Name: generalized psychophysiological interaction (ppi) analysis of memory related connectivity in individuals at genetic risk for alzheimer's disease
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Description: Watch this Scientific Journal Video about Generalized Psychophysiological Interaction PPI Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease at JoVE.com

This work was supported by the National Institute of Aging (grant number R01AG013308 to SYB, F31AG047041 to TMH). The authors used computational and storage services associated with the Hoffman2 Shared Cluster provided by UCLA Institute for Digital Research and Education's Research Technology Group.

The present study was performed in compliance with the UCLA Institutional Review Board (IRB) protocols and approved by the UCLA Human Subjects Protection Committee. All participants gave written informed consent in order to enroll in this study.
1. Participant Selection
<ol>
	<li>Obtain IRB approval to perform the study.</li>
	<li>Screen individuals aged 55 and older for cognitive decline using a standardized neuropsychological battery. Include tests of General Intelligence (Subtests of the ...

<ol>
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Early task-based fMRI studies were designed to uncover statistical relationships between particular cognitive processes or demands and changes in the BOLD signal relative to a baseline measurement. This traditional approach is useful for identifying specific regions in the brain where activity is modulated by an experimental task. In contrast, a PPI analysis is chiefly concerned with the modulation of functional connectivity, or synchrony of activity, that results from a task-induced cognitive process. PPI measures conte...

The term &#34;connectome&#34; was coined in 2005 marking a paradigm shift in neuroscience that continues to this day1. The brain is increasingly described in terms of functional networks, connectivity and interactions between and among regions on a large scale. Nevertheless, the delineation of regional functional specialization and associations between fMRI-measured activity and task demands are still valid and useful approaches. In light of the growing interest in connectomics, functional connectivity approaches to task fMRI analysis are growing in popularity. One approach to measuring functional connectivity changes dependent on task demands makes use of the concept of PPI. A PPI is the interaction of an active task phase or particular task demand (&#34;psycho&#34;) with the functional connectivity (&#34;physio&#34;) of a region of interest or &#34;seed&#34; in the brain. PPI differs from bivariate, correlation-based analysis of functional connectivity, which generally measures the degree of correlation between the activity in two regions without any constraints related to task demands.
The concept and framework of a PPI analysis was originally described by Friston and colleagues in 19972. The authors asserted that their approach was important because it would allow the investigation of connectivity to be more functionally specific and allow for inferences that activity in a distal seed could be modulating activity resulting from a task demand. In 2012, McLaren and colleagues added to this original framework and described a gPPI approach in which all task phases and their interactions are included in a single model3. This approach leads to results that are more sensitive and specific to the task phase and interaction being investigated. It is this updated gPPI approach that we employ in the present study (see step 6.2.2 in Protocol). The gPPI approach has now been cited in over 200 studies. For clarity, hereafter we use &#39;PPI&#39; to describe common features of both the standard and generalized version. &#39;gPPI&#39; will be used to discuss specific advances associated with the newer framework.
The overall goal of a PPI analysis is to understand how the demands of a cognitive task influence or modulate the functional connectivity of a seed region. A PPI analysis requires a strong a priori hypothesis. Activity in the seed region must be modulated by the task in order for the PPI approach to work effectively4. For example, in the present study, we based our seed selection on the strong evidence that hippocampal activity is modulated by the cognitive demands of a memory task. Using PPI, regions that are significantly more or less functionally connected to the hippocampus during specific task phases can be identified. In short, we ask the question, &#34;in which regions is activity more correlated with the seed during context A as compared with baseline?&#34; We can also ask the logical opposite (as it is important to understand the difference): &#34;in which regions is activity less correlated with the seed during context A as compared to baseline?&#34; When interpreting group differences in PPI effects, it is important to examine the data and whether positive or negative change in functional connectivity, or both, is driving group differences.
The PPI approach has been used to study dynamic task control hubs in healthy controls, how modulation of functional connectivity is related to cognitive performance in Alzheimer&#39;s disease (AD), intelligence in individuals with autism, motor network connectivity in individuals with Parkinson&#39;s disease, face processing in individuals with body dysmorphic disorder and anorexia, emotion regulation, memory, and many other specific questions related to connectivity5,6,7,8,9,10,11. In the present study, we compare changes in functional connectivity of subregions of the hippocampus during memory encoding and retrieval between a group of individuals at increased genetic risk for AD to a group without the risk factor12. The following describes the protocol that we used, applying the gPPI approach, to allow us to test if task-elicited changes in functional connectivity differ in association with the presence of APOE&#949;4, a genetic risk factor for AD.

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		<tr height="21">
			<td height="21" style="height:21px;width:307px;">3T manetic resonance imaging scanner</td>
			<td style="width:280px;">Siemens Medical Solutions</td>
			<td style="width:237px;">MAGNETOM Trio, A Tim System</td>
			<td style="width:267px;">3T MRI Scanner</td>
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			<td height="21" style="height:21px;width:307px;">FSL (FMRIB Software Library)</td>
			<td style="width:280px;">Oxford University</td>
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			<td>Functional Imaging Processing Software</td>
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			<td height="42" style="height:42px;width:307px;">AFNI (Analysis of Functional Neuroimaging)</td>
			<td style="width:280px;">National Institute of Mental Health, National Institutes of Health</td>
			<td style="width:237px;">Any version after May 2015</td>
			<td>Functional Imaging Processing Software</td>
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			<td height="21" style="height:21px;width:307px;">SPM8 (Statistical Parametric Mapping)</td>
			<td style="width:280px;">University College of London</td>
			<td style="width:237px;">SPM8</td>
			<td>Functional Imaging Processing Software</td>
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			<td height="21" style="height:21px;width:307px;">Matlab Software</td>
			<td style="width:280px;">The Mathworks, Inc</td>
			<td style="width:237px;">Version R2012a</td>
			<td>Computing Software</td>
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			<td height="21" style="height:21px;width:307px;">SDS Software</td>
			<td style="width:280px;">Applied Biosystems, Inc</td>
			<td>7900HT Fast Real-Time PCR System</td>
			<td>Real Time PCR</td>
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			<td height="21" style="height:21px;width:307px;">Taqman Assays</td>
			<td style="width:280px;">ThermoFisher Scientific</td>
			<td style="width:237px;">Specific to SNP</td>
			<td>SNP Genotyping</td>
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generalized psychophysiological interaction (ppi) analysis of memory related connectivity in individuals at genetic risk for alzheimer's disease

In neuroimaging, functional magnetic resonance imaging (fMRI) measures the blood-oxygenation-level dependent (BOLD) signal in the brain. The degree of correlation of the BOLD signal in spatially independent regions of the brain defines the functional connectivity of those regions. During a cognitive fMRI task, a psychophysiological interaction (PPI) analysis can be used to examine changes in the functional connectivity during specific contexts defined by the cognitive task. An example of such a task is one that engages the memory system, asking participants to learn pairs of unrelated words (encoding) and recall the second word in a pair when presented with the first word (retrieval). In the present study, we used this type of associative memory task and a generalized PPI (gPPI) analysis to compare changes in hippocampal connectivity in older adults who are carriers of the Alzheimer's disease (AD) genetic risk factor apolipoprotein-E epsilon-4 (APOE&#949;4). Specifically, we show that the functional connectivity of subregions of the hippocampus changes during encoding and retrieval, the two active phases of the associative memory task. Context-dependent changes in functional connectivity of the hippocampus were significantly different in carriers of APOE&#949;4 compared to non-carriers. PPI analyses make it possible to examine changes in functional connectivity, distinct from univariate main effects, and to compare these changes across groups. Thus, a PPI analysis may reveal complex task effects in specific cohorts that traditional univariate methods do not capture. PPI analyses cannot, however, determine directionality or causality between functionally connected regions. Nevertheless, PPI analyses provide powerful means for generating specific hypotheses regarding functional relationships, which can be tested using causal models. As the brain is increasingly described in terms of connectivity and networks, PPI is an important method for analyzing fMRI task data that is in line with the current conception of the human brain.

With two different active task phases (encoding and retrieval) and two seed regions (anterior and posterior hippocampus) there are four conditions to report results for each group. The within-group task activation maps (not shown here, see Harrison et al., 201612) show that the occipital lobe, auditory cortex, large regions of parietal lobe, frontal language areas, superior temporal gyrus, and caudate (more pronounced during retrieval) have significant BOL...

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Generalized Psychophysiological Interaction PPI Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease

This manuscript describes how to implement a psychophysiological interaction analysis to reveal task-dependent changes in functional connectivity between a selected seed region and voxels in other regions of the brain. Psychophysiological interaction analysis is a popular method to examine task effects on brain connectivity, distinct from traditional univariate activation effects.

Generalized Psychophysiological Interaction (PPI) Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease

In neuroimaging, functional magnetic resonance imaging (fMRI) measures the blood-oxygenation-level dependent (BOLD) signal in the brain. The degree of ...

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Neuroscience

Preparation of Oligomeric &beta;-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices

Preparation of Oligomeric ÃƒÅ½Ã‚Â²-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices

Impairment of synaptic connections is likely to underlie the subtle amnesic changes occurring at the early stages of Alzheimer s Disease (AD). ...

Selection of Aptamers for Amyloid &beta;-Protein, the Causative Agent of Alzheimer&#39;s Disease

Selection of Aptamers for Amyloid ÃƒÅ½Ã‚Â²-Protein, the Causative Agent of Alzheimer's Disease

Alzheimer's disease (AD) is a progressive, age-dependent, neurodegenerative disorder with an insidious course that renders its presymptomatic diagnosis ...

Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaque formation is one of the pathological hallmarks ...

Morris Water Maze Test for Learning and Memory Deficits in Alzheimer&#39;s Disease Model Mice

Morris Water Maze Test for Learning and Memory Deficits in Alzheimer's Disease Model Mice

The Morris Water Maze (MWM) was first established by neuroscientist Richard G. Morris in 1981 in order to test hippocampal-dependent learning, including ...

Morphological Analysis of Drosophila Larval Peripheral Sensory Neuron Dendrites and Axons Using Genetic Mosaics

Morphological Analysis of Drosophila Larval Peripheral Sensory Neuron Dendrites and Axons Using Genetic Mosaics

Nervous system development requires the correct specification of neuron position and identity, followed by accurate neuron class-specific dendritic ...

T-maze Forced Alternation and Left-right Discrimination Tasks for Assessing Working and Reference Memory in Mice

Forced alternation and left-right discrimination tasks using the T-maze have been widely used to assess working and reference memory, respectively, in ...

Optical Recording of Suprathreshold Neural Activity with Single-cell and Single-spike Resolution

Signaling of information in the vertebrate central nervous system is often carried by populations of neurons rather than individual neurons. Also ...

Visualization and Genetic Manipulation of Dendrites and Spines in the Mouse Cerebral Cortex and Hippocampus using In utero Electroporation

Visualization and Genetic Manipulation of Dendrites and Spines in the Mouse Cerebral Cortex and Hippocampus using In utero Electroporation

In utero electroporation (IUE) has become a powerful technique to study the development of different regions of the embryonic nervous system 1-5. To date ...

Tactile Conditioning And Movement Analysis Of Antennal Sampling Strategies In Honey Bees (Apis mellifera L.)

Tactile Conditioning And Movement Analysis Of Antennal Sampling Strategies In Honey Bees Apis mellifera L.

Honey bees (Apis mellifera L.) are eusocial insects and well known for their complex division of labor and associative learning capability1, 2. The worker ...