الفهرس 
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Abstract
The development of the nervous system occurs through the interaction of several synchronized processes, some of which are complete before birth, while others continue into adulthood. The development of the human brain may be divided into several phases. After implantation, formation and separation of the germ layers occur (gastrulation), followed by dorsal and ventral induction phases, and phases of neurogenesis, migration, organization and myelination.
There are two periods in development of the human brain (1)-The embryonic period terminating at 8 weeks of gestation it includes three in time overlapping phases: formation and separation of the germ layers, dorsal induction phase and ventral induction phase, (2)-the fetal period extends from the ninth week of development to the time of birth, This period is characterized by neuronal maturation.
At first, each cerebral hemisphere consists of a thick basal part, the subpallium, giving rise to the basal ganglia, and a thin part, the pallium, that becomes the future cerebral cortex. The subpallium appears as medial and lateral elevations, known as the ganglionic or ventricular eminences. The caudal part of the ventricular eminences is also known as the caudal ganglionic eminence, and primarily gives rise to parts of the amygdala. The medial ganglionic eminence is derived from the diencephalon, and is involved in the formation of the globus pallidus , the basal nucle of meynert and the bed nucleus of the stria terminalis the larger lateral ganglionic eminence is derived from the telencephalon, and gives rise to the caudate nucleus and the putamen from its intermediate part and The olfactory tubercle and the nucleus accumbens arise from the rostral part. The neurons of the substantia nigra are generated at two different points of the basal plate at the level of the isthmus and migrate in a radial pattern as two definite streams towards the ventral mesencephalon.
In the basal ganglia structures (caudate, putamen and globus pallidus) Tunel-labelled cells were observed from the 12th week of gestation onwards. The numerical density of the total number of neurons was significantly decreased, whereas the labelling index of apoptotic cells was significantly increased with advancing gestational age.
from a clinical point of view disorders of movement due to abnormal functioning of the basal ganglia can be divided into two broad groups (1) the hypokinetic - rigid syndromes, the fundamental disturbances of which consist of hypokinesia and/or bradykinesia, i.e. difficulty and/or slowness in initiating and completing movements, generally associated with rigidity; and (2) the dyskinesias, including tremor, chorea and ballismus, dystonia and athetosis, tics and myoclonus.Disorders with a hypokinetic-rigid syndrome in childhood include early-onset Parkinson disease, juvenile Huntington disease,Wilson disease, juvenile GM2 gangliosidosis, multiple-system atrophies, Hallervorden–Spatz disease and many other rare disorders.
Three approaches appeared to form mappings of human brain, first is the classical maps (the most used up till now is Brodmann 1909) but a clear disadvantage when structural data from these maps are to be matched with functional data obtained from different brains. A second approach used noninvasive imaging techniques (e.g., PET and more recently, fMRI) have mapped the cerebral cortex with ever-increasing spatial resolution, but they relate foci of activation only to macroanatomical landmarks (i.e., gyri and sulci). A third recent approach is to start from both anatomy and function and to fuse the two lines together, namely computerized brain atlases which offers the computational tools that are necessary to achieve this goal.
Several cortical areas involved in basal ganglia system:
The primary motor cortex M1 (Brodmann’s area 4): which plays a key role in the execution of skilled movement. The premotor cortex PM (area 6): with two distinct parts the dorsal and ventral premotor cortices. The supplementary motor area (SMA): also has two parts the caudal part SMA proper rostral part pre-SMA, these areas have intimate relation linked anatomically by the cortico-basal ganglia loops.
The anterior cingulate cortex (ACC): each of the rostral (CMAr), dorsal (CMAd), and ventral (CMAv) cingulate motor areas basically participates in motor-related functions such as preparation and execution of movements. The pyramidal system is constituted by the cortical fibers reaching the bulbar pyramids at the level of the inferior Olive. The extrapyramidal pathways are those motor pathways that do not pass through the pyramids of the medulla oblongata. They consist of central pathways that modulate CNS motor areas in cerebral cortex, cerebellum, the brain stem, and spinal cord. The primary function of the extrapyramidal system is the ‘fine-tuning’ of voluntary movement to render it amenable to higher levels of conscious control .More recently, debate has centred on other roles, particularly in cognition and motivation.
Initially, basal ganglia were a descriptive term for onto- and phylogenetic or topographic classifications. A variable list of structures was included as basal ganglia,different typs of classification of basal ganglia component one divided BG as the dorsal and ventral basal ganglia, another classification divided BG into two functional units, the striatal complex and the pallidal complex and based on their connection into input nuclei, output nuclei, and intrinsic nuclei.
The input nucleus is the striatum which consists of two compartments: striosoms that sends output to the dopamine neurons in substantia nigra pars compacta and the matrix that sends output to substantia nigra pars reticulate and internal globus pallidus. Striatum contains different types of neurons; 1-MSN (striatonigral and striatopallidal) represent about 98% of cells, 2-interneurons (GABAergic and cholinergic) represent about 2% of cells localized on this neurons many types of receptors as D1, D2, D4, A2A, mGluR1/5 and muscarinic receptors.
Synaptic plasticity in the striatum is a synaptic modification represents a fundamental mechanism for altering neural circuit function. A basic assumption in contemporary neuroscience is that long-term synaptic plasticity, widely studied in the forms of longterm potentiation (LTP) and long-term depression (LTD), is a central physiological mechanism that underlies learning.
The dissociation between the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) at the level of behaviour is mirrored by distinct rules of synaptic plasticity in these regions.
Several types of synapses present:
1. Cortico- and thalamostriatal synapses on MSNs.
2. Cortico- and thalamostriatal synapses on GABAergic interneurons.
3. Interneuron synapses on MSNs.
4. MSN synapses on MSNs.
The output nuclei are the internal globus pallidus (Gpi) and substantia nigra pars reticulata (SNr) are rather considered to be similar: They both receive inputs from the striatum, Gpe and STN, and project to the cerebral cortex through the thalamus.
The intrinsic nuclei are the external globus pallidus; works to control basal ganglia output through: (1)-Direct projections to the (Gpi) and substantia nigra pars reticulata; (2)-Indirect projections to these nuclei via the subthalamic nucleus; (3)-Projections to the reticular thalamic nucleus, Substantia Nigra Pars Compacta and the ventral tegmental area gives rise to dopaminergic projections to the caudate-putamen, subthalamic nucleus and pallidum.and subthalamic nucleus and The subthalamic nucleus (STN) has been regarded as an important modulator of basal ganglia output.
Five parallel segregated circuits for BG system; motor, oculomotor, dorsolateral Prefrontal, lateral orbitofrontal and anterior cingulated detected, with The fact that each of the corresponding circuits involves distinct regions of striatum, pallidum, substantia nigra, thalamus and cortex offers the possibility within the limits of activation localization corresponds, and with that, its function.
In recent years, an increasing number of computational models have addressed various aspects of basal ganglia function. The motivation for constructing such models derives from a pressing need to interpret the growing mountain of complex biological data associated with the basal ganglia.the rapid accumulation of anatomical, biochemical, physiological, pharmacological and behavioural Information is exposing the inadequacy of qualitative models to explain current data and predict future experimental outcomes. To proceed further in our understanding of the functional dynamics of information processing within the basal ganglia, and its interactions with the rest of the brain, quantitative models of all aspects of basal ganglia biology will be needed. This appeared in increasing number of computational models which have addressed various aspects of basal ganglia function.
The computational models divided into; (1) neural network models that capture neurobiological or neuroanatomical processes which show the classical box and arrow model, the action selection model and the reinforcement learning model. (2) Abstract models which typically are not constrained by known biological limitations (incorporating neither anatomy nor physiology).and the mathmatics play an important role behind it. Combining these two modeling approaches might prove more fruitful than using either in isolation.
There are 2 simple and robust conceptual models of movement disorders in basal ganglia disease, one describing the neural mechanisms underlying parkinsonian akinesia and the other explaining the appearance of abnormal involuntary movements (dyskinesias). These represent 2 diametrically opposed mechanisms, at opposite ends of the pathophysiological spectrum parkinsonism emerges as a complex network disorder, in which abnormal activity in groups of neurons in the basal ganglia strongly affect the excitability, oscillatory activity, synchrony and sensory responses of areas of the cerebral cortex that are involved in the planning and execution of movement, as well as in executive, limbic or sensory functions.
In parkinson’s disease many changes occur in the following structure:
1. Changes in basal ganglia explained by: Altered firing rates or The rate model: this model explains the firing rate changes in the basal ganglia as the result of disturbances of the balance of activity in the direct and indirect pathways. This due to changes in neurotransmitters in form of dopamine loss due to degeneration of dopaminergic SNc neurons which increases inhibition of Gpe activity, disinhibits STN neurons, and therefore leads to excessive activity in targets of STN efferents, including Gpi and SNr. Also Dopamine loss triggers prominent secondary morphological changes in reduction of the density of dendritic spines on MSNs and also triggers changes in the density and sensitivity of dopamine receptors. About GABA its level increased in Gpe and decrease in STN, as regarding to glutamate showed increased activity in the glutamatergic STN. Other mechanisms as Bursting activity in the STN develops early in the course of dopamine depletion, At the level of single cells, oscillations another mechanism in the alpha- and beta- frequency ranges are prominent in recordings in Gpe, Gpi, and STN of MPTPtreated monkeys, and in parkinsonian patients undergoing functional neurosurgery, In the dopamine-depleted state, however, the synchrony between neighboring basal ganglia cells, and even between nuclei, is significantly increased, usually together with the emergence of oscillatory activity, Changes in sensory response patterns and changes in task-related activity of basal ganglia neurons.
2. Changes in thalamic activity: the metabolism in the thalamic VA and VL nuclei is increased in Parkinsonism, perhaps reflecting increased basal ganglia input to this area. On the contrary a reduction of CM/Pf activity which may, secondarily, result in reduced driving of ‘direct’ pathway MSNs, and worsening of Parkinsonism.
3. Changes in cortical activity: cortical activation in motor tasks is reduced in Parkinsonism, specifically in the supplementary motor area (SMA) and in the anterior cingulate cortex. In parkinsonian patients, the performance of motor and other tasks often recruits brain areas that are not activated in non-parkinsonian individuals, such as areas in the lateral premotor cortex, cerebellum and posterior parietal and occipital lobes. Similarly, cognitive tasks may affect activation in areas that are not normally activated.
4. Changes in brainstem activity: There is evidence that abnormalities in brainstem regions, specifically the PPN, may be involved in the development of some of the core signs of Parkinsonism.
Chorea refers to irregular, flowing, non-stereotyped, random, involuntary movements that often possess a writhing quality referred to as choreoathetosis. In primate model of chorea and in human condition of hemiballismus and dopa- induced choreatic dyskinesia, it has been shown that the over all activity of Gpi neurons is decreased however tonic reduction of Gpi activity alone cannot explain chorea.
A comprehensive animal model is essential in the effort to successfully design drug therapies that selectively reverse or prevent the patterns of pathogenesis in HD. Firstly Transgenic mice models is A major breakthrough in the HD field was the creation of a mouse model named R6 lines. Changes detected in this model on the level of neurotransmitter receptors Glutamate receptors, dopamine receptors and A2A receptors are downregulated and also on the level of neurotransmitter synthesis specially GABA ,changes also in cytoskeletal and structural proteins and other molecules. Other models as Murine knock-out models and Excitotoxic lesion models also widely studied.
Dystonia is a syndrome characterized by sustained muscle contractions leading to abnormal postures and twisting movements. It is believed to arise from abnormal function of the cortex basal ganglia-thalamus-cortex loop circuitry. Two forms of abnormalities occur in dystonia 1- Neurophysiological explained by deficient inhibition in cortical and subcortical structures, abnormalities in sensory processing, sensory motor integration failure and muscloskeletal constraints. 2- Neurochemical appeared in decreased GABA levels selectively in cortical and subcortical regions contralateral to the dystonic limb, dopaminergic dysfunction Dystonias are characterized clinically as forms of secondary dystonia (tardive dystonia) or dystonia-plus (dopa-responsive dystonia). Also cholinergic dysfunctions detected.
In the generation of tics, it is hypothesized that an aberrant focus of striatal neurons becomes inappropriately active, causing unwanted inhibition of a group of basal ganglia output neurons, which in turn disinhibit the motor pattern generators (MPGs) in the cerebral cortex and brainstem leading to an involuntary movement. Recent postmortem work suggesting that there might be decreased intrastriatal inhibition in TS brains.
Neuroimaging techniques are of steadily increasing importance for clinical diagnosis and treatment monitoring. It showed that most groups use magnetic resonance imaging (MRI), fMRI, computerized tomography (CT) and single photon emission computerized tomography (SPECT).
According to Structural imaging, CT brain scans are rarely helpful ,magnetic resonance imaging MRI in parkinsonism are generally normal, although occasionally patients show increased signal from the substantia nigra, whereas patients with striatonigral degeneration (SND) or multiple system atrophy (MSA) have been reported to show reduced posterolateral putamen signal, ‘hot cross bun’ appearance. Progressive supranuclear palsy (PSP) is associated with low putamen signal on T2-weighted MR sequences, Evidence of brainstem and/or cerebellar atrophy may also be present, along with increased signal from the middle cerebellar peduncles on T2-weighted images. Structural MRI studies in early HD tend to support the postmortem findings of widespread generalized atrophy throughout the cortex, with disproportionate volume loss in the striatum. where both GM and WM are measured, there is a suggestion that WM loss is relatively greater or seen earlier in the course of the degeneration. Abour MRI study in dystonia showed abnormal T2 relaxation times within the basal ganglia in patients with this disorder.
Functional imaging in contrast to structural imaging detects Functional deficits which may be more extensive than structural findings would indicate, or may occur before the detection of anatomic changes, or may even occur in the absence of any structural lesions.
PET imaging offers functional insights unavailable from anatomic imaging alone. PD-related covariance pattern (PDRP) in PET was characterized by increased glucose metabolism of the lentiform nucleus, thalamus, and brainstem as well as decreased glucose metabolism of the lateral premotor cortex and the supplementary motor area (SMA). An HD-related pattern (HDRP) also identified. HDRP is characterized by not only caudate and putaminal hypometabolism but also includes mediotemporal metabolic reductions as well as relative metabolic increases in the occipital cortex. The torsion dystonia-related pattern (TDRP) is characterized by hypermetabolism of the basal ganglia, cerebellum, and SMA. PET in Tourette syndrome showed metabolic increases in the lateral premotor and supplementary motor association cortices and the midbrain and metabolic decreases in the caudate and thalamus.
Similar to PET, SPECT generates tomographic images of the three dimensional distribution of a radioisotope. SPECT in Parkinson’s disease showed various degrees of cortical hypoperfusion and cerebellar hypoperfusion, and normal findings all have been described. SPECT in huntigton disease show decreased or absent tracer uptake in the caudate or basal ganglia of symptomatic patients. In Tourette’s syndrome hyperperfusion of the frontal lobes, cingulate, basal ganglia, thalami may be found all together in the same patient or in different combinations.
Functional MRI relies on detecting small changes in the signals used to produce magnetic resonance images but without use of radioisotopes. In Parkinson’s disease patients exhibited a relatively decreased fMRI signal in the rostral part of the supplementary motor area and in the right dorsolateral prefrontal cortex, as previously shown in PET studies. Concomitantly, the same patients exhibited a significant bilateral relative increase in fMRI signal in the primary sensorimotor cortex, lateral premotor cortex, inferior parietal cortex, caudal part of the SMA and anterior cingulate cortex. Also changes detected in treated patients either with medications (L-dopa) or DBS, In the HD showed significant activation in the right head of caudate nucleus, as well as bilateral thalami, left middle temporal, right superior temporal, right superior frontal, right middle and inferior frontal and right postcentral gyri., reduced activation in the HD was observed in the right middle frontal, left middle occipital, left precuneus, and left middle frontal gyri.
Diffusion tensor imaging (DTI) as a novel magnetic resonance imaging modality is rapidly becoming a primary technique for noninvasive studies of the structure of living tissue such as human brain. Studies using DTI showed that FA in the substantia nigra is reduced in patients with PD compared to healthy individuals. In addition the DTI has amajor Role in under Standing of DBS and its side effects.