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The striatum integrates excitatory inputs from the cortex and the thalamus to control diverse functions. Although the striatum is thought to consist of sensorimotor, associative and limbic domains, their precise demarcations and whether additional functional subdivisions exist remain unclear. How striatal inputs are differentially segregated into each domain is also poorly understood. This study presents a comprehensive map of the excitatory inputs to the mouse striatum. The input patterns reveal boundaries between the known striatal domains. The most posterior striatum likely represents the 4th functional subdivision, and the dorsomedial striatum integrates highly heterogeneous, multimodal inputs. The complete thalamo-cortico-striatal loop is also presented, which reveals that the thalamic subregions innervated by the basal ganglia preferentially interconnect with motor-related cortical areas. Optogenetic experiments show the subregion-specific heterogeneity in the synaptic properties of striatal inputs from both the cortex and the thalamus. This projectome will guide functional studies investigating diverse striatal functions. To fully understand how the brain works, we need to understand how different brain structures are organized and how information flows between these structures. For example, the cortex and thalamus communicate with another structure known as the basal ganglia, which is essential for controlling voluntary movement, emotions and reward behaviour in humans and other mammals. Information from the cortex and the thalamus enters the basal ganglia at an area called the striatum. This area is further divided into smaller functional regions known as domains that sort sensorimotor, emotion and executive information into the basal ganglia to control different types of behaviour. Three such domains have been identified in the striatum of mice. However, the boundaries between these domains are vague and it is not clear whether any other domains exist or if the domains can actually be divided into even smaller areas with more precise roles. Information entering the striatum from other parts of the brain can either stimulate activity in the striatum (known as an “excitatory input”) or alter existing excitatory inputs. Now, Hunnicutt et al. present the first comprehensive map of excitatory inputs into the striatum of mice. The experiments show that while many of the excitatory inputs flowing into the striatum from the cortex and thalamus are sorted into the three known domains, a unique combination of the excitatory inputs are sorted into a new domain instead. One of the original three domains of the striatum is known to relay information related to associative learning, for example, linking an emotion to a person or place. Hunnicutt et al. show that this domain has a more complex architecture than the other domains, being made up of many distinct areas. This complexity may help it to process the various types of information required to make such associations. The findings of Hunnicutt et al. provide a framework for understanding how the striatum works in healthy and diseased brains. Since faulty information processing in the striatum is a direct cause of Parkinson’s disease, Huntington’s disease and other neurological disorders in humans, this framework may aid the development of new treatments for these disorders.

Separate measurements of B(max), the density of available receptors, and K(D), the equilibrium dissociation constant in the human brain, with PET have contributed to our understanding of neuropsychiatric disorders, especially with respect to the dopamine D(2)/D(3) receptor system. However, existing methods have limited applications to the whole striatum, putamen, or caudate nucleus. Improved methods are required to examine B(max) and K(D) in detailed functional striatal subdivisions that are becoming widely used. In response, a new method (bolus-plus-infusion transformation [BPIT]) was developed. After completion of a validation study for (11)C-raclopride scans involving 81 subjects, age-associated changes in B(max) and K(D) were examined in 47 healthy subjects ranging in age from 18 to 77 y. The BPIT method was consistent with established reference tissue methods regarding regional binding potential. BPIT yielded time-consistent estimates of B(max) and K(D) when scan and infusion lengths were set equal in the analysis. In addition, BPIT was shown to be robust against PET measurement errors when compared with a widely accepted transient equilibrium method. Altogether, BPIT was supported as a method for regional binding potential, B(max), and K(D). We demonstrated age-associated declines in B(max) in all 5 functional striatal subdivisions with BPIT when corrected for multiple comparisons. These age-related effects were not consistently attainable with the transient equilibrium method. Irrespective to methods, K(D) remained unchanged with age. The BPIT approach may be useful for understanding dopamine receptor abnormalities in neuropsychiatric disorders by enabling separate measurements of B(max) and K(D) in functional striatal subdivisions.

Neuromodulation treatment effect size for bothersome tinnitus may be larger and more predictable by adopting a target selection approach guided by personalized striatal networks or functional connectivity maps. Several corticostriatal mechanisms are likely to play a role in tinnitus, including the dorsal/ventral striatum and the putamen. We examined whether significant tinnitus treatment response by deep brain stimulation (DBS) of the caudate nucleus may be related to striatal network increased functional connectivity with tinnitus networks that involve the auditory cortex or ventral cerebellum. The first study was a cross‐sectional 2‐by‐2 factorial design (tinnitus, no tinnitus; hearing loss, normal hearing, n = 68) to define cohort level abnormal functional connectivity maps using high‐field 7.0 T resting‐state fMRI. The second study was a pilot case–control series (n = 2) to examine whether tinnitus modulation response to caudate tail subdivision stimulation would be contingent on individual level striatal connectivity map relationships with tinnitus networks. Resting‐state fMRI identified five caudate subdivisions with abnormal cohort level functional connectivity maps. Of those, two connectivity maps exhibited increased connectivity with tinnitus networks—dorsal caudate head with Heschl's gyrus and caudate tail with the ventral cerebellum. DBS of the caudate tail in the case‐series responder resulted in dramatic reductions in tinnitus severity and loudness, in contrast to the nonresponder who showed no tinnitus modulation. The individual level connectivity map of the responder was in alignment with the cohort expectation connectivity map, where the caudate tail exhibited increased connectivity with tinnitus networks, whereas the nonresponder individual level connectivity map did not. Successful neuromodulation for bothersome tinnitus may more attainable by adopting a target selection approach guided by personalized striatal networks or functional connectivity maps. Here, we present a two‐pronged fMRI study (cohort and case–control) demonstrating increased caudate‐corticocerebellar connectivity in both a large cohort of tinnitus sufferers and a single patient that was a neuromodulatory DBS responder.