Differential Activation of Brain Areas in Parkinson's Disease

Complexity in Brain Activation
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If understanding how brain works was analogous to building a puzzle,
we'd only be starting to gather the pieces

Parkinson's Disease is a multisystem neurodegenerative disorder that presents with a diverse set of symptoms ranging from tremor and bradykinesia to cognitive impairment, hallucinations , sleep disorders and dementia . It is the second most prevalent neurodegenerative disease behind Alzheimer's and is becoming more important as the population ages.[1]

Recent studies have made use of various forms of imaging such as functional magnetic resonance imaging[20], transcranial sonography[26], diffusion tensor imaging[27], and single-photon emission computed tomography[30] to evaluate the integrity and activity of brain networks and regions. In addition to shedding light on the pathologies underlying symptomatic manifestations of the disease, both functional and structural imaging could be used as potential tools for diagnosis in a clinical setting.

1) Functional Magnetic Resonance Imaging (fMRI)

How does fMRI work?
Great 22 second summary
of fMRI

Functional magnetic resonance imaging exploits the difference in magnetization between oxygenated- and deoxygenated- hemoglobin to indirectly assess brain activity. The metabolic processes associated with neuronal activation cause local vasodilation, an increase in blood flow to the area, and consequently a change in magnetic signature that can be detected using an MRI machine.

Functional magnetic resonance imaging is commonly held as the golden standard for functional imaging - publications citing its use in imaging for research purposes greatly outnumber other techniques such as SPECT and DTI. However, fMRI is not without its caveats. Because of its dependence on the blood-oxygen-level-dependent (BOLD) effect, there is a temporal delay in the use of fMRI in the order of seconds.[2] The spatial resolution of fMRI depends on the chosen size of the voxel and is, at best, is able to discern between structures that are 1 mm apart. Although its spatial resolution is not bad, fMRI is outclassed in this respect by techniques such as MR spectroscopy that has a resolution in the order of 10 micrometers. Claustrophobia is cited as the major risk factor of fMRI to patients.[3]

1.1) Functional Connectivity at Rest

fMRI Scans of Tremor PD Patients
Compared to Healthy Controls[6]
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Increased (A-D) and decreased (E-G)
M1 hand area functional connectiivty

A survey of 116 cortical and subcortical areas in PD patients via wavelet correlation analysis has shown global decreases in functional connectivity.[4] Nodal efficiencies of various brain areas including the precuneus, cuneus, superior parietal lobe, superior occipital lobe, middle frontal lobe, supplementary motor cortex and select cerebellar regions were significantly decreased in PD patients compared to healthy individuals.[4] These changes in network connectivity are thought to be due to the depletion of dopamine, which, in addition to being a neurotransmitter, serves to initiate, maintain and modulate neural function within networks.[5]

Functional connectivity profiling of the subthalamic nucleus in PD patients at rest through the use of fMRI has revealed increased activation of circuits between the subthalamic nucleus and cortical motor areas.[6] This is believed to be a result of reduced dopaminergic input from the striatum via both direct and indirect feedback loops.[7] [8] This motor cortex-subthalamic pathway has been associated with the coupling of neural oscillators[9] and the initiation of voluntary movement. Its hyperactivation in PD patients suggests its involvement in the underlying pathophysiology of dyskinesia and resting tremor. A pattern of increased and decreased activation was observed in the M1 hand region of PD patients who experienced tremor.[6] It remains unresolved whether this was reflective of changes in functional connectivity or coactivation in response to the movement associated with the tremor.

1.2) Activity-dependent Responses

1.2 a) Olfaction Task

Activation patterns following exposure to
pleasant olfactory stimuli (ie. rose fragrance)[11]
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Note hyperactivation in areas such as the anterior cingulate cortex

A decline in olfaction has been observed to precede the onset of resting tremor and other motor symptoms in PD patients by 4 years.[10] PD patients not only score significantly lower on tests of olfactory function, but also rate odour stimuli as less intense and more pleasant than control individuals.[11] Researchers have shown that there is a significant difference in the regions of the brain that are activated by olfactory stimuli between PD patients and healthy individuals. Interestingly, it has been shown that these abnormal activation patterns themselves differ depending on the affective-reception of the stimulus.[11]

Pleasant odors (like roses) were observed to activate a widespread sample of brain areas including the bilateral thalamus, amygdalae, insular cortex, hippocampus, and prefrontal and temporolateral regions in healthy individuals.[11] In response to the same stimulus, however, PD patients were observed to have an increased activation in the caudate, the ventral striatum, the superior medial prefrontal cortex, the anterior cingular cortex and lateral prefrontal corticies compared to control.[11] This hyperactivations are believed to be reflective of the effects of the pleasant stimulus in the upregulation of dopaminergic pathways that are otherwise dampened in PD patients. Another difference observed in PD patients compared to healthy individuals was the hypoactivation of the subcortical structures implicated in the processing of olfactory stimuli (ie. the amygdalae, hippocampi and thalamus).[11] This finding is consistent with the known contributions of olfaction to the limbic system and the decreased sensitivity to the amygdala to emotional stimuli observed in PD patients.[12]

Dihydrogen sulfide, the culprit behind the unpleasant smell of rotten eggs, was observed to activate the left hippocampus and the amygdalae in healthy individuals.[11] Activation of the left hippocamus and amygdala were also shown in PD patients, but there was significantly less activity in both the right amygdala and the bilateral heads of the caudate nucleus.[11] The amygdalo-hippocampal complex is believed to facilitate intensity processing and its hypoactivation may explain the rating of stimuli by PD patients as 'less intense'.[13]

1.2 b) Memory Task

fMRI scan showing PD patients (vs. control)
during a recognition memory task[16]
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Note the hypoactivation of the paracingulate gyrus in blue

Impairment of memory begins to manifest at the early stages of Parkinson's Disease and presents as several types of dysfunction as the disease progresses.[14] Learning and delayed recall are first to be affected while a decline in recognition memory is not usually evident until the later stages.[15] The latter can be assessed using a recognition memory fMRI paradigm wherein participants are given a list of 35 words that they are instructed to memorize.[16] During the fMRI scan, participants are then asked to identify the words from a list of 70 words. Patients were observed to commit more false positive responses (ie. identifying a word as one from the learned list when in fact it was novel) than the control group).[16] Furthermore, patients' performance on the task was shown to decline at a faster rate than healthy individuals.[16]

Task-related hypoactivation over time was observed in a subset of brain areas including the orbitofrontal regions, superior parietal lobes, anterior paracingulate regions and the posterior region of the left middle temporal gyrus in Parkinson's Disease patients.[16] Decreased deactivation of the paracingulate gyrus and precuneus were also characteristic of the patient group.[16] The impaired regulation of both activation and inactivation of these cortical areas has also been reported in Parkinson's Disease patients during other tasks such as card sorting.[17] Cross correlation connectivity analysis showed a loss of integrity in the functional connectivity between these areas as well as between the right middle frontal gyrus and the bilateral superior parietal lobes.[16] The differential activation of these areas supports previous findings of their implementation in the recognition memory network.[18] Dysfunctions of this network has been shown to precede memory loss in PD patients[18] and may be useful for early detection of the disease.

1.2 c) Motor Task

fMRI scan during motor task with affected hand
in hemiparkinsonian patients[21]
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Note the bilateral activations of the
cingulate and dorsolateral prefrontal cortices

The hallmark motor symptoms of Parkinson's disease have been postulated within the functional cortical deafferentation hypothesis to be due to the dysfunction of the motor circuit.[19] Assessment of motor function-related changes in the activation of cortical and subcortical areas involves the use of fMRI during sequential unilateral finger-to-thumb opposition movement. Participants are instructed to complete this task with either the left or right hand or bimanually for 60 s ON-OFF cycles. Consistent with the characteristic motor dysfunction of the disease, a study showed that Parkinson's Disease patients exhibited slower motor movement compared to health control individuals.[20] There was significant hyperactivation of the contralateral primary motor cortex, putamen, and thalamus compared to control and coactivation of the ipsilateral putamen.[20]

An fMRI study of early hemiparkinsonian patients also revealed altered activation in several cortical motor areas including the dorsolateral prefrontal cortex and the bilateral primary motor cortices and supplementary motor areas.[21] This is proposed to be due to compensatory recruitment of motor circuits in response to hypoactivation of dopaminergic neural connectivity and basal ganglia dysfunction.[21]

The pathological activation of the basal ganglia during motor tasks in patients is noted to be similar to that found in Schizophrenia, but the resulting activity in the contralateral primary motor cortex between the two differs.[20]

1.2 d) Facial Recognition and Hallucinations

fMRI Results for one-back repetition detection tasks
(PD with hallucinations < PD without hallucinations [23]
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Note the hypoactivation of the interior and superior frontal gyri
and the anterior cingulate gyrus

Visual hallucinations have been reported in approximately 25% of patients with Parkinson's disease.[22] They appear to be associated with visual complications such as impaired colour discrimination and contrast sensitivity, and deficits in both facial and object recognition .[23] These symptoms are thought to be due to reductions in gray matter within the visual association areas of the brain as well as with irregular activation of the posterior and frontal brain regions.

To examine the functional differences in Parkinson's Disease brains in detail, a study was conducted using fMRI and one-back repetition detection tasks,[23] This test involved the presentation of novel images of human faces for 1000 ms between 1400 ms interstimulus intervals. The images were randomized and subjects were instructed to press a key when they observed two consecutive images that were identical. The test was repeated with nonmeaningful mosaic colour patterns as a control.

Parkinson's Disease patients with visual hallucinations were observed to have significantly reduced activation in prefrontal areas including the interior, superior and middle frontal gyrus as well as in the anterior cingulate gyrus.[23] This hypoactivation was asymmetrically skewed to the right hemisphere, paralleling the emerging findings that facial recognition in healthy individuals is processed by a right-lateralized connection of neurons that spans the prefrontal and temporo-occipital cortices.[24]

It is hypothesized that decreased activation in these frontal regions is associated with an attention deficit towards visual stimuli. A proposed model by Collerton et al. called the 'Perception and Attention Deficit Model' postulates that attention to an external sensory input activates a specific 'proto-object' that enters into conscious awareness through competitive antagonizing of other proto-objects.[25] Due to a dysfunction in the lateral frontal-cortex network, patients with visual hallucinations have an impaired ability to differentiate between meaningful and nonmeaningful information and to suppress irrelevant stimuli. This is believed to allow for multiple, non-specific proto-objects to be activated and 'seen'.

Parkinson's Disease patients who do not experience hallucinations experienced hyperactivity in the right superior frontal gyrus compared to healthy individuals.[24] This may be reflective of the difficulty that patients have with facial perception tasks and the greater amount of cognitive effort they exert in order to complete the tasks.

2) Diffusion Tensor Imaging (DTI)

DTI Tensor Imaging of PD patient vs. control[27]
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Regions of decreased fractional anisotropy are shown in blue

Exploring Brain Connectivity

Diffusion Tensor Imaging is a form of magnetic resonance imaging that measures the magnitude and direction of diffusion that water molecules within the brain experience under a controlled magnetic field. This technique allows for the assessing of fractional anisotropy in the brain that can be used to infer the integrity of neuronal fiber tracts and tissue microstructure.

Studies have shown that a reproducible pattern of degeneration in the substantia nigra, thalamus, and motor, premotor and supplementary motor areas at the microstructural level can be seen through DTI in Parkinson's Disease patients.[27] These structures are largely consistent with those that were identified to have abnormal activation patterns via other functional imaging techniques.[20][21][26] The extent of microstructure degradation observed correlated with the severity of Parkinson's Disease in the patients.[27]

Interestingly, there was a positive correlation between the fractional anisotropy within the somatosensory cortex and the severity of Parkinson's Disease.[27] This parallels fMRI studies that have shown hyperactivation in the somatosensory cortex and supports the hypothesis that the plasticity of the brain allows for compensation of dysfunctional motor control.[28]

3) Single-photon Emission Computed Tomography (SPECT)

Single-photon emission computed tompography[29]
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Note the decline in dopamine transporter density (red)
in the striatum as PD progresses

Single-photon Emission Computed Tomography (SPECT) is an imaging technique that requires the injection of radioisotopes into the bloodstream of patients. The radioactive tracer emits gamma radiation that is detected by a scanner at various angles. These pictures are then reconstructed through the use of computers. Regions of high metabolic activity produce a stronger signal because of the increased localize flow and metabolism of the tracer. The spatial resolution of SPECT is poor compared to fMRI but its high temporal resolution makes it advantageous to image more transient changes in cortical activity. This may prove to be useful in looking at Parkinsonian symptoms such as hallucinations and REM disorder.

A recent publication made use of SPECT to investigate the underlying changes in brain activation and integrity associated with mild cognitive impairment (MCI) in Parkinson's Disease patients. The researchers found that there was under-recruitment in multiple brain networks in patients during working memory tasks compared to healthy control individuals.[30] These areas included the right dorsal caudate nucleus and the bilateral anterior cingulate cortices[30] - areas that were interestingly also shown to be significantly hypoactivated in PD patients during olfactory tasks. [11] I123-FP-CIT, a radioisotope of iodine, SPECT was also conducted to assess presynaptic dopamine integrity. It was discovered that patients with Parkinson's Disease had significantly reduced presynaptic uptake of dopamine in the straitum than the healthy group.[30] These insights into the underlying reasons behind altered activation patterns in pathological conditions cannot be made with the use of fMRI.

4) Transcranial Sonography (TCS)

Transcranial Sonography[26]
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Transcranial B-mode sonography (TCS) is a form of structural imaging that is emerging as tool for the diagnosis of Parkinson's Disease. Like obstetrical sonography, TCS exploits the various acoustic impedances of different structures and constructs an image based on reflection and scattering patterns. Visualization of the substantia nigra and the basal ganglia is made possible through the use of ultrasound on the surface of the preauricular bone.[26] TCS allows for the detection of and increased echogenicity signature associated with Parkinson's Disease pathology in the substantia nigra that would otherwise go unnoticed via MRI.[26]

Although it is, to an extent, like comparing apples and oranges, the use of TCS over the fMRI has numerous advantages. Imaging using a sonography scanner is real-time and, at 0.8mm in the determined axis, has higher spatial resolution than field-strength magnetic resonance imaging. TCS is also cheaper than an MRI scan and may be useful in circumstances where transportation of a patient to an MRI machine may not be feasible. Furthermore, substantia nigra hyperechogenecity appears to precede clinical diagnosis of Parkinson's Disease and may therefore be useful as a marker for increased susceptibility to the disease. The increased echogenecity of the substantia nigra is believed to be due to the sequestering of iron deposits that occurs due to changes in neurons and their environment during neurodegeneration.[26]

5) Imaging as a Biomarker

Both structural and functional imaging of the brain can not only be used to explore the underlying pathophysiology of diseased states, but also as potential tools for diagnosis in a clinical setting.

The overactivation of the contralateral primary motor cortex, putamen and thalamus during motor tasks, for example, have been shown to precede motor dysfunction in Parkinson's Disease patients.[20] Likewise, dysfunctions of cerebral networks implicated in recognition appear before actual deficits in memory.[18] These findings may be instrumental in the use of bioimaging as an alternative to genetic screening for susceptibility towards Parkinson's Disease. Early detection is critical in the treatment of Parkinson's Disease because there is potential for therapies such as deep-brain-stimulation to confer neuroprotective effects if administered early on.

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