Neuron Networks in Healthy and Diseased Brains

NetworkThe dream of mapping the brain rests on the notion that the trillions of connections between 80 billion neurons form networks that are correlated with mental states. Please see the post, Limits of Current Neuroscience, for a discussion of the many complications in this approach, including the importance of brain waves, glia networks and poor resolution of our imaging devices. Most important is that there is no evidence for a mechanism in the brain that coordinates brain activity to form mental states. There is no center controlling the wide ranging circuits producing the subjective experience of mind. 

Despite all of these difficulties some progress is being made. Because of the monumental complexity of the neuronal connections, attempts are being made to use mathematical analysis of networks to find patterns related to normal brain function and disease states. Analysis applies network theory and statistics to neuronal connections, as well as genes, metabolic pathways, and social and economic interactions.

From Was a bee
From Was a bee

This post will discuss the promise of network theory for understanding neuron networks in healthy and diseased brain. It is clear from other posts that the mapping of the connections of the brain is a very long way off (see posts Limits of Current Neuroscience and The Connectome). But, it is possible that network theories might help sooner.

One theory is that over working of hubs can produce a damaged network and failure of the hiecharchies that maintain the functions of the brain. 

Brain Networks Have Specific Patterns

Snorri95 wik LayeredScaleFreeNetworkBrain networks are now assumed to be energy efficient local hubs that, also, include some long-range connections to other hubs. Most networks are “scale free,” that is many neurons have a large number of connections. With many highly connected nodes, there is less chance of brain failure. If one node is disrupted, there are many others to continue functioning.

Recent research shows that in the normal brain there are many local hubs that are highly connected together—such a brain network is called a “rich club”. A rich club implies that a group of nodes, or hubs (center of neuronal cell bodies) are very highly connected—that is, more heavily interconnected with each other than expected by chance. These highly locally connected hubs are, also, connected long range with other hubs.

PD   Cajal_cortex_drawingsAnother recent assumption is that modules have an internal and external hierarchy related to function. These arrangements start in the fetal development and are dependent upon specific genetic networks.

Because of these connection patterns, brain diseases might damage function by affecting not just local hubs or the global connectivity, but rather a complex combination of both. Alzheimer’s is one example where the pathology affects mostly rich hub areas. But, in strokes or brain injury, which tend to be local problems, global signaling is damaged, as well as the destruction of local hubs. (See post on Complexity of the Frontal Lobe). Later in this post, disease states will be more fully explored.

Healthy Brain Networks

Schulllz wik   Small-world-network-exampleThe first network research showed that neurons form small world networks—many short connections in highly connected hubs. In small world networks, nodes are not necessarily near each other, but most nodes (which are highly connected internally) can be reach by all other nodes with a small number of steps.

Small world networks were first demonstrated in a worm with 300 neurons and 6000 connections (picture below). Later, it was shown that all animals studied had great clustering of small connections into hubs—local connectedness—and then many of these distant hubs were connected together. It is now thought that this pattern allows different functions to work together effectively and with the least energy cost.

The question of cost of maintaining wiring versus the need for flow of information is the critical trade off of energy use and function.

Mentatseb wik .elegans-brain-networkThe small world hubs in the brain, however, have very different levels of importance and connections in a system. Those hubs with the greatest interconnectivity are called the “rich clubs” and appear to be the most important for global functioning. Rich clubs have, also, been called the “connectivity backbone.”

Studies show, in fact, that small world networks and rich clubs have most of the information flow in the brain. Genetics and aging play a role in networks, as do hormone differences. In one study higher intelligence was correlated with the length of the rich club connections.

From CopperKettle
From CopperKettle

Normal brains, also, demonstrate a hierarchy of modules—many sub networks and sub sub networks in layers. This can be seen easily in the cortex layers for vision, hearing, smell and the somatosensory and motor regions. The functions of these layers add more complexity to the question of cost versus function.

The current conclusion is that normal brains have three interacting characteristics. One is highly locally connected and very organized local hubs. The second is many short connections between hubs—each reaching others with a few steps. The third is that different hubs have very different clustering and importance. The brain is hierarchal and modular at the same time.

Brain Networks in Dementia

JNT FIGURE 2-27-10Research into Alzheimer’s shows many varied complex processes that involve mis folded proteins, breakup of microtubules and interactions with immune cells such as microglia. It has been thought that accumulation of amyloid into plaques causes disruption of neurons. But, recently, it was demonstrated that breakup of microtubules with defective tau molecules might precede amyloid accumulation. These extremely complex overlapping properties have not yet demonstrated its cause or treatments.

Is there any evidence that alterations in neuronal network patterns are part of the cause of Alzheimer’s? The general assumption has been that neurons, damaged by plaque or neurofibrillary tangles, or some other cause, produce breaks in the connections between neurons. These breaks are thought to damage the overall function of regions of the brain related to memory and cognition.

AlzheimerContrary to these assumptions are some recent studies that show an increase in some connections in Alzheimer’s. A pattern of both more and less connections can, also, alter the overall network structure. Multiple studies have shown decreased efficiency in small local connections of hubs and some areas where there are increases in traffic.

These two different findings arise from different research imaging techniques. Some studies focus on clusters, some on the length of the longest connections. Studies of length of the longest connections between hubs have, also, come up with conflicting results.

Research shows that damage to synapses can occur because of increased neuronal firing. Some think that destruction of neurons by amyloid or tau releases glutamate, which increases neuron firing activity. This leads to increased connectivity in some regions and, then, eventually decreased connectivity with important hubs damaged.

PD PET normal v alzStudies of path lengths have not been consistent or useful. Findings are consistent with destruction of modules and synchronous activity. One characteristic of networks is that nodes have a specific level of connectivity with other nodes of the same type. Strangely, in Alzheimer’s this tendency of increased connectivity between similar nodes is decreased and in a different type of dementia—frontal temporal dementia—the opposite occurs.

In Alzheimer’s, the most common finding is the destruction of nodes, which are part of hubs in the frontal, temporal and parietal cortex. The destruction of hubs seems to be specific to Alzheimer’s. The average lengths of connections appear to correlate with cognition, as it does in healthy brains.

Brain Networks in Multiple Sclerosis (MS)

multiple-sclerosis-s4-illustration-of-nerve-fibers-and-myelin-attack-in-msMS has traditionally been thought of as a disease of connections with reduced white matter axons, not alterations in neuron cell bodies. This damage occurs through loss of myelin (see post on New Complexity in Myelin Code), often in the longest connections that travel several feet from the spinal cord to the arms and legs.

Studies of brain circuits in MS show damage to the small world networks are caused by decreases in white matter, or axons. They demonstrate decreased efficiency in both local and global networks for very important regions that are part of the default mode network (see post on Meditation for a description of the default mode network). The default mode network encompasses circuits that are active for the brain at “rest” when not doing a task, but reflecting, such as in daydreaming. It, also, includes motor and sensory regions connected with these mental states.

PD  Default_mode_network-WRNMMCOther local diseases of myelin—in the eye, for example—show damage to larger networks. In this local eye disease, small world local connections were increased.

Both diseases have increases of network connections from neuroplastic re organization. Synchronous brain waves are, also, altered with increases in theta and beta and decreases in alpha. Because of this re organization, MS patients develop networks that are more highly connected and organized with some additional synchronous waves. These changes in the hierarchal arrangements are correlated with cognitive and motor loss.

Brain Networks in Traumatic Brain Injury (TBI)

2D Mri Brain Image with 6mm Pituitary TumorTBI is very difficult to study because of the specific different anatomical damage caused by each injury. There are some common features, however.

The structure of the skull creates a typical damage to the frontal region in many automobile whiplash accidents. In damage from war with improvised explosive devices (IED) there are specific white matter lesions with damaged long axons. But, unfortunately, most TBI have variations that make comparative study difficult.

Clearly, there is a loss of connections in TBI. These decrease the energy efficiency of the brain and alter use of efficient local connections. In TBI, there is, also, extensive neuroplasticity and re organization of the hubs and connections. In severely damaged people, there are alterations in all of the synchronous brain waves, while mild damage leads to alterations in theta and alpha only during memory tasks.

Was a bee wik Network_representation_of_brain_connectivityMost studies show a loss of long global connections. This occurs with breakup of the small world hubs and connections. The local connections become longer and less efficient. TBI can damage the modules and the hierarchy. In blast damage, the main problem occurs in long connections between modules, like Alzheimer’s.

In TBI there is prominent damage to hubs in the cortex regions of the default mode network and association cortex. In severe damage with low consciousness from many medical causes, there are subtle alterations in the spatial structures of hubs. These changes in the distribution of hubs might well be from neuroplasticity alterations compensating for damage in cortex regions.

TBI, in particular, has decreased long distance connections of axons and neuroplastic re organization with less efficient local connections and changes in hubs.

Brain Networks in Epilepsy

BrainwavesThe understanding of seizures has been that they start in a particular region and spread. Now, research is questioning whether the problem is a larger network problem—a seizure network—rather than a seizure focus.

Temporal lobe epilepsy patients are found to have altered hubs with increased local connections and longer local axons. They, also, have less stable structures for hierarchies. There are less long-range connections. In epilepsy, the network differences progress over years, with both focal and generalized seizure types. The default mode network is one of the most altered regions.

One unusual finding is that during a seizure the network shifts to more normal structures, raising the question whether the brain’s attempt to re organize back to normal is the cause of the seizure. Alterations to re organize into a normal state occurr just before and after seizures. These findings, however, are not definitive. Studies with surgical intervention to cure severe seizures are consistent with alterations in hubs being relevant for the start and spread of seizures.

From SAgor153
From SAgor153

The conclusions about both local and generalized seizures are increased connections locally, but somewhat disrupted longer axons and decreased long-range global connections. The worse these findings are, the more severe the seizures and the more severe are associated cognitive changes. The severity of network alterations correlates with poor ability to treat.

Seizures can occur from a local area, which is more excitable electrically. There is a possibility that increased activity could correlate with more local abnormal connections from re organization (neuroplasticity) in response to abnormalities. The damage to long-range connections could be involved in spreading of a seizure.

Are There Any Conclusions about Disease Networks

From CopperKettle
From CopperKettle

In all of the diseases discussed, there are altered network structures. Most of them have increased clusters of abnormal hubs. The hubs have longer local connections probably as compensation. The long-range global connections are disrupted. Damage to the hubs includes a re organization of the local nodes and their connections. Specific hubs are damaged and reorganize in more haphazard ways using less efficient longer local connections.

In diseases that progress, abnormalities in the network become greater. In strokes and brain injuries neuroplasticity can bring them back to normal over time. The size of the alterations correlates with the severity of the disease. Local diseases (tumors, seizures) have major alterations in those local hubs. In the diseases that widely affect the brain such as Alzheimer’s, traumatic brain injury and Parkinson’s there are many alterations but some regions are worse than others.

Hubs have very different significance in the functioning normal brain. Normal brain hubs are highly connected into rich clubs, where many hubs are highly connected together. This is optimal for energy use and information flow.

Amorrissette3 wik   DMN  RestingStateModelsThe damage to the default node network (DMN) and association areas appears to be of great importance in many diseases. The DMN was described in detail in several other posts as the region that is most highly correlated to the self. It correlates with mental activity at rest, without attention to anything in particular—thinking, daydreaming and meditating. This appears to be a central region for cohesion of thinking about one’s self and life and appears to be central to the brain’s general functioning, as well.

Modules of the brain are structured into hubs that have a hierarchy. Multiple layers keep information flowing without stress on any one particular hub. Other hubs do tasks and feed into the higher level hubs. These higher-level hubs then signal long distance with higher-level information.

Diseases sap the ability of a hub to perform its task, which creates re organization through neuroplasticity. This alters the flow of information to other hubs increasing their load. Increased activity occurs in the module’s most crucial hubs that have the most connections. One theory is that this overload of flow creates the serious problems.

Neuron Networks in Healthy and Diseased Brains

Keiono wik   model_1000nodesLike all current studies of the connections of the brain, these are short on details in the vast structure of the brain. While very interesting, these network findings and theories in no way explain the fundamental question in brain science—the central region that binds together all of the aspects of the brain to form subjective experience of mind. The basic question of how mind is related to the brain is not answered in any way by any current neuroscience research.

B0005622 Enhanced MRI scan of the headNeuroplasticity occurs in large circuits (see post, Vast Array of Neuroplasticity Mechanisms) using many different mechanisms simultaneously. The re organization that occurs with abnormal network structures occurs, also, at great distances.

How does one region of the brain know to join a network with another? How does the circuit know to use multiple different mechanisms in different parts of the brain at the same instant? How does the network know how to correct itself through neuroplasticity? Where is the coordinating center for all of this?

A previous post described electrical fields and gradients as critical to allow organs to know what shape they will be. But, even in studies of brain electricity there has been no center of the brain that pulls together all the disparate elements of a mental event, including networks. Where is the direction for each hub, node, module, hierarchy and global network?   

The scientific view that best describes all of these situations is the interaction of mind with the molecules, cells and regions of the brain.