analysis of time and frequency domains of speech characteristics representative of the presence of disease.

The onset of Parkinson's, for example, may not exhibit any outward symptoms for up to ten years prior to the onset of involuntary, rhythmic shaking of a patient's hands, head or both. Other symptoms may include excessive salvation, and abdominal cramps. In the advanced stages of Parkinson's, memory and thought processes may also deteriorate. An early non-tremor phase detection of Parkinson's and other neuro diseases or neurodegeneration is desirable so that appropriate remedial medication may improve the quality of life for the patients as well as reduce the cost of healthcare both to the subject's families and to government and private health care systems.

Presently, no reliable pre-symptomatic diagnostic method or apparatus is known to exist. Furthermore, physicians find it difficult to distinguish Parkinson's from other neuro diseases in their early phases. Time consuming and expensive methods such as magnetic resonance imaging or body fluid analysis are neither completely effective nor economical.

Recently, researchers offered some evidence of a genetic link for late-onset Parkinson's disease. Some psychologists claim to identify Alzheimer with 80% success from touch tone telephone instructions such as “spell fun” and press “1” if a recorded sentence makes sense etc. Extensions of available diagnostic techniques occasionally help prediagnose neuro-dysfunctions other than Parkinson's. For instance, a male patient on Parkinson's medication was found to suffer from another neuro disorder, whereas a female patient on Parkinson's medication was found to suffer from extreme stress instead. Therefore, the need for accurate methods of detection of a variety of neurodiseases are badly needed.

Many inventors have claimed to noninvasively detect diseases while using body sensors, such as devices for diagnosing migraine headaches by monitoring the effective diameter of preselected blood vessels supplying blood to the brain. Similarly, the use of a retinal image to determine retinal disease and the use of a confocal microscope to observe diseases of finger nail, toe nail, and the skin or a mucus membrane have been described in the prior art. Remote monitoring of multiple medical parameters via RF signals from a patient attached to monitors is also known. However, there is no system or apparatus available to remotely and completely noninvasively, without any sensors attached to the body, detect the early phases of neuro diseases such as Parkinson's, neuro atrophy, dyskinesia, etc.


An objective of this invention is to provide a truly noninvasive, electronic, and remotely useable apparatus and method for detection and diagnosis of the early, non-tremor phase of Parkinson's disease, and other diseases such as neuro atrophy and neuro degradation, etc.

Another object of this invention is to utilize human speech, which is known to contain correlates of neurological disorders such as Parkinson's disease, Alzheimer, neural atrophy or neuro degradation, etc. in the detection of such disorders.

A further object is to provide a numerical indicator of the severity of neurological diseases, including Parkinson's disease.

A further object of this invention is to eliminate the need for having prior medical history or a baseline of a subject in order to detect and diagnose neurological disorders.

A further object is to provide telephone-based monitoring of a subject for the detection of neurobased diseases.

Speech involves nearly 67.5% of the cerebral/neurological centers of the brain and at least one hundred muscles and, therefore, is one of the most reliable body signals containing information about neuro-disorders. The nerve cells in certain of the Basal Ganglia of the brain (the Substatia Nigra, Locus Careruleus, the Globus Pallidus, and their afferent and efferent nerve connections) are subject to degeneration. It is further known that these neurological centers control movement, particularly semiautomatic movements such as swinging arms while walking. The deterioration of these nerve centers upsets the delicate balance between two body chemicals, dopamine and acetylchlorine, that are essential for controlling the transmission of nerve impulses within these parts of the nervous system. Parkinsonian symptoms are the result of the loss of such controls and coordination. Similarly, other neuro disorders affect coordination, memory, control, and cognitive functions. Even endocrinological disorders affect some of these cerebral subsystems, although medical educators treat neurological and endocrinological systems as two separate systems, even in the face of the fact that the cerebral system controls disorders in both systems. The forgoing forms the theoretical basis of the discovery that neuro disorders are manifested in speech signals, and certain parameters thereof are indicative of early phase onset of such disorders.

Briefly described, the method of this invention includes the steps of transducing a set of unmodified spoken words or numbers into electrical signals which are bandlimited and amplified. The band limiting is automatically accomplished when using a telephone for example, but a separate bandlimiting filter may be used to limit the speech to frequencies between 65 Hz and 3,000 Hz. These signals are analyzed in both time and frequency domains to detect diagnostic parameters for neuro disorders such as Parkinson's, among many other neuro diseases. For example, a subject may be asked to recite five words in sequences, such as one. one. two. eight. nine, into a microphone or into a telephone connected to a computer, and the speech signal is analyzed in both the time and frequency domains to detect and measure the manifestation of neurological disorders in the envelope of the time representation and spectral density of the words. Thus, the envelope of the spectrum of the word “one” of a neuro-normal individual resembles a bell shaped curve, whereas in the case of a person having Parkinson's disease, the envelope is distorted in a very unique manner indicated by a depression in its structure. Such a distortion may resemble the back of a two-humped camel. It is noted, however, that in the case of individuals with severe alcohol or drug damaged brain cells it may not be possible to easily detect these diagnostic parameters.

In accordance with the invention, therefore, detection is carried out when the subject's body is in contact with neither a sensor nor an instrument, nor subjected to any other invasive means such as requiring to provide body fluids or breath, and without the need to perform any psychomotor functions or Magnetic Resonance Imaging scans of brain or imaging thereof.


The foregoing, and additional objects, features and advantages of the present invention will become apparent to those of skill in the art from the following detailed description of a preferred embodiment thereof, taken with the accompanying drawings, in which:

FIG. 1 is a graphical illustration of a speech signal time domain, showing time vs. amplitude;

FIG. 2 is a graphical illustration of a speech signal frequency spectrum showing spectral density vs. frequency; and

FIGS. 3A and 3B are block diagrams of a neurological impairment measurement apparatus for use in the present invention, FIG. 3A being in situ using a microphone, and FIG. 3B being remote by using a telephone.


Turning now to a more detailed description of the present invention, a preferred form of the method of the invention includes the steps of transducing a set of words spoken by a subject to be tested into electrical signals, such speech signals producing typical wave patterns, such as those illustrated at 10 in FIG. 1. The signals are amplified, frequency band limited, converted to digital signals, and are Fast Fourier Transformed (FFT) to obtain the frequency spectra of the speech. A typical spectrum is illustrated by waveform 12 in FIG. 2 .

The processing of the received and transduced speech signals may be carried out in the neurological disorder detector apparatus 14 illustrated in FIGS. 3A and 3B. As illustrated, a microphone 16 ( FIG. 3A ) such as a Radio Shack model 33-985, or a digital microphone such as that provided by Analog Devices, Inc. or the equivalent, or a telephone 17 ( FIG. 3B ) is used to transduce spoken words into their corresponding electrical signals which are supplied by way of line 18 to suitable signal processing equipment indicated at 20. Such equipment may be a commercially available personal computer such as a 386DX30 or any newer computers, including suitable audio processing boards.

The processor 20 preferably includes an amplifier 22 for receiving audio signals on line 18 with the amplified signals being applied by way of line 24 to a band pass filter 26. Such a filter may be an antialiasing filter such as “Tahiti” model personal computer board available from Turtle Beach Systems, Inc. which filters and digitizes the audio signals as indicated by the analog to digital circuit 28. The digitized signals are then Fast Fourier Transformed (FFT) as indicated at FFT block 30. and the resulting signal is processed in processor 32 of computer 20. utilizing commercially available digital signal processing software, such as a Spectra Plus 3.0″ available from Pioneer Hill Software, Inc. to produce the power spectral density signals 12 of FIG. 2 on output line 34. The same process and functions can be carried out using telephone 17 to call to the personal computer 20. as illustrated in FIG. 3B. incorporating a computer telephony Interactive Voice Response board 35. such as that available form COPIA INTERNATIONAL and the Fast Fourier Transform Software as identified in FIG. 3A .

The basic equation for determining the power spectral density is as follows:

S ⁡ ( f k ) = [ ( 1 / N ) ⁢ ∑ n = 0 N - 1 ⁢ ⁢ x ⁡ ( t n ) ⁢ exp ⁡ ( - j ⁢ ⁢ w k ⁢ t n ) ] 2 ( Eq. ⁢ 1 )

T o = Sampling ⁢ ⁢ period = 1 f o

The function x(tn -nTo ) is an n-point sequence of digitized speech that is T seconds in length. In the case of Discrete Fourier Transformation, the function x(f) becomes:

x ⁡ ( f k ) = 1 / N ⁢ ∑ n = 0 N - 1 ⁢ ⁢ x ⁡ ( nT o ) ⁢ exp ⁡ ( - j ⁢ ⁢ 2 ⁢ π ⁢ ⁢ kn / N ) ( Eq. ⁢ 2 )
and its power spectral density is defined as:
S (fk )=|x (fk )| 2 (Eq. 3)

The power spectral density S(fk ) is converted into decibels (db), and smoothed with 2-6 db smoothing window. It is then processed to obtain its envelope and its envelope peaks and nulls, and is sent to a printer 36 or is stored for additional analysis to detect various neuro-disorders parameters.

The value of the measurement is supplied by way of line 34 to display or storage unit 36 such as a printer, a FAX machine, a modem, or the like, which allows the value to be displayed, printer or stored for future use, or sent to a remote location over a communication link. For example, the computer 64 may incorporate a FAX modem which will transmit the measurement to a remote computer or FAX machine by way of any commercially available communication link.

As illustrated in FIG. 2. the spectral density signals 12 are included in an envelope 40 which tracks the speech frequency peaks 42. 43. 47. in the first formant in the frequency domain 65 Hz to 3,000 Hz. Between successive maximum peaks 43 and 46. labelled “A” and “B”, respectively, the envelope 40 dips below the average amplitude, in decibels, of peaks A and B, indicated at long-dashed line 50. by an amount “d”, above the null, labelled N and indicated at peak 44 in FIG. 2 .

These maximum peaks on opposite sides of a minimum point generally occur only one in the spectrum, so are readily identifiable. The relationship of a depression in the envelope 40 to the average value (A+B)/2 of the highest peaks on either side of the depression indicated by line 50 can be used, in accordance with the invention, to determine a Parkinson's Severity Index (SI) which indicates a measure of the progression of this disease as a percentage of fully developed Parkinson's. The ratio of the amplitude, in decibels (db) of the depression d to the average level of the adjoining shoulder peaks on both sides of the depression (A+B)/2, is multiplied by a constant-K, so that:
SI= 2d K /(A+B ) (Eq. 5)

Small depressions, of less than the maximum db smoothing levels, which may lie between 2 to 6 db for example, are not used in this calculation. Lower values of Si may indicate early phase Parkinson's, whereas large values are indicative of an advanced stage thereof.

Similarly, dyskinesia is indicated by an almost linear decay of the power spectral density in the upper half of the frequency range of the first formant. Brain cell damage by excessive alcohol or drug abuse distorts the spectral density of the first formant into a single peak instead of a normal multi-harmonic spectra. The location of the single peak is determined by the chemical abused. Neuropathy is represented by a null near the middle of the first formant spectral density, and its envelope resembles a two hump camel top with a dip at lower end of spectrum. Some neuro disorders cause complete disappearance of certain harmonics in the spectral density. Neurologists in general have problems distinguishing between various neuro disorders, since they tend to go over a check list of symptoms to identify these, and many symptoms are not necessarily limited only to a single neuro disorder. There are other unique spectrum distortions attributed to other neuro disorders, such as, but not limited to, missing a particular harmonic, attenuation of the magnitude of the said spectrum, and distortion of a section of spectrum, including numerous parameters of disorders represented by combinations of nearly 6,000 bits of information in the band limited speech signal as described above. Simply described, maximas, minimas, up and down slopes of all the harmonics, high frequency jitter riding on the up and down slopes of each harmonic, and various combinations thereof have been identified by this invention to represent endocronological, physical, and psychological parameters, and there exist numerous other combinations which identify other and endocron types of disorders. which can also be detected in this manner.

It will be understood that variations and modifications of the invention as described herein may be made without departing from the true spirit and scope of the invention as set out in the accompanying claims.

Electro-Physiological Approaches to Monitoring Neuro- Degenerative Diseases

Chapter 17 Electro-Physiological Approaches to Monitoring Neuro- Degenerative Diseases Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

[1] Animal Health Department, National University of Colombia, Bogota, Colombia

1. Introduction

Electrical brain activity is recorded by means of a variety of techniques, including different approaches, for instance surface field electrodes among others. Additionally, specific local neuronal responses are suitable for recording. As an example, those known as evoked response potentials allow to determine whether neural pathways and neuronal groups are performing properly.

Neuro-degenerative diseases involve lost of integrity of a number of neuronal nuclei; in turn, this represents significant changes in electrical brain activity that might be compared with unaltered individuals. Several experiments have shown the potential usefulness of evoked response potentials ERP brain correlates as bio-markers, diagnostic and prognostic tools of some neurodegenerative diseases. Also, neuropsychological tests have demonstrated correlations with electrophysiological findings, and are helpful to detect early cognitive decline or disease progression in neurodegenerative diseases.

Electrodiagnostic examination should make available useful information for researchers and physicians. Furthermore, it could help to the correct diagnosis of the illness, its differential diagnosis to the identification of the pathophysiological abnormalities probably responsible for the pathology

2. Electro-physiological techniques

Surface electrode cortical EEG:

The electroencephalogram EEG is usually described in terms of its rhythmic activity, which is helpful in relating the EEG to the brain function [1 ]. Neuronal activity during information processing is represented by oscillations within local or widespread neuronal networks. These oscillations can be recorded by means of surface electrodes over the skull. The rhythmic activity in EEG is commonly divided in specific frequency bands: 0.5–4Hz (delta), 4–8Hz (theta), 8–10Hz (alpha 1), 10–12Hz (alpha 2), 12–30Hz (beta), and 30–100Hz (gamma) [2 ]. The FFT decomposes the EEG time series into a voltage by frequency spectral graph commonly called the “power spectrum”, with power being the square of the EEG magnitude, and magnitude being the integral average of the amplitude of the EEG signal, measured from(+) peak-to-(-)peak), across the time sampled, or epoch [3 ]. As a result of this procedure the quantitative electroencephalogram QEEG is obtained [4 ], [5 ].

Recording deep brain electrodes

Local field potential and action potentials can be captured by means of very fine conductive electrodes for research and surgical monitoring purposes [6 ], [7 ]. In addition, deep brain electrodes implanted into the brain are used to apply electrical stimulation in order to treat disorders that have electrical generators [6 ].

*Figure authorized for publication by the corresponding author from: Rodriguez-Oroz MC et al. Brain. 2011 Jan;134(Pt 1):36-49.

Figure 1.

Deep brain electrodes to treat Parkinson’s disease: (A) Electrode with four active contacts (0, 1, 2 and 3 from ventral to dorsal and each 1.5 mm high at 0.5 mm intervals; total length 7.5 mm) was placed at the selected coordinates in the subthalamic nucleus with the most ventral contact (contact 0) placed in the ventral part of the nucleus *

3. Alzheimer electroencephalographic patterns

The electroencephalogram EEG measures neuronal activity, and is an objective way to assess the degree of cognitive disturbance. Researchers have investigated how well cognitive function in dementia assessed by psychometric tests correlates with electrical brain activity (EEG). Results from such an experimental approach shows a slowing of the EEG, and an increase of dipole strength in the slow frequency bands, a more anterior equivalent dipole of alpha- and beta-activity, correlated with increasing cognitive deterioration in AD patients [8 ].

Relative power in different EEG frequency bands from EEG signals have been used in order to improve the diagnosis of AD. Frequency bands between 4 and 30 Hz have been systematically tested; the relative power of a certain frequency band is obtained by dividing the power of this frequency band by the power of the total frequency band. The frequency band 4-7 Hz is the optimal frequency range for detecting AD [9 ]. Progressive atrophy of hippocampus correlates with decreased cortical alpha power in AD patients. Moreover, the small hippocampal volume is measured in magnetic resonance imaging of the AD subjects [10 ], [11 ]. Additionally, the power of occipital, parietal, and temporal alpha sources is low in AD patients [10 ].

A promising study by Kann demonstrated the implication of the fast neuronal network oscillations in the gamma range (

30-90 Hz) in complex brain functions. Sensory processing, memory formation and, consciousness are brain functions highly vulnerable to neurodegenerative pathologies [12 ].

Cortical pathology in AD is related to decreasing fast frequency power; whereas increased slow frequency EEG power is observed in mixed dementia compared to AD. The quantitative EEG contributes to a better understanding of the electrical brain pattern in AD [13 ]. Slowing on qEEG is a marker for subsequent rate of cognitive and functional decline in mildly demented AD patients. Frequency bands analysis of EEG recordings from AD subjects shows lower parieto-occipital beta values, and higher frontocentral and parieto-occipital theta values. Additionally, lower parieto-occipital beta values are related to more decline in activities of daily living [14 ], [15 ]. Also, connectivity between frontal and parietal sites in AD patients is reduced, thus, resulting in significant decreased of coherence in the left fronto-parietal EEG [16 ].

In some cases there is no correlation between the increase of delta waves in the electroencephalogram, and the severity of mental deterioration of the AD patients, but this facts correlate by taking in account the intensity of delta waves rather than just their presence. The delta waves generated with participation of the cortex, thalamus, and brainstem seems to be more variable in different stages of AD. Measures of the theta activity discriminated between mild, marked, and severe cases of AD to some extent. The cognitive and EEG changes are probably related to atrophy of the cholinergic neurons in the hippocampal structures [17 ].

EEG recordings at rest and during visual stimulation processed by means of Fast Fourier Transform (FFT) are helpful to determine intra- and inter-hemispheric coherence in AD patients. Those studies have shown statistically significant phase dispersion especially at occipital and parietal regions in AD [18 ]. Coherence analysis of the EEG during photic stimulation also is low in AD patients, irrespective of the stimulus frequency, due to a failure of normal stimulation-related brain activation. What is more, when coherence analysis is done from recordings of the brain´s left hemisphere and the right one, impairment of interhemispheric functional connectivity is found [15 ].

4. Alzheimer diagnosis

A combination of computed techniques to analyze EEG recordings, such as the Higuchi fractal dimension (HFD), spectral entropy (SE), spectral centroid (SC), spectral roll-off (SR), and zero-crossing rate (ZCR), results in a AD diagnostic accuracy of 78%. HFD is a quantitative measure of time series complexity derived from fractal theory. Among spectral measures, SE measures the level of disorder in the spectrum, SC is a measure of spectral shape, and SR is frequency sample below which a specified percent of the spectral magnitude distribution is contained. Lastly, ZCR is simply the rate at which the signal changes signs. Even though, the individual accuracies ranged from 60-66%, that itself is not enough to be clinically useful alone. Combining these features and training a support vector machine (SVM) represent a novel alternative computed technique to reach high diagnostic accuracy for AD [19 ].

An electrophysiological marker in the early detection of neurodegeneration is found in the EEG pattern during stimulation for visual evoked potentials (VEP) in mild AD patients. In mild AD the altered activity concentrates on deep structures of the left hemisphere, say hippocampus and midbrain [20 ]. Visual evoked potentials in diagnosed Alzheimer patients (ApoE epsilon4 carriers) have significantly longer peak latencies and a trend to higher interpeak latencies of late potential components. However, potential amplitudes are similar in carriers and no carriers. It appears that the ApoE epsilon4 allele mainly promotes neuronal dysfunction [21 ]. In an ERPs lexical-decision task AD patients do not display repetition priming for words repeated at long lags [22 ].

Neuropathological findings in AD correlate with sensory-affective dissociation. Pain anticipation and autonomic reactivity depend on both the cognitive status and the frequency bands of the electroencephalogram, especially delta and theta frequencies. The painful stimulation perception is well preserved in AD, however, the affective and cognitive functions, which are related to both anticipation and autonomic reactivity are very affected [23 ].

A helpful tool to confirm an AD diagnosis is the electrophysiological correlate of minipolymyoclonus and a bi-frontal negativity in the EEG that precedes the myoclonic jerk. This electrophysiological fact may reflect activity of a subcortical generator. [24 ].

Quantitative relative power analysis of magnetoencephalography recordings can find widespread abnormalities in oscillatory brain dynamics in AD patients. In the delta band the AD patients have a consistently higher relative power, especially in the right occipital area. Delta activity is increased in AD patients, whereas alpha, and beta activity was decreased. Particularly the beta band (13–30 Hz) shows a very significant decrease in relative power in AD. In the theta band the significant decrease in relative power of the left temporal region. In the beta band, all separate cortical regions demonstrated a significant decrease of relative power in AD [25 ]. Furthermore, the auto mutual information (AMI) provides a measure of future points predictability from past points in the magnetoencephalogram (MEG). Studies analyzing the (MEG) background activity in patients with AD, using the AMI reveals that the absolute values of the averaged decline rate of AMI is lower in AD patients than in control subjects. Thus, based on this kind of analysis is suggested that neuronal dysfunction in AD is associated with differences in the dynamical processes underlying the MEG recording [26 ].

REM sleep is a behavioral state characterized by atonia, and high frequency-low amplitude EEG among other features. Polysomnographic studies have found AD patients with REM sleep with-out atonia. The lack of atonia during REM sleep might involve alteration of the extrapyramidal motor control [27 ]. During quiet sleep in healthy human EEG there are components that consist of a brief negative high-voltage peak, usually greater than 100 µV, followed by a slower positive complex around 350 and 550 ms and at 900 ms a final negative peak, known as K-complex [28 ]; they are generated in response to external stimuli such as sounds, touches on the skin [29 ], and internal ones such as inspiratory interruptions [30 ]. They also occur in widespread cortical locations [28 ] though they tend to predominate over the frontal parts of the brain [31 ]. K-complexes synchronize the thalamocortical network during sleep, producing sleep oscillations such as spindles and delta waves [32 ]. Additionally, it has been suggested that K-complexes play an important role in memory consolidation [33 ]. In patients with Alzheimer disease, the electroencephalogram during wakefulness shows pathologic signs of abundant, delta activity. AD patients produced significantly fewer evoked K-complexes and had substantially smaller N550 amplitudes than controls. Even though observed increases in pathologic delta-frequency electroencephalographic activity, patients with Alzheimer disease have an impaired capacity to generate normal physiologic delta responses such as K-complexes during quiet sleep [34 ].

5. Alzheimer early detection

The progressive deterioration of AD patient progresses is caused by the loss of functional connectivity within neocortical association areas. Much more sensitive methods to identify early alterations of neuronal networks makes possible to predict the onset of AD. Diffuse slowing is correlated with the cognitive decline. This is a method to extract meaningful EEG parameters for the early diagnosis and staging of Alzheimer's disease [35 ]. Also, a clear difference between AD patients carrying the ApoE epsilon4 allele and no carriers is detected in the EEG; neurophysiological endophenotype of non-demented individuals at genetic risk for AD have increased excitability and dysfunction of deep brain and alpha rhythm-generating structures even decades before the first clinical symptoms of presumable dementia. Under hyperventilation the presence of the epsilon4 allele in AD relatives is associated with the manifestation of synchronous high-voltage delta-, theta-activity and sharp-waves, pronounced decrease in alpha and increase in delta and theta relative powers [36 ]. Mildly demented AD patients have an increase of relative delta power in the left side, and a decrease for relative alpha power in the right side; this preserves a linear correlation, and allows to predicting activity daily living ADL loss timing, and general behavioral and cognitive deterioration in mild Alzheimer's disease [5 ]. The delta relative power in the left side predicts both the loss of ADL and death, whereas right theta predicted the onset of incontinence [37 ]. In addition, the qEEG measures is correlated with neuropsychological test scores related to abilities that are impaired in the early stages of disease, such as delayed recall and verbal fluency [11 ].

Prognosis of early AD onset can be done by means of calculating the REO/REC power ratio; this tool takes the spectral analysis of the EEG recorded under awake resting eyes closed (REC) and open (REO) conditions. Demented AD patients show an increased REO/REC power ratio in the 6.5-12 Hz band. Patients lacking a dominant peak in the 6.5-12 Hz band, but with high power in 1-6.5 Hz band have an earlier age of disease onset [38 ].

Increased risk of mortality in AD is associated with higher theta, lower alpha, and lower beta activity in the parieto-occipital EEG. Also, higher theta activity in the fronto-central EEG has a prognosis value. Decreases of beta and alpha activity on quantitative spectral EEG are independent predictors of mortality in patients with early Alzheimer disease [39 ].

IFAST (implicit function as squashing time) is an artificial neural networks (ANNs) assembly; it is capable of compressing the temporal sequence of EEG data into spatial invariants. This model represents spatial features of the EEG patterns at scalp surface by means of filtering EEG tracks according to four different frequency ranges (0.12 Hz, 12.2 - 29.8 Hz; 30.2 - 40 Hz, and Notch Filter 48 - 50 Hz). The spatial content of the EEG voltage is extracted by IFAST step-wise procedure using ANNs. The data input for the classification operated by ANNs are the connections weights of a nonlinear auto-associative ANN trained to reproduce the recorded EEG tracks. This method allows distinguish between mild cognitive impairment (MCI) stable and MCI subjects who will convert to Alzheimer's disease (MCI/AD), with a high degree of accuracy. Eyes-closed resting EEG data in individual MCI/AD subjects show significant differences in the 10-12 Hz band when compared to MCI subjects [40 ].

Event-modulated EEG dynamic analysis makes it possible to investigate the functional activation of neocortical circuits [41 ]. Evoked Response Potentials (ERP) brain correlates are useful preclinical markers to identify individuals at risk for AD. Additionally, the ERP measures can predict its presence. Asymptomatic PSEN1 mutation carriers have greater occipital positivity, but less positivity in frontal regions than control subjects. Those differences are more evident during the 200-300 msec period of the ERP. It seems like carriers rely more upon perceptual details of the items to distinguish between them, while control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items [42 ].

An electrophysiological marker in the early detection of neurodegeneration is found in the EEG pattern during stimulation for visual evoked potentials VEP in mild AD patients compared to Elderly controls, and MCI. Elderly controls have a neural pattern with a right–left dominance; in MCI this pattern seems to be displaced from right hemisphere to the left one, while in mild AD the activity concentrates on deep structures of this hemisphere (hippocampus and midbrain). Mild AD and MCI were more active for beta and gamma band, but at the same time beta and alpha band are more active than theta band. Elderly controls showed dominance of gamma and beta band in all significant areas. Mild AD and MCI have different neural patterns but show virtually similar frequency band activations, while elderly people differ from them in space and frequency bands [20 ].

* Figure authorized for publication by the corresponding author from: Cheng PJ, Pai MC. Clin Neurophysiol. 2010 Sep;121(9):1519-25

Figure 2.

Event-related potential study: Comparison between alzheimer diseases patients and normal control patients: (A) N170 at the four electrode sites; (B) the amplitudes of N170 between groups and types, AD: Alzheimer’s disease. *

Visual ERP features have shown that different neural regions are responsible for the early visual processing in the structural encoding of scenes and faces. P100 is a part of the evoked response suitable to examine basic visual processing, N170 brings information about structural encoding, and N250 is related to familiarity. The pattern of P100 and that of N170 suggest that mild Alzheimer disease patients maintain basic visual processing and structural encoding abilities, and scene recognition is impaired earlier than face recognition in the course of Alzheimer disease [43 ]. There is a diminished N400 component during a semantic categorization task in elderly subjects which suggest that due to the difficulty in accessing information there are deficient associative connections within the semantic network [44 ]. Auditory sensory and cognitive cortical potentials in persons with familial Alzheimer disease (FAD) mutations are abnormal approximately 10 years before dementia will be manifest. FAD mutation carriers had significantly longer latencies of the N100, P200, N200, and P300 components, and smaller slow wave amplitudes. Longer event-related potential latencies suggest slowing of cortical information processing in FAD mutation carriers [45 ]. The P300 latency is very useful in diagnosis, since it is found to be altered in cases with AD at an early stage, with very little cognitive degeneration [46 ].

6. Parkinson electroencephalographic patterns

Recordings in humans as a result of functional neurosurgery have revealed a tendency for basal ganglia neurons to oscillate and synchronize their activity, giving rise to a rhythmic population activity, manifest as oscillatory local field potentials. The most important activity is synchronized oscillation in the beta band (13-30 Hz), which has been picked up at various sites within the basal ganglia-cortical loop in PD. Dopaminergic medication and movement suppress this activity, with the timing and degree of suppression closely correlating with behavioral performance. for that reason synchronization in the beta band has been hypothesized to be essentially antikinetic in nature and pathophysiologically relevant to bradykinesia [47 ].

Post-movement beta synchronization is an increase in EEG beta power after movement termination. Parkinson patients have longer movement duration than controls, and also execute longer movement with their left hand, unrelated to the side of tremor. In Parkinson patients post-movement beta synchronization is significantly smaller contralateral to the tremulous hand movement. The post-movement beta synchronization has anterior shifting in Parkinson-patients; whilst in tremor dominant Parkinson's disease the asymmetric decrease of post-move beta synchronization is related to the laterality of tremor rather than bradykinesia [48 ].

Local Field Potentials LFP recording beta oscillatory activity is generated largely within the dorsal portion of the sub thalamic nucleus STN and can produce synchronous oscillatory activity of the local neuronal population. Recent studies suggest that beta (15-30 Hz) oscillatory activity in the subthalamic nucleus (STN) is severely increased in PD, and may interfere with movement execution [49 ].

Parkinson's disease is known to result from basal ganglia dysfunction. Electrophysiological recordings show abnormal synchronous oscillatory activity in the cortico-basal ganglia network in parkinsonian patients and animals. Also, it has been recorded an altered response pattern during movement execution in the pallidum of parkinsonian animals. In Parkinson animal models, spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor symptoms developed. Thus, causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. Consequently, the pathological disruption of movement-related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and is probably the best responsible candidate for this motor symptom [50 ].

The observation of a voluntary movement executed by another person is associated with an alpha and beta EEG desynchronization over the motor cortex, thought to reflect activity from the human "mirror neuron" system. Movement observation is accompanied by bilateral beta reduction in subthalamic power and cortico-STN coherence in PD, which is smaller than the decrease observed during movement execution, but significant when compared with control conditions. Movement observation is accompanied by changes in the beta oscillatory activity of the STN, similar to those observed in the EEG. These changes suggest that the basal ganglia might be engaged by the activity of the human mirror system [51 ].

The difficulty that patients have in initiating voluntary movement in the absence of any external cues might be due to the fact that the amplitude of movement-related cortical potential is equal to those prior to random-choice movements. The implication is that processes involved in self-selection of movement are abnormal in Parkinson's disease [52 ].

Parkinson disease patients show deficits in simple visuo-perceptual functions. Moreover, PD patients had impairment in tasks requiring set shifting from one reaction to another that may suggest frontal lobe dysfunction. The memory deficit in PD may derive from lowered motivation or initiating behavior [53 ].

Looking for electrophysiological correlates of perceptual categorization in Parkinson's disease, visual event-related potentials (ERPs) in a natural scene categorization task become a suitable tool. In healthy control subjects, there is a significant early difference (150-250 ms poststimulus) between ERPs elicited by pictures containing animals and scenes without animals. In spite of relatively preserved basic-level visual functions, this is not the case in untreated PD patients. These results move up the possibility for striatal contributions to visual categorization and may present a novel protocol for further clinical studies [54 ].

It has been reported an oscillatory theta-alpha activity in the ventral subthalamic nucleus associated with impulse control disorders ICD in patients with Parkinson’s disease. This activity is distinct from that associated with L-dopa-induced dyskinesias LID and is also coherent with EEG activity recorded in frontal areas. The activity recorded in PD patients with impulse control disorders come out from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Patients with impulse control disorders display theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that is generated 2-8 mm below the intercommissural line. In PD the oscillatory activity of the subthalamic nucleus recorded through the electrodes implanted for deep brain stimulation displays dopamine-dependent changes whereby the OFF to ON motor state is signalled by a marked reduction in beta band activity [55 ]. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations [6 ]. Diffuse lesions correlate with slowing of the EEG in patients with severe cognitive impairment [56 ], [57 ], [58 ]. All patients with dementia have an increase in slow waves in all the EEEG electrodes recording. In addition, all PD patients present diffuse slowing in the EEG with increased delta power [57 ].

Movement disorders in PD are due to the imbalance of inhibitory and excitatory processes involving motor cortical and subcortical neuronal circuits together with a nigrostriatal dopamine deficit [59 ]. A paired-pulse paradigm is usually used to study postexcitatory inhibition effect related to sensory gating mechanisms and synaptic processes in neurotransmitters release. There are two mechanisms that might explain paired-pulse inhibition phenomena. The first mechanism is the decrease in release probability of excitatory neurotransmitters from terminals of afferent axons. Another possible mechanism of the decrement of the second response on paired stimulation is connected with synaptically released GABA from terminals of inhibitory interneurons [60 ]. As the paired-pulse facilitation, paired-pulse inhibition is considered to be a form of a short-term synaptic plasticity. The investigation of cortical evoked potentials to paired-pulse sensory stimulation may provide additional information about mechanisms of neurological disturbances in PD [60 ].

7. Parkinson diagnosis

When individuals performed a reaching motor task (catching a ball in free fall), beta band asymmetry is observed. This result show a pattern of asymmetry in the somatosensory cortex, associated with a preparatory mechanism. With respect to task moment, after the ball's fall, the asymmetry is reduced. Moreover, the difference in asymmetry between the regions is related to a supposed specialization of areas (i.e. temporal and central). The temporal region is associated with cognitive processes involved in the motor action (i.e. explicit knowledge). On the other hand, the central sites are related to the motor control mechanisms per se (i.e. implicit knowledge). The premotor cortex shows a decrease on neural activity in the contralateral hemisphere (i.e. to the right hand). This finding is in agreement with others suggesting a participation of the frontal cortex in the planning of the apprehension task. This sensorimotor paradigm may be added to the inventory of tasks used to study clinical conditions such as depression, alzheimer and Parkinson diseases [61 ].

The corpus callosum (CC) is the morphological correlate of inter-hemispheric connectivity. Its integrity is of great importance for motor function and inter-hemispheric coordination of bimanual movements. Callosal fiber tracts are highly vulnerable as they are involved in number of neurodegenerative disease like parkinsonian syndromes and amyotrophic lateral sclerosis, even at early stages of the diseases. Transcraneal magnetic stimulation of the transcallosal inhibition may be performed by measurement of the ipsilateral silent period (iSP). The most common finding is a loss or a prolongation of the iSP latency [62 ].

As PD progresses, components of the autonomic, limbic, and somatomotor systems become damaged [63 ]. The substantia nigra and other regions of nuclear gray matter in the midbrain and forebrain become the focus of initially slight and then severe pathologic changes. At certain point, most individuals probably cross the threshold to the symptomatic phase of the illness, the pathologic process comes to involve the neocortex, and the disease is manifested in all its clinical magnitude. These diffuse lesions correlate with slowing of the EEG in patients with severe cognitive impairment [56 ], [57 ], [58 ].

The auditory evoked potentials of different latencies are useful in the evaluation of cognitive changes associated to PD. Middle latency auditory evoked potentials are abnormal in most PD patient. P300 is absent significantly more often in PD patients with cognitive impairment [64 ].

Parkinson Early Detection:

Spectral ratio is the sum of the power values in the alpha and beta waves divided by the sum of the values in the slow waves. Since, all patients with dementia have an increase in slow waves in all the EEEG electrodes recording, the spectral ratios decrease have significant predictive value in PD at all electrode locations except for the frontal pole. In addition, all PD patients present diffuse slowing in the EEG giving to delta power significance as predictive electrophysiological biomarker for dementia in PD [57 ]. ERP is also useful tool for the evaluation of neuropsychological impairments in PD. In the classic oddball task P300 is elicited by target. Even though, P300b findings in PD have shown inconsistent results, prolonged P300b latency in PD patients with dementia have been consistently observed [65 ].

The hazard of developing dementia is 13 times higher for those with low background rhythm frequency (lower than the grand median of 8.5 Hz) than for those with high background rhythm frequency. The QEEG measures of background rhythm frequency and relative power in the band are potential predictive biomarkers for dementia incidence in PD [57 ].

8. Huntington electroencephalographic patterns

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder, with neurodegeneration mainly affecting the striatum. In Nogo as opposed to Go trials two fronto-central ERP components are elicited: the Nogo-N2 and Nogo-P3. These components are supposed to depend on (medial) prefrontal regions, especially the anterior cingulate cortex (ACC). In HD the Nogo-P3 demonstrates a strong attenuation, while the Nogo-N2 does not differ from controls. The decline in inhibition is likely mediated via a dysfunction in the ACC, which is known to be dysfunctional in HD. Moreover, the decline in response inhibition in HD is gene-associated. The differentially affected Nogo-components suggest that they rely on different neuronal circuits, even within the ACC. For HD this suggests that this structure is not entirely dysfunctional [66 ].

Cognition is affected early in Huntington disease, and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. HD gene carriers and controls respond differently to theta burst stimulation, with controls having more inhibition than HD gene carriers. However, there is no difference between pre-manifest and early symptomatic HD gene carriers. Motor cortex plasticity is abnormal in HD gene carriers but is not closely linked to the development of motor signs of HD [67 ]. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex in rats shows an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after theta burst stimulation. This is a behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD [68 ].

The onset of Huntington disease (HD) might be atypical. Rarely, there is severe cognitive impairment and diffuse cortical atrophy before the onset of motor manifestations or symptoms of an extrapyramidal movement disorder. Thus, especial consideration must there be for patients with early dementia of unknown etiology [69 ].

The visually evoked potential is abnormal in patients with Huntington disease. Both early and late wave components are affected, and the averaged amplitude for the patients is reduced in comparison with normal control subjects. Despite striking attenuation and disorganization of the complex, latency of initial wave components is normal. The abnormality is not present in patients with a variety of other nonfocal cerebral disorders nor in children of patients with Huntington disease [70 ]. There are marked impairments of patients with HD in early visual sensory processing (early components). The early visual components show a significant latency shift (delay of about 50 milliseconds) in HD. In the search paradigms the P3 components differentiating target and standard stimuli is virtually absent in HD as is the ERP effect indexing word recognition. This is accompanied by a marked delay in search times and lower hit rates in the search tasks and grossly reduced recognition accuracy in the memory task. Deficits in visual search might be due to an impairment to deploy attentional resources across the visual field and/or an inability to control eye movements [71 ].

9. Huntington diagnosis

Huntington disease usually causes cognitive decline previously to motor symptoms. Studies performed in a HD animal model to assess this issue suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior [68 ].

10. Huntington early detection

It is well known that HD affects cognition earlier than motor system. The motor-evoked potential to burst stimulation is a suitable tool to evaluate motor synaptic plasticity. This might bring out clues about motor control decline related to HD before having symptoms of abnormal motor behavior [67 ].


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